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Diabeloop SP7 project Version 5.4 of 18/12/2017 RCB ID: 2016-A01198-43 Strictly confidential document, property of CERITD. Copyright CERITD. Reproduction strictly prohibited.

Rendre l’insouciance et la qualité de vie Title of the study: Evaluation in type 1 diabetic patients, in a crossover, randomized open-label

control trial of the safety and efficiency, for three months at home, of the Artificial Pancreas Diabeloop compared to conventional external insulin pump augmented with continuous glucose

measurement.

Acronym: DIABELOOP SP7

Protocol version: 6 of 22/01/2018

RCB ID: 2016-A01198-43

Sponsor CERITD (Centre d’Etudes et de Recherches pour

l’Intensification du Traitement du Diabète).

Bioparc-Génopôle Évry-Corbeil. Campus 3,

bâtiment 5. 01, rue Pierre Fontaine 91058 Evry

Cedex. Téléphone : 01 64 96 88 96.

fax : 01 60 88 93 59. www.ceritd.fr

Scientific Manager

Prof. Pierre Yves BENHAMOU Department Head, Endocrinology Diabetology Nutrition Tel. +33 (0)4 76 76 88 56 – Mobile +33 (0)6 81 25

37 20

[email protected]

PROTOCOLE DE RECHERCHE

BIOMEDICALE PORTANT SUR

UN DISPOSITIF MEDICAL

http://www.ceritd.fr/

mailto:[email protected]

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This protocol has been drafted in accordance with ISO 14155: May 2012

Since 1988 the implementation of clinical trials in France has been governed by the law 88-1138 of 20

December 1988 (so-called “Huriet-Serusclet” law) and its implementing decree.

This legislative and regulatory system was modified by the transposition into French law of European

Directive 2001/20/EC of 4 April 2001 relating to the implementation of Good Clinical Practice in the

conduct of clinical trials on medicinal products for human use. This transposition introduced new provisions

aiming to harmonize the level of protection of research subjects regardless of the health product that is the

subject of the biomedical research (BMR). BMR regulations on medical devices (MDs) and in vitro

diagnostic medical devices (IVMD) were therefore modified. The investigator undertakes to conduct this

study in accordance with public health law 2004-806 of 9 August 2004 relating to biomedical research, the

implementing decree 2006-477 of 26 April 2006, as well as related ordinances and decisions. The rules of

Good Clinical Practice (GCP) for biomedical research will also be applied.

PRINCIPAL

INVESTIGATORS

● Dept. of Endocrinology and Diabetology, Centre Hospitalier

Sud Francilien, Corbeil-Essonnes (91), Dr Sylvia FRANC.

● Dept. of Nutrition, Metabolic Diseases, Endocrinology, CHU

de Marseille – Hôpital Sud, Prof Denis RACCAH

● Dept. of Endocrinology, Diabetology and Nutrition, CHU de

Reims, Prof Brigitte DELEMER.

● Dept. of Endocrinology, Diabetology and Nutritional

Diseases, CHU de Strasbourg, Prof Nathalie JEANDIDIER.

● Dept. of Endocrinology, Metabolic Diseases and Nutrition,

CHU de Nantes, Dr Lucy CHAILLOUS.

● Dept. of Endocrinology, Diabetology and Metabolic

Diseases, Hôpital Civil Lyon Sud, Prof Charles THIVOLET.

● Dept. of Endocrinology and Diabetology, CHRU Jean

Minjoz, Besançon (25), Dr Sophie BOROT.

● Dept. of Endocrinology and Diabetology, CHU de Nancy, Nancy (54), Prof Bruno GUERCI

● Dept. of Endocrinology,Diabetology and Nutritional Diseases, CHU de Grenoble, Grenoble (38), Prof Pierre-Yves BENHAMOU

● Dept. of Endocrine Diseases, CHU de Montpellier,

Montpellier (34), Prof Eric RENARD

● Dept. of Endocrinology and Diabetology, CHU Côte de Nacre, Caen (14), Prof Yves REZNIK

- Dept. of Diabetology, Metabolic Diseases, Nutrition, CHU

Rangueil, Toulouse (31), Prof Hélène HANAIRE.

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TABLE OF CONTENTS

LIST OF FIGURES ................................................................................................................................. 5 LIST OF TABLES .................................................................................................................................. 6 LIST OF ABBREVIATIONS ................................................................................................................. 7 PAGE DE SIGNATURE ......................................................................................................................... 8 STUDY SYNOPSIS ................................................................................................................................ 9 I - RATIONALE OF THE DIABELOOP PROJECT ........................................................................ 29 I. 1. TYPE 1 DIABETES ............................................................................................................................... 29

II - THE DIABELOOP PROJECT ..................................................................................................... 32 II. 2. TECHNICAL PROPOSAL ...................................................................................................................... 33

II. 3. OTHER PROJECTS ON THE SAME THEME ....................................................................................... 34

11.4 . GENERAL STRUCTURE OF THE DIABELOOP PROJECT ............................................................... 37

III COMPONENTS OF THE SP7 PROJECT ....................................................................................... 39 111.1. THE TERMINAL (SMARTPHONE) .................................................................................................... 39

111.2. BLOOD GLUCOSE CONTROL ALGORITHM .................................................................................. 39

111.3. THE DEXCOMTM G5 SYSTEM .......................................................................................................... 39

111.4. THE CELLNOVO PUMP ..................................................................................................................... 41

111.5. THE KALEIDO EXTERNAL INSULIN PUMP .................................................................................... 42

111.6. THE OPEN LOOP SYSTEM (OL) ....................................................................................................... 42

111.7. THE CLOSED LOOP SYSTEM (CL) .................................................................................................. 43

III.6.A CONFIGURING THE REGULATION SETTINGS ............................................................................................. 45

III.6.B DEFAULT CONFIGURATION ........................................................................................................................... 46

III.6.D. NOTION OF RESPONSIVENESS ......................................................................................................................... 47

III.6.A RESPONSIVENESS DURING NORMOGLYCEMIA ........................................................................................ 47

III.6.B RESPONSIVENESS DURING HYPERGLYCEMIA .......................................................................................... 49

III.6.C RESPONSIVENESS DURING NORMOGLYCEMIA AND HYPERGLYCEMIA ............................................ 51

III.6.D TARGET BLOOD GLUCOSE ............................................................................................................................. 52

III.6.E THE HYPOGLYCEMIA LIMIT ........................................................................................................................... 53

III.6.F WEIGHT ............................................................................................................................................................... 54

III.6.G CHANGING THE SETTINGS WHEN AVERAGE BLOOD GLUCOSE IS HIGH ........................................... 54

III.6.H CHANGING THE SETTINGS WHEN THE PATIENT HAS SEVERAL HYPOGLYCEMIC EPISODES ....... 55

IV. STUDY OBJECTIVES ................................................................................................................ 57 IV.1. PRIMARY OBJECTIVE ............................................................................................................................ 57

1V.2. SECONDARY OBJECTIVES .................................................................................................................... 57

V - STUDY DESIGN ............................................................................................................................ 58 V.1. TYPE OF STUDY ........................................................................................................................................ 58

V.2. STUDY DESIGN .......................................................................................................................................... 59

V.3. PARTICIPATING CENTERS AND INVESTIGATORS............................................................................... 60

V.4. DATA AND SAFETY MONITORING BOARD, DSMB ........................................................................... 62

V.5. STUDY POPULATION ................................................................................................................................ 62

VI - STUDY WORK FLOW ................................................................................................................. 64 V1.1. PRE-SCREENING VISIT V0 .................................................................................................................... 64

VI.2. INCLUSION VISIT V1 .............................................................................................................................. 64

VI.3. PILOT STUDY (VISIT V1BIS) ................................................................................................................. 65

1. VISIT A ......................................................................................................................................................................... 66

2. VISIT B ......................................................................................................................................................................... 67

3. VISIT C ......................................................................................................................................................................... 68

4. VISIT D ......................................................................................................................................................................... 68

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5. PRACTICAL IMPLEMENTATION OF THE SETTINGS ........................................................................................... 68

VI.4. RANDOMIZATION VISIT (V2) ............................................................................................................... 69

VI.5. VISITS 3 (START OF 1ST TREATMENT PERIOD) ................................................................................ 69

A. CLOSED LOOP TREATMENT PERIOD (ARM 1): .................................................................................................. 70

B. OPEN LOOP TREAMENT PERIOD (ARM 2): ......................................................................................................... 71

VI.6. VISIT 4 ...................................................................................................................................................... 71

CLOSED LOOP TREATMENT PERIOD (ARM 1) ............................................................................................................ 71

OPEN LOOP TREATMENT PERIOD (ARM 2) ................................................................................................................. 72

VI.7. VISIT 5 ...................................................................................................................................................... 72



VI.8. VISIT 6 ...................................................................................................................................................... 72



VI.9. VISIT 7 ...................................................................................................................................................... 73

A. CLOSED LOOP TREATMENT PERIOD (ARM 1) .................................................................................................. 73

A. OPEN LOOP TREATMENT PERIOD (ARM 2) ....................................................................................................... 73

VI.10. VISIT 8 (END OF 1ST TREATMENT PERIOD) .................................................................................... 73



VI.11. PRACTICAL IMPLEMENTATION OF THE SETTINGS ....................................................................... 74

VI.12. WASH-OUT PERIOD ............................................................................................................................. 75

VI.13. VISITS 9 (START OF 2ND TREATMENT PERIOD) ............................................................................... 75

C. OPEN LOOP TREATMENT PERIOD (ARM 1) ........................................................................................................ 75

D. CLOSED LOOP TREATMENT PERIOD (ARM 2) ................................................................................................... 76

VI.14. VISIT 10 .................................................................................................................................................. 77

OPEN LOOP TREATMENT PERIOD (ARM 1):................................................................................................................ 77

CLOSED LOOP TREATMENT PERIOD (ARM 2):........................................................................................................... 77

VI.15. VISIT 11 .................................................................................................................................................. 77



VI.16. VISIT 12 .................................................................................................................................................. 77

A. OPEN LOOP TREATMENT PERIOD (ARM 1): ...................................................................................................... 77

B. CLOSED LOOP TREATMENT PERIOD (ARM 2): ................................................................................................. 78

VI.17. VISIT 13 .................................................................................................................................................. 78



VI.18. VISIT 14 (END OF STUDY) ................................................................................................................... 78

A. OPEN LOOP TREATMENT PERIOD (ARM 1): ...................................................................................................... 78

B. CLOSED LOOP TREATMENT PERIOD (ARM 2): ................................................................................................. 79

VI.19. VISIT SCHEDULE ARM 1 ..................................................................................................................... 79

VI.20. VISIT SCHEDULE ARM 2 ..................................................................................................................... 85

VI.21. PROCEDURE FOR SITUATIONS REQUIRING A CAPILLARY GLUCOSE MEASUREMENT ........... 89

VI.22. ACTION TO TAKE IN CASE OF KETOSIS ........................................................................................... 90

VI.23. STUDY FLOWCHART ............................................................................................................................ 91

VII DATA CAPTURE AND HANDLING .......................................................................................... 92 VII.1. DATA CAPTURE ..................................................................................................................................... 92

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VII.2. DATA MONITORING ............................................................................................................................. 92

VII.3. DATA ANALYSIS .............................................................................................................................. 93

VIII STATISTICAL ANALYSIS PLAN .............................................................................................. 93 VIII.1. STATISTICAL ANALYSIS METHODOLOGY ...................................................................................... 93

VIII.1.A. ANALYSIS OF THE PRIMARY OBJECTIVE .................................................................................... 93

VIII.1.B. ANALYSIS OF SECONDARY OBJECTIVES ..................................................................................... 94

VIII.1.C. PRELIMINARY ANALYSIS ............................................................................................................... 94

VIII.1. D. ANALYSIS OF THE PILOT PHASE .................................................................................................. 95

VIII.1.E. CONCLUSION OF THE STUDY ........................................................................................................ 95

VIII.2. CALCULATION OF SAMPLE SIZE ...................................................................................................... 96

IX ANALYSIS OF THE METHODOLOGICAL IMPACT OF CHANGING THE CELLNOVO

PUMP AT THE END OF THE 1ST CROSSOVER PERIOD ............................................................... 97 1. IMPACT ON THE PRELIMINARY ANALYSIS AT THE END OF THE 1ST CROSSOVER PERIOD: .......................... 97

2. IMPACT ON THE DURATION OF THE WASH-OUT PERIOD: ............................................................................ 98

3. IMPACT ON THE CONCLUSIONS OF THE FINAL ANALYSIS: ............................................................................ 98

X SAFETY ASSESSMENTS ............................................................................................................... 99 XI - MATERIAL AND LEGAL ASPECTS ....................................................................................... 100 XI.1. SIGNED INFORMED CONSENT ............................................................................................................ 100

XI.2. PROFESSIONAL SECRECY, CONFIDENTIALITY ............................................................................... 100

XI.3. INSURANCE ........................................................................................................................................... 101

XI.4. ANONYMITY OF STUDY SUBJECTS ................................................................................................... 101

XI.5. QUALITY ASSURANCE ........................................................................................................................ 101

XI.6. PATIENT COMPENSATION – EXCLUSION PERIOD ......................................................................... 101

XI.7. PUBLICATIONS ..................................................................................................................................... 102

XI.8. RECORDKEEPING ................................................................................................................................ 102

XII - REFERENCES .......................................................................................................................... 103 XIII - APPENDICES .......................................................................................................................... 105 XIII.1. APPENDIX: SATISFACTION QUESTIONNAIRE– BASELINE ............................................ 105

XII.2. APPENDIX: INSERTING THE DEXCOM SENSOR AND LOCKING THE TRANSMITTER .......... 117

XIII.3. APPENDIX: LIST OF STUDIES CARRIED OUT WITH THE DIABELOOP ALGORITHM .................... 119

DIABELOOP SUB-STUDY 6.1.A ....................................................................................................................... 123

DIABELOOP SUB-STUDY 6.2 .............................................................................................................................. 127

LIST OF FIGURES

Figure 1: Study flowchart ...................................................................................................................... 27

Figure 2: Study diagram ......................................................................................................................... 28

Figure 3: Overall diagram of the Diabeloop system .............................................................................. 32

Figure 4: Schedule of Diabeloop sub-studies ........................................................................................ 37

Figure 5: DexcomTM G5 receiver ............................................................................................................ 41

Figure 6: Artificial Pancreas Diabeloop system ..................................................................................... 44

Figure 7: Steps to access the regulation settings (click on the red box) ............................................... 46

Figure 8: Responsiveness to correct hyperglycemia ............................................................................. 47

Figure 9: Comparison of 3 levels of responsiveness during normoglycemia and the impact on blood

glucose values: default situation (middle), low responsiveness (left) and high responsiveness (right).

The default graph is based on actual data from a patient in Diabeloop SP6.2 over 3 days in closed

loop. Blood glucose and insulin values were modified by hand to illustrate the impact of changing the

setting (green dashed line is blood glucose, blue line is the amount of insulin prescribed, red line is

the hypoglycemia limit and orange line is the hyperglycemia limit). ................................................... 49

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Figure 10: Comparison of 3 settings for responsiveness during hyperglycemia: default situation

(middle), situation of low responsiveness (left) and high responsiveness (right). Green dashed line is

blood glucose, blue rectangles are the insulin boluses, blue line is basal rate insulin injections, red

line is hypoglycemia limit and orange line is hyperglycemia limit. The data are from a patient in study

SP6.2. Bolus doses and blood glucose values were modified to illustrate the impact of changing the

responsiveness during hyperglycemia. ................................................................................................. 50

Figure 11: target blood glucose set at 110 mg/dl, increase in basal rate, modification of blood glucose

profile. ................................................................................................................................................... 53

Figure 12: target blood glucose set at 120 mg/dl, decrease in basal rate to return to return to target

range. ..................................................................................................................................................... 53

Figure 13 : hypoglycemia limit .............................................................................................................. 54

Figure 14: decision tree for modifying the settings when average blood glucose is too high .............. 55

Figure 15: decision tree for modifying the settings when the patient has several hypoglycemic

episodes. ................................................................................................................................................ 56

Figure 16: Study diagram....................................................................................................................... 59

LIST OF TABLES

Table 1: VISIT SCHEDULE ARM 1 (CL in 1st period – OL in 2nd period) .................................................. 18

Table 2: VISIT SCHEDULE ARM 2 (OL in 1st period – CL in 2nd period) .................................................. 22

Table 3: Diabeloop system settings ....................................................................................................... 46

Table 4: Insulin doses of each compensation bolus injected in the above graphs. As the doses are

illegible they are shown in tabular format. ........................................................................................... 50

Table 5: DIABELOOP SP6.7 study centers .............................................................................................. 60

Table 6: Analysis of primary endpoint - study SP6.2 ........................................................................... 136

Table 7: Time spent in 70-180 during the 3 nights - Diabeloop SP6.2. ............................................... 137

Table 8: Time spent in 70-180 during 72 hours – Diabeloop SP6.2 .................................................... 138

Table 9: Average blood glucose during 72 hours – Diabeloop SP6.2 .................................................. 139

Table 10: Delta of time spent in 70-180 (D2-D1) ................................................................................ 140

Table 11: Delta of time spent in 70-180 (D3-D1) ................................................................................ 141

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LIST OF ABBREVIATIONS

ADA American Diabetes Association

ADE Adverse device effect

AE Adverse event

AP Artificial Pancreas

BLE Bluetooth low energy

BMI Body mass index

CGM Continuous Glucose Monitoring

CHO Carbohydrate

CIC Clinical Investigation Center

CL Closed loop

CPP Ethics Committee

CRF Case report form

CSP Public Health Code

DBP Diastolic blood pressure

DOB Date of birth

DSMB Data Safety Monitoring Board

DT1 Type 1 diabetes

eCRF Electronic case report form

FIT Functional insulin therapy

GCP Good Clinical Practice

GSM Global System for Mobile communication

HbA1c Glycated hemoglobin

HBGI High Blood Glucose Index

HR Heart rate

ITT Intent To Treat

JDRF Juvenile Diabetes Research Foundation

LBGI Low Blood Glucose Index

MD Medical device

MPC Model Predictive Control

OL Open loop

PPG Postprandial glycemia

SADE Serious adverse device effect

SBP Systolic blood pressure

USADE Unanticipated serious adverse device effect

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PAGE DE SIGNATURE

I have been informed of my responsibilities as investigator in the DIABELOOP SP6.7 study

and I undertake to comply with Good Clinical Practice, the laws in force, and the study

protocol. I agree to conduct the study in accordance with these directives and to assist the staff

mandated by the sponsor with quality control of the data collected.

Principal Investigator Full name:

Date: Signature:

Scientific Manager Full name:

Date: 22/01/2018 Signature:

Sponsor

CERITD Full name: Dr. Guillaume Charpentier

Date : 22/01/2018 Signature:

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STUDY SYNOPSIS

Title

Evaluation in type 1 diabetic patients, in a crossover,

randomized open-label control trial of the safety and efficiency,

for three months at home, of the Artificial Pancreas Diabeloop

compared to conventional insulin pump augmented with

continuous glucose measurement.

Acronym DIABELOOP SP7

Sponsor CERITD – campus 3, bâtiment 5. 1, rue Pierre Fontaine 91058

Évry Cedex

Scientific coordinator

Professor Pierre Yves BENHAMOU

Department Head, Endocrinology Diabetology Nutrition. CHU

de Grenoble

Coordinating investigator Dr Guillaume Charpentier, Centre Hospitalier Sud Francilien.

(91)

Principal Investigators

● Dept. of Endocrinology and Diabetology, Centre

Hospitalier Sud Francilien, Corbeil-Essonnes (91), Dr

Sylvia FRANC.

● Dept. of Nutrition, Metabolic Diseases, Endocrinology,

CHU de Marseille – Hôpital Sud, Prof Denis RACCAH

● Dept. of Endocrinology, Diabetology and Nutrition, CHU

de Reims, Prof Brigitte DELEMER.

● Dept. of Endocrinology, Diabetology and Nutritional

Diseases, CHU de Strasbourg, Prof Nathalie

JEANDIDIER.

● Dept. of Endocrinology, Metabolic Diseases and

Nutrition, CHU de Nantes, Dr Lucy CHAILLOUS.

● Dept. of Endocrinology, Diabetology and Metabolic

Diseases, Hôpital Civil Lyon Sud, Prof Charles

THIVOLET.

● Dept. of Endocrinology and Diabetology, CHRU Jean

Minjoz, Besançon (25), Dr Sophie BOROT.

● Dept. of Endocrinology and Diabetology, CHU de Nancy, Nancy (54), Prof Bruno GUERCI

● Dept. of Endocrinology,Diabetology and Nutritional Diseases, CHU de Grenoble, Grenoble (38), Prof Pierre-Yves BENHAMOU

● Dept. of Endocrine Diseases, CHU de Montpellier,

Montpellier (34), Prof Eric RENARD

● Dept. of Endocrinology and Diabetology, CHU Côte de Nacre, Caen (14), Prof Yves REZNIK

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- Dept. of Diabetology, Metabolic Diseases, Nutrition, CHU Rangueil, Toulouse (31), Prof Hélène HANAIRE.

Methodology

Comparative crossover trial in two treatment periods:

Diabeloop treatment and usual treatment period combined with

real-time continuous glucose measurement, randomized,

open-label, controlled, interventional, national and multicenter.

Medical condition or

pathology studied

Type 1 Diabetes

Medical device being

evaluated

Experimental group: Diabeloop closed loop system

composed of DexcomTM G5 sensor (Dexcom Inc., San Diego,

CA) + Smartphone (remote control) in which the Diabeloop

algorithm is integrated + CellNovo patch pump and Kaleido

patch pump for Arm 2. A remote monitoring system is provided

for remote monitoring by a healthcare team.

Control group: Open loop system consisting of the patient’s

usual insulin pump pre-programmed with the usual treatment +

DexcomTM G5 interstitial glucose level sensor (CGM).

Primary objective To assess whether the Diabeloop system's regulatory algorithm provides superior glucose control than usual insulin pump therapy over a 12-week period.

Secondary objectives

Secondary objectives:

Comparison day and night for 12 weeks, of glycemic control with insulin administration by the Diabeloop system versus the usual personal algorithm of the type 1 diabetic patient: 1. Efficacy: Evaluate the superiority of glycemic control with the Diabeloop system for 12 weeks compared to the patient's usual personal algorithm. 2. Safety: Assess night and day safety of glycemic control with the Diabeloop system versus the patient’s usual treatment in terms of episodes of hypoglycemia and severe hyperglycemia. 3. Benefit: Determine the percentage of time spent in the system in functional mode, and the acceptance of the system by patients.

Primary endpoint The primary endpoint will be the time spent in the 70/180 mg/dl target measured continuously for 12 weeks with Dexcom™ G5 CGM.

Secondary endpoints

1. Efficacy:

● Time spent in hypo <70 mg/dl measured continuously for 12 weeks with the DexcomTM G5 CGM.

● Percentage of time spent in intervals [70-180] mg/dl, [80-140] mg/dl, > 180 mg/dl during nights and over 24h for 12 weeks.

● Measurement of HbA1c at the beginning and end of each treatment period.

● Average blood glucose over the entire period. ● Calculated risks of hypoglycemia and hyperglycemia

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(LBGI, HBGI) over the entire 12-week period. ● Total insulin intakes during the tests. ▪ Assessment of the coefficient of variation of glycemia

(Monnier et al, Diabetes Care 2016 Dec 30) 2. Safety:

● Number of hyperglycemic episodes defined by the American Diabetes Association (ADA):Severe hyperglycemia > 360 mg/dl (20 mmol/l) as measured by DexcomTM G5 CGM or significant ketosis (plasma ketone> 3 mmol/l).

● Number of hypoglycemic episodes, defined by any crossing of the threshold of 60 mg/dl (3.33 mmol/l), 70 mg/lL (3.9 mmol/l), and <54 mg/dl (3 mmol/l) measured by the DexcomTM G5 CGM.

● Number of severe hypoglycemic events requiring intervention of a third party for sugaring.

● Number of severe hypoglycemic events with loss of consciousness.

● Number of hospitalizations for severe hypoglycemia or ketoacidosis.

● Number of sugarings and the amount of carbohydrate ingested in the last week of each treatment period.

▪ Number of technical incidents causing closed loop interruptions.

3. Benefit:

● Percentage of time spent in closed loop in functional mode.

▪ For use and acceptance, a satisfaction questionnaire is provided on the daily management of diabetes, the change of daily life with the system and the fear of hypoglycemia.

Population 12 centers; 5 to 6 subjects/center.

60 patients of which 50 usable in analysis

Maximum duration of the

patient's participation

68 weeks

Inclusion Criteria

● Type 1 diabetic patient for at least two years; ● Treated with external insulin pump for at least 6

months; ● HbA1c ≤ 10%; measured within last 4 months in a

medical analysis laboratory or equivalent; ● Insulin requirements ≤ 50U per day; ● Living in an area covered by a GSM network (Global

System for Mobile Communications); ● Non-isolated patient, not living alone, or having a

"resource" person living nearby and having a telephone and the key to his home;

● Patient not considering a trip out of France during the "closed loop" period;

● At least 18 years old; ● Affiliated with Social Security; ● Having signed the free and informed consent form.

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Exclusion criteria

● Patient presenting any serious pathology that could alter the participation in the study;

● Having a long-term treatment with a drug containing paracetamol;

● Patient under legal protection; ● Pregnant or likely to be pregnant; ● Lack of effective contraception in women of

childbearing age; ● Breastfeeding; ● Psychological and / or physical condition that may affect

the proper follow-up of study procedures; ● Severe hypoglycemia leading to seizures or loss of

consciousness in the past 12 months; ● Decreased awareness of hypoglycemia (Gold score>

4); ● Impaired renal function (creatinine clearance

<30ml/min); ● Patient who has had a pancreas or pancreatic islet

transplant; ● Persons with serious hearing and / or visual problems

not corrected; ● Person refusing to 2 capillary blood glucose

measurements daily.

Study work flow

The study will be conducted as a crossover trial, with two different treatment periods of 12 weeks separated by a wash-out lasting at least 8 weeks.

According to the order of the draw, patients will be equipped with either the Diabeloop system or the usual system

Study visits are described below:

1.

1. Inclusion visit V1:

2.

During the V1 visit, the investigator collects the consent of the patient meeting the criteria for inclusion and non-inclusion, signed and dated. DexcomTM G5 sensor and CellNovo external insulin pump will be installed during this visit for a two week run-in period to familiarize the patient with the use of the Cellnovo pump and to educate them to best adapt their treatment with the sensor data. The patient will be trained in the use of the Dexcom G5 continuous glucose sensor and the CellNovo external insulin pump.

2. Pilot study (visit V1bis):

This sub-study has three objectives: a. Optimize the algorithm's self-learning by evaluating the

convergence of "real-life" parameters with patient data from several weeks.

b. Experimentation of the possible "adjustments" of the

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"aggressiveness of the algorithm" accessible to caregivers and / or patients

c. Check the operation of the remote monitoring system The evaluation criterion:

a. Time spent in hypoglycemia (<50 mg/dl, <70 mg/dl), time spent in hyperglycemia, comparison of patient parameters at the beginning and end of closed loop therapy.

a. Operation of the platform: doctor / patient connection, synchronization of patient data, data display, alarm transmission / reception …

This sub-study will be conducted only at the University Hospital of Grenoble and at the Hospital Center Sud-Francilien for a period of 3 to 4 weeks at home with 6 to 8 patients (3 to 4 patients per center) recruited for the closed loop / open loop crossover trial who would like to participate in the pilot study. The six to eight patients will be equipped with a new Dexcom G5 sensor and a CellNovo insulin pump driven by a Smartphone (Android) in which the Diabeloop algorithm is integrated.

The doses of insulin prescribed by the Diabeloop algorithm will be administered to the patient automatically via the pump controlled by the Smartphone. Patients will be followed by a healthcare team 24 hours a day via the "myDiabeloop.fr" platform as well as a team of engineers in case of technical problems.

The patient will be admitted to the study center on D1 to test the Diabeloop system at home for a period of 3 to 4 weeks. As the patient is in a closed loop, placing under the Diabeloop system will be performed during a conventional hospital stay of 48 to 72 hours depending on the specific needs of each patient. During this period of hospitalization, the healthcare team, in collaboration with the engineers, guarantees and validates the patient's ability to manage his Diabeloop system on a daily basis.

Diabeloop engineers provide, in person or by telephone, at the request of the study center, the initial technical training of the patient (explanation of the handling of the pump, the Smartphone and the sensor, use of consumables, what to do in case of alarms ... ), prior to hospitalization. This makes it possible to familiarize the patient upstream with the system, to answer questions and address possible apprehensions. This initial technical training, prepared by a delivery of the Diabeloop user manual, to assess the patient's ability to manage his treatment autonomously, is reviewed with the engineer during hospitalization and before discharge, in collaboration with the hospital team.

At the end of the hospitalization, the healthcare team gives the necessary consumables to the patient for a period of three or four weeks and a data collection booklet. Medical, paramedical and technical assistance are set up via

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remote monitoring for:

- Continuous assessment of treatment,

- Medico-technical follow-up

- 24 hours a day by nurses and engineers

- Technical and safety monitoring. A phone call from the healthcare team will be made within 48 hours after the start of the pilot study at home. The patient is seen by his healthcare team at the study center, the first week after leaving the hospital, then the second week and the 3rd or 4th week after leaving the hospital for the end of the pilot study.

At the end of the pilot study, an exploratory analysis of efficacy and safety will be carried out. A full report will be submitted to Data and Safety Monitoring Board to review the benefit / risk ratio.

3. Randomization visit (V2):

Patients with the ability to manage their daily treatment with CGM data and the Cellnovo pump will be able to test the closed loop and the open loop. Otherwise the included patients will be considered as a screen failure. To find out the order of the tests, the investigator randomizes patients via the electronic CRF into 2 arms:

- Arm 1: The patient will be closed loop in the 1st period and open loop in the 2nd period.

- Arm 2: The patient will be in open loop in the 1st period and closed loop in the 2nd period.

3. The randomization will be stratified by center.

4. Closed or open loop start visit (V3):

For the treatment period with the Diabeloop closed-loop system, the patient will be equipped with a Dexcom G5 glucose sensor, a Smartphone with a Diabeloop application for automatic prescriptions (basal and bolus) and the Cellnovo pump (for arm 1) or Kaleido pump (for arm 2) which delivers insulin continuously. The usual treatment period: the open loop system consists of the patient’s usual insulin pump pre-programmed with the patient’s usual treatment previously prescribed by the doctor. The patient will be equipped with a CGM Dexcom G5 for continuous measurements of interstitial glucose levels.

a. Closed loop treatment period:

The patient will be admitted to the study center on D1 to test the Diabeloop home system for a period of 12 weeks. As the patient will be in a closed loop, set-up of the Diabeloop system

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will be carried out during a conventional hospitalization of 24h including overnight or 48h according to the specific needs of each patient. A hospitalization of 48h will be necessary to train arm 2 in the use of the Kaleido pump. During this period of hospitalization, the patient will receive training in the Diabeloop system consisting of the terminal, the Dexcom sensor, the Cellnovo pump for arm 1 and the Kaleido pump for arm 2. The healthcare team, in collaboration with the engineers, guarantees and validates the patient's ability to manage his Diabeloop system on a daily basis. Diabeloop engineers generally provide face-to-face or telephone training, at the request of the study center, for the initial technical training of the patient (explanation of the handling of the pump, the smartphone and the sensor, use of consumables, action to be taken in case of alarms ...), prior to hospitalization. This makes it possible to familiarize the patient upstream with the system, to answer questions and address possible apprehensions. This initial technical training, prepared by a delivery of the Diabeloop user manual, to evaluate the patient's ability to manage his treatment autonomously, is reviewed during hospitalization and before discharge, in collaboration with the hospital team.

At the end of the hospitalization, the healthcare team gives the patient:

- necessary consumables for a period of three months

- a data collection booklet

- the user manual version 5 of 25/04/2017 for arm 1

- the user manual version 8 of 26/10/2017 for arm 2.

Medical, paramedical and technical assistance are set up via remote monitoring for:




- Technical and safety monitoring. A phone call from the healthcare team will be made within 48 hours after the start of the home study. The patient is reviewed by his or her study team, 1 week after leaving the hospital, 2 weeks later and every 3 weeks until the end of the session.

b. Open loop treatment period:

The patient will be admitted to the study center on D1 for a 12-week session at home with his usual treatment programmed into his usual insulin pump combined with the DexcomTM G5 CGM.

The healthcare team guarantees and validates the patient's ability to manage his treatment with his usual pump combined with the Dexcom G5 CGM on a daily basis. She gives the necessary supplies to the patient for a period of three months and a data collection booklet.

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A follow-up visit is scheduled every 3 weeks until the end of the open-loop session.

c. End of study visit:

At the end of the study, the patient will be asked to complete a satisfaction questionnaire and visual analogue scales.

d. Wash-out period:

A washout period of at lrast 8 weeks is provided between the two open and closed loops. Patients will keep the DexcomTM G5 sensor and their usual insulin pump.

Justification of the number of

patients

The primary endpoint is the time spent in the [70-180] mg/dl

target for 12 weeks with the Dexcom ™ G5 CGM. Fifty

evaluable patients will be able to show, with the clinical

hypotheses observed in study SP6.2 and with a first species

risk α = 0.05 (bilateral situation), a difference between the two

groups with a satisfactory statistical power greater than 94%.

Conclusion:

In order to have at least 50 evaluable patients, 60 patients will be included in this study. Number included: 71 patients

Preliminary statistical analysis

In order to be able to have safety data as soon as possible, a preliminary analysis will be conducted after the 1st cross-over period, i.e., in a parallel plan situation (closed loop vs. open loop).

Statistical analysis

a. Safety analysis set: all randomized patients exposed at least once during the study

b. Efficacy analysis set (modified ITT population): all randomized patients who completed the 2 evaluation sessions (open and closed loop).

The analysis will be performed on the modified ITT population. The primary endpoint will be the time spent in the 70/180 mg/dl target measured continuously for 12 weeks with Dexcom ™ G5 CGM. The null hypothesis tested will be: absolute intra-patient variation between the percentage of time spent in the glycemic intervals closed loop - open loop = 0. The comparison of the 2 sessions will be carried out for the continuous variables using an analysis of variance model for cross-over design (subject to compliance with the application conditions), including the HbA1c value at the start of each period as adjustment variable. For the binary variables, the 2 sessions will be compared using a conditional logistic regression model including the HbA1c value at the start of each period as adjustment variable.

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Safety criteria Clinical collection of adverse events, especially severe hypoglycemia and ketoacidosis

Early end of study

● Withdrawal of patient consent ● Patients who do not have the ability to manage their

treatment with CGM data and Cellnovo pump on a daily basis;

● Patients who do not have the ability to manage their treatment with Kaleido pump on a daily basis;

● Lost to follow-up ● Decision by investigator in patient's best interest

Inclusion duration 7 months

Study duration 17 months

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Table 1: VISIT SCHEDULE ARM 1 (CL in 1st period – OL in 2nd period)

Visit Description Date of visit Duration

PRE-SCREENING Visit 0

(during a

usual

medical

visit)

Pre-screening visit:

information notice

given to patient

-1 to -7 days before

visit V1

INCLUSION AND

RUN- IN PERIOD

Visit 1 Inclusion visit:

Signature of informed

consent, HbA1c (from

patient’s file if 4

months), pregnancy

test. Installation and

training on CGM and

Cellnovo pump for 2-

week run-in period.

Evaluation of patient’s

ability to manage

treatment with the

Cellnovo and Dexcom

G5. « Baseline »

satisfaction

questionnaire.

Start at T0 2 to 3 hou rs

PILOT STUDY

Visit A

(Only

concerns

CHSF and

Grenoble

CHU)

Initial training on the

Diabeloop system.

Installation of system

for 4 to 6 weeks. Data

collection booklet

given to patient.

1 to 2 weeks after visit

1

Conventional

hospitalization of 48

to 72 hours

Visit B Optimization of

treatment with

Diabeloop system

according to patient’s

needs. Review use of

system with the patient.

1 week after visit A

1 hour

Visit C Optimization of

treatment if necessary.

1 week after visit B 1 hour

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Review use of system

with the patient.

Visit D Upload data from

pump, CGM and

algorithm.

2 weeks maximum

after visit C

1 hour

RANDOMIZATION

Visit 2 Randomization visit for

patients with the ability

to manage their

treatment with the

Cellnovo pump and

Dexcom G5.

Diabeloop user

manual given to

patients assigned to

arm 1 and telephone

exchanges with the

engineers if necessary.

Patients will keep the

Dexcom sensor and

Cellnovo pump.

2 weeks after visit 1

[at least 1 to 3 days

after visit D for

patients who

participated in the pilot

study]

1 hour

ARM 1

CLOSED LOOP

Visit 3 Initial training on

Diabeloop system.

Installation of system

and practical exercises.

Evaluation of patient’s

ability to manage the

treatment.

Pregnancy test,

HbA1c

Data collection booklet

given to patient.

Between 1 and 15-30

days maximum after

visit 2

Conventional

hospitalization of 24

to 48 hours

Visit 4

Optimization of



with the patient.

1 week after visit 3 1 hour

Visit 5 Optimization of


Upload data from

pump and CGM.

2 weeks after visit 4 1 hour

Visit 6 Upload data from 3 weeks after visit 5 1 hour

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pump and CGM.


with the patient.

Optimization of


Visit 7 Upload data from

pump and CGM.


with the patient.

Optimization of


Give patient diary to

record

snacks+sugarings

during last week at end

of session.

3 weeks after visit 6 1hour

Visit 8 End of closed loop.

Satisfaction

questionnaire filled out.


recovered. Upload

data from pump,

CGM and algorithm.

Remove Diabeloop

system. Patients will

keep the CGM for the

wash-out period.

HbA1c.

3 weeks after visit 7 1 to 2 hours

WASH OUT Wash-out period.

Patients will keep the

Dexcom G5 CGM and

take back their usual

pump.

Immediately after visit

7

8 weeks minimum

OPEN LOOP

Visit 9 Installation of system

and practical exercises.

Pregnancy test,

HbA1c.


given to patient.

At least 8 weeks after

the end of visit 8

1 to 2 hours

Visit 10 Review use of Dexcom 1 week after visit 9 1 hour

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Face-to-

face visit

CGM with the patient.


CGM. Review use of

Dexcom CGM with the

patient.



CGM. Review use of

open loop system with

the patient.



CGM. Review use of

open loop system with

the patient. Give

patient diary to record

snacks+sugarings

during last week at end

of session.


Visit 14 End of open loop.

HbA1c.

Satisfaction

questionnaire filled out.


recovered. Upload

data from CGM.

Remove all study

medical devices.

3 weeks after visit 11 1 to 2 hours

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Table 2: VISIT SCHEDULE ARM 2 (OL in 1st period – CL in 2nd period)


PRE-SCREENING Visit 0 (during a

usual medical

visit)


information notice

given to patient


visit V1

INCLUSION AND

RUN- IN PERIOD


Signature of

informed consent,

HbA1c (from


months), pregnancy


training on CGM

and Cellnovo pump

for 2-week run-in

period.

Evaluation of

patient’s ability to

manage treatment

with the Cellnovo

and Dexcom G5.

« Baseline »

satisfaction

questionnaire.

Start at T0 2 to 3 hours

PILOT STUDY

Visit A (Only

concerns CHSF and

Grenoble CHU)

Initial training on

the Diabeloop

system. Installation

of system for 4 to 6

weeks. Data

collection booklet

given to patient.

1 to 2 weeks after

visit 1

Conventional

hospitalization

of 48 to 72

hours


treatment with

Diabeloop system

according to

patient’s needs.

Review use of

system with the


1 hour

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patient.


treatment if

necessary. Review

use of system with

the patient.



pump, CGM and

algorithm.

2 weeks maximum

after visit C

1 hour

RANDOMIZATION

Visit 2 Randomization visit

for patients with the

ability to manage

their treatment with

the Cellnovo pump

and Dexcom G5.

Patients will keep

the Dexcom sensor

and take back their

usual pump


[1 to 3 days after

visit D for patients

who participated in

the pilot study]

1 hour

ARM 2

OPEN LOOP

Visit 3 Installation of

system and practical

exercises.

Pregnancy test,

HbA1c

Data collection

booklet given to

patient.

1 to 3 days after

visit 2

1 to 2 hours

Visit 4

Face-to-face visit

Review use of usual

pump and Dexcom

CGM system with

the patient.



CGM. Review use

of usual pump and

Dexcom CGM

system with the

patient



CGM. Review use


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of the open loop

system.


CGM. Review use

of the open loop

system. Give patient

diary to record

snacks+sugarings

during last week at

end of session.



HbA1c.

Satisfaction

questionnaire filled

out. Data collection

booklet recovered.

Upload data from

CGM. Remove all

study medical

devices. Diabeloop

system user manual

given to patients

assigned to arm 2

for the 2nd period in

CL and telephone

exchanges with the

engineer if

necessary.



Patients will keep

their usual pump and

Dexcom G5 CGM.

Immediately after

visit 7

8 weeks

minimum

CLOSED LOOP


the Diabeloop

system and Kaleido

pump. Installation of


exercises.

Evaluation of


At least 8 weeks

after visit 8

Conventional

hospitalization

of 48 hours

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manage treatment.

Pregnancy test,

HbA1c

Data collection

booklet and user

manual given to

patient.


treatment if

necessary. Review

use of system with

the patient.



treatment if

necessary.

Upload data from

pump and CGM.

2 weeks after visit

10

1 hour


pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary.

3 weeks after visit

11

1 hour


pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary. Give

patient diary to

record

snacks+sugarings

during last week at

end of session.

3 weeks after visit

12

1hour

Visit 14 End of closed loop

and end of study.

3 weeks after visit

13

1 to 2 hours

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Satisfaction



booklet recovered.

Upload data from

pump, CGM and

algorithm. Remove

Diabeloop system.

HbA1c

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Figure 1: Study flowchart

Recruitment & consent

HbA1c + Creatinine + Baseline

satisfaction questionnaire

2 week run-in period

Initial training on use of CGM and pump

Evaluation of patient

Optimization of treatment with pump + CGM

Patient compliance

Randomization

HbA1c at start of 1st period

Treatment period

Closed loop 12 weeks

Diabeloop system

Treatment period

Open loop 12 weeks

Usual pump + Dexcom CGM

Treatment period

Open loop 12 weeks


Questionnaire + VAS

HbA1c at end of 1st period

Wash-out period 8 weeks minimum

Patients equipped with usual

pump+CGM

Treatment period

Closed loop 12 weeks Diabeloop system with Kaleido pump

HbA1c

End of study

Satisfaction questionnaire + VAS

Final data analysis

Preliminary analysis

Arm 1 Arm 2

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Figure 2: Study diagram

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I - RATIONALE OF THE DIABELOOP PROJECT

I. 1. Type 1 diabetes

Type 1 diabetes is an auto-immune condition affecting insulin-secreting beta cells in the

pancreas. The auto-immune reaction completely destroys the beta cells leading to an inability of the

pancreas to make insulin. This results in the development of diabetes, whose only treatment is the

administration of insulin. Without insulin, death occurs from ketoacidosis. Even with all the

progress that has been made in insulin therapy, there is room for improvement and today it is still

difficult to achieve perfect long-term blood glucose control. The patient’s health and quality of life

must dodge around two pitfalls: chronic glycemic imbalance, evaluated by quarterly testing of

HbA1c: the DCCT study (1) found an exponential relation between mean HbA1c values over a 10-

year period, and the occurrence of disease-specific microvascular (retinopathy, nephropathy) and

neuropathic complications, in addition to an increased risk of macrovascular complications

(coronary insufficiency, arteritis and stroke). Conversely, this study also found an exponential

relation between lower HbA1c values and increased risk of severe hypoglycemia with sudden loss

of consciousness, convulsions and coma. In addition to the specter of these immediate or longer

term threats, it is necessary to emphasize the daily burden of diabetes management and the great

difficulty of adhering to it perfectly in the long term, which often has a significant impact on quality

of life, both family and professional, and is a frequent cause of distress, depression and partial

abandonment of therapy (2).

Insulin is the mainstay of DT1 treatment. As insulin is destroyed by the digestive juices, it must be

administered by the parenteral route. For practical reasons it is administered subcutaneously, which is

unable to mimic the physiological portal route. This results in delayed bioavailability which creates

problems of anticipation imperfectly improved by the development of rapid-acting insulin analogues.

Insulin must be administered in a way that attempts to reproduce its physiological secretion and

cover two different types of requirement:

Basal requirement: independently of food intake, hepatic glucose production occurs between

meals and during the night. This is regulated by basal insulin secretion, which is absent in DT1. The

so-called slow-acting insulins are used to replace and mimic this basal insulin secretion. These

insulins are modified so that their subcutaneous diffusion extends over 12 or 24 hours.

a) The arrival of the slow insulin analogs heralded a major breakthrough because these

insulins have little or no peak, a fairly flat action profile, and better day-to-day reproducibility than

classic NPH insulins (4). However there is considerable inter-patient and especially intra-patient

variability from day to day, arising from the persistent variability of the pharmacokinetics and

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pharmacodynamics of these insulins. Furthermore, these insulins cannot adapt to the physiological

variations in insulin sensitivity over a 24-h period, which result in lower insulin requirements

during the first part of the night, abruptly increasing toward dawn (“dawn phenomenon”) (5), and

intermediate during the day. These variations can be quite large in a same subject and compromise

satisfactory control of basal blood glucose levels. In addition to these day-night variations, other

occasional abrupt variations can occur, such as those induced by physical activity. Physical activity

causes a delayed and prolonged decrease in insulin requirements, according to its intensity, for

which a slow-acting insulin administered the previous evening is unsuited. Anticipation strategies,

more or less adapted, have therefore been proposed to patients (reduce the nearest rapid insulin

prandial bolus and/or have a carbohydrate snack).

b) Continuous subcutaneous infusion of a rapid insulin analogue via insulin pump has

been an important advance for some patients. This technique makes it possible to program different

basal rates over a 24-h period according to the patient’s insulin requirements, and to reduce the

basal rate “on demand”, according to pre-established algorithms, when an unplanned physical

activity occurs. Furthermore, continuous insulin infusion improves day-to-day variability in fasting

blood glucose, as reflected in the significantly smaller standard deviations of average fasting

glucose levels and, correlatively, hypoglycemia (6) and, ultimately, HbA1c (7) compared to

multiple injections. Nevertheless the results are still imperfect, with poor reproducibility of fasting

blood glucose control and persistent day-to-day variability that may be significant in some patients.

This exposes patients either to a risk of hypoglycemia, especially during the night, or to chronic

intermediate hyperglycemia, according to the strictness of the chosen control option. The reasons

for this persistent variability are multiple and poorly understood:

• Related to the pump: the pumps currently on the market are syringe pumps. While the

accuracy of the pump measured over a 24-hour period is generally good, the situation is quite

different when measured over periods of a few minutes, where inaccuracies of 18-34% have been

observed in different models of pumps. This phenomenon is related to the elasticity of the plastic

syringe whose plunger progresses by fits and starts (stick-slip effect).

• Related to the catheter: besides minor problems of dislodging, bending or occlusion, it

should also be considered that insulin traveling through a 60cm catheter may stagnate for several

hours, and undergo degradation leading to partial inactivation. The impact of these phenomena on

observed blood glucose variability is not fully understood, but they might underlie some

unexplained episodes of fasting hyperglycemia whose frequency seems to vary according to the

rapid analogue used (8).

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• Related to the intradermal cannula: The patient’s position (lying on the cannula while

asleep, or leaning forward during a meal and administering a bolus) can significantly delay effective

diffusion of insulin into subcutaneous tissue. The same is probably true of the thickness of the

subcutaneous tissue.

• Related to the insulin: the bioavailability of insulin analogues administered by the

subcutaneous route is imperfect.

• Related to the patient: unpredictable variability in insulin sensitivity over the 24 hour

period.

Current possibilities for making technical improvements are based on a system of continuous

insulin administration capable of automatically correcting episodes of unforeseeable glucose

variability according to predetermined, patient-specific algorithms.

c) Insulin requirements during meals: The insulin requirement for a meal depends on

the amount of carbohydrate ingested: studies (9), have demonstrated a simple linear relationship

between the amount of carbohydrate ingested and the insulin dose required for their storage. This

has led to the development of personalized algorithms, either empirical or based on the patient’s

weight and an approximate estimate of their overall insulin sensitivity (10). Each patient thus has an

“insulin/carbohydrate ratio”. In current practice, the correctness of this approach, as long as the

patient is trained to correctly estimate carbohydrate intake, has recently been demonstrated by an

analysis of postprandial glucose levels observed after several thousand meals: mean PPG values are

very close to the recommended physiological target (1.40 g/l) regardless of the time of the meal or

the amount of carbohydrate ingested (10). There is, of course, a fairly high variability of blood

glucose values around a correct average, which is probably due to the imprecision of patient-

estimated carbohydrate intake, again highlighting the utility of a system capable of

automatically correcting unforeseeable episodes of glucose variability.

d) Insulin requirements during physical activity: Physical activity is accompanied by

a reduction in insulin requirements that can extend beyond the end of the activity. In practice, this is

a major cause of hypoglycemia when it is not anticipated. Algorithms capable of anticipating this

temporary reduction in insulin requirements have been developed and validated. They all involve a

reduction in the rapid insulin meal bolus closest to the time of the activity if the activity is close to a

meal and take into account the presumed intensity of the activity (11). Algorithms that temporarily

reduce the basal rate are also proposed when the activity will take place far from the meal (12). The

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interest of this type of approach is undeniable but the problem of accuracy and patient anticipation

remains.

In general, significant progress has been made in the management of DT1. In France, the mean

HbA1c of a national representative sample of DT1 patients is 7.9% (3), which is not too bad compared to

mean HbA1c values of DT1 patients at baseline in large studies like DCCT (8.8%) or DAPHNE (9.3%).

Nevertheless, 38% of patients had HbA1c > 8%, i.e., an average blood glucose value associated with a

very high risk of future complications.

The best method currently available for routine use is continuous insulin pump therapy with a

rapid insulin analogue and a personalized algorithm of the patient’s basal rates, prandial

requirements and physical activity. However, there is still day-to-day variability, which can be quite

considerable, and which hinders the achievement of a good average glycemic equilibrium and is the

main determinant of the risk of hypoglycemia. This risk of hypoglycemia is the limiting factor in

good glycemic control (13). It only now seems possible to overcome this “therapeutic wall” thanks

to the development of hybrid closed loop systems that can automatically prevent or correct

unexpected glucose variability.

II - THE DIABELOOP PROJECT

Figure 3: Overall diagram of the Diabeloop system

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The innovative features of the Diabeloop project revolve around two main themes:

1. The blood glucose control algorithm

The heart of the system, this algorithm is the first part of the Diabeloop project which offers a

strong innovation compared to the state of the art.

2. The Diabeloop system

As a whole, the Diabeloop system will in itself be innovative and at the cutting edge of technology.

Although the Diabeloop project is not the only project focusing on diabetes (see. § II.2. Other projects on

the same theme), at the present time there is no other automatically adaptive and functional system of

blood glucose regulation.

The Diabeloop is composed of several prototypes described below (Cf. § III. The components of the

Diabeloop project).

II. 2. Technical proposal

Recent technological advancements in the miniaturization of external insulin pumps and continuous

glucose sensors have paved the way towards the realization of an artificial pancreas, a real hope for DT1

patients and physicians.

The purpose of the Diabeloop project is to develop and clinically validate an automated blood

glucose regulation system. This system will comprise:

• A glucose sensor that “continuously” measures interstitial glucose levels.

• A pump allowing “continuous” delivery of insulin.

• A Smartphone with the features described below.

• An algorithm that determines the insulin doses to be administered based on interstitial

glucose levels, the information input by the patient and the treatment prescribed by the doctor.

• A remote medical monitoring service to monitor patient status. All patient data, and in

particular, interstitial glucose levels, insulin doses and intercurrent events, will be uploaded onto a

secure website accessible to the healthcare teams.

The Smartphone used in this project has several functions:

• Collection of data: storage and transmission to the control algorithm.

• Control algorithm with determination of insulin doses according to interstitial glucose

levels, treatment prescribed by doctor and information entered by the patient.

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• A user interface for patients to monitor their treatment and input information.

• Secure data transmission to the healthcare team

II. 3. Other projects on the same theme

Several groups are working on the blood glucose control algorithm to create and validate an

artificial pancreas prototype, an innovative therapeutic solution for the treatment of type 1 diabetes. These

projects include:

European project AP@home (Bringing the Artificial Pancreas @ home), as part of the 7th

Framework Programme for Research and Technological Development (7PC) (14).

Two closed loops (CL) were tested in parallel in comparison with the open loop (OL: patient’s

usual treatment) in 48 subjects followed for 24 h. Time spent in target was similar between the closed

loops and the open loop. Time in hypoglycemia was three-fold lower in closed loop (2%) than in open

loop (6%), to the detriment of average blood glucose values, which were higher in CL than in OL.

Compared to DIABELOOP, the loops used for the AP@home study did not include de facto

presence of physical activity, and the clinical investigations did not explicitly take into account this

factor which has a significant impact on blood glucose.

In September 2015 the AP@home group reported the results of a 2-month outpatient

crossover trial in 35 adult patients. The closed loop using an Accu-Check Roche Combo pump and

Dexcom G4 sensor was only operational during the night. The control group also used the sensor in

a crossover plan.

The primary outcome (time spent in 70-180 mg/dl target during the night) was significantly

improved in closed loop (66.7% vs 58.1%), with less time spent in hypoglycemia (1.7% vs 3%) and

in hyperglycemia, and no adverse effects (22).

In November 2015 this consortium reported the results of a trial similar to the one envisaged

here. This was a crossover trial in 58 patients of which 33 adults for 12 weeks at home. A Navigator

Abbott sensor and Dana syringe pump with tubing were used. Time spent in glycemic target 70-180

mg/dl (primary endpoint) was 11% higher in the hybrid closed loop (68±11% vs 57±14%), while

average blood glucose, HbA1c and time spent in hypoglycemia were also significantly improved.

No safety issues were reported (23).

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JRDF Artificial Pancreas Project in the United States

Prof Kovatchev is the director of the Center for Diabetes Technology at the University of Virginia

and the investigator in a number of projects on the artificial pancreas, among which is the “JDRF

Artificial Pancreas Project at UVA” from 2006 to 2014. The algorithms developed at UVA were also

tested in AP@home (Cf. supra, iAP), partly also because of regulatory constraints.

These clinical trials differed in terms of number of subjects or focus on nocturnal control,

pediatrics. Between 2012 and 2014 there were 6 clinical trials: JDRF-1 (feasibility tests of outpatient

closed loop insulin delivery), Helmsley-1 (diabetes camp with remote hypoglycemia monitoring), JDRF-2

(multi-site randomized crossover trials and efficacy of outpatient closed loop system), NIH-1 (5-day tests

of the “bedside artificial pancreas”), AP@home with pilot tests for 5 nights, Helsmley-2 (closed loop

nights with the Unified Safety System during a diabetes camp), and a study in adolescents on omitted

bolus. The results of the algorithm are presented with the paragraph on the European AP@home project.

Physical activity is not explicitly taken into account.

DREAM project

DREAM project results were published in 2013 (15). The article presents the outcomes of an

algorithm based on Fuzzy Logic used in overnight sessions in adolescents at a diabetes camp

(randomized, closed loop versus open loop with “low-glucose-suspend”). The system is a “fully

automated, wireless closed loop with a learning algorithm, an alert module and a personalized

configuration”.

This group reported data from a randomized crossover trial of overnight control for 6 weeks

of home use in 24 patients aged 12 to 43 years. The primary endpoint was the time spent in

hypoglycemia < 70 mg/dl during the night. The primary endpoint was significantly reduced in

closed loop (2.5 vs 5.2%), as was the time spent in hyperglycemia > 240 mg/dl, with an increase in

the time in target 70-140 mg/dl (47.4 vs 36.4%). No adverse effects were reported, and in particular

no cases of severe hypoglycemia in the experimental group (24).

European Project PcDiab (PcDiab FP7-Health Cooperation)

The PcDiab project is not competitive with the Diabeloop project because it is based on bi-

hormonal regulation with insulin and glucagon (hormone with opposite effect to insulin). Currently,

glucagon is not sufficiently stable in soluble form to be used in pump therapy over long periods of several

days.

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“Bionic Pancreas” project from Boston University (E Damiano)

This is a study of bi-hormonal regulation published in The New England Journal of Medicine

(11) whose objective is to develop a bi-hormonal automated bionic pancreas allowing more

autonomy and better glycemic equilibrium for type 1 diabetics. This study reproduced the same

real-life conditions including meals and uncontrolled physical activity. The results are excellent and

the use of glucagon appears to be beneficial on two fronts: average blood glucose and

hypoglycemia. However, a major obstacle persists: currently available glucagon is unstable and

must be changed every 24 hours. For this reason, like the PcDiab project, the Bionic Pancreas is not

a direct competitor of Diabeloop because it is based on blood glucose control with two hormones:

insulin and glucagon.

One of the clinical partners in the Diabeloop project, Prof Eric Renard (Montpellier CHU), is also a

partner in the American and European projects. The American project has a considerable headstart, since

it began in 2006, and the European project, very sophisticated, enjoys a high level of funding.

Nonetheless, the Diabeloop project has significant advantages:

- First of all, a major strong point is the strength and involvement of a team like LETI, which

does not seem to have an equivalent in the two competing projects, and which should provide a

competitive edge in terms of the control algorithms, more robust than those used in the American or

European projects.

- The 9 clinical teams working in partnership on the project are used to working

together and have already demonstrated their involvement in the development of new technologies

(16).

- The Diabeloop system itself is a “semi-closed” loop, i.e., requiring patient intervention for

meals or unplanned physical activity. It is therefore a simpler project than its competitors, and more

directly operational, but open to future improvements.

Altogether, the Diabeloop SP7 project is a full-fledged part of the international competition

through its use of a proven and robust study design (crossover), over a period of 3 months day and

night. Its originality lies in its use of medical remote monitoring prefiguring its future routine use,

which reinforces the safety of the system, on the one hand, and its use of a patch pump combined

with the Dexcom G5 sensor to enhance the acceptability of the system, on the other hand.

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11.4 . General structure of the Diabeloop project

The project is structured around 7 sub-studies whose interrelationships are indicated by

arrows in the following PERT chart:

Figure 4: Schedule of Diabeloop sub-studies

SP 0 – Project management: The purpose of this sub-study is to ensure good project

management, coordination of tasks, planning, and so on.

SP 1 – Administrative tasks: As part of the Diabeloop project, two clinical phases involving

study subjects are planned: one to collect data, and one for the validation phase. The aim of

this sub-study is to anticipate the various administrative tasks so as not to be held up by

unfulfilled legal obligations at the start of these phases.

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SP 2 – Development of system components: The purpose of this sub-study is to develop the

different components of the Diabeloop system: the heart of the software, the connection of the

pump and sensor to the Smartphone and the user interfaces.

SP 3 – Data collection in the hospital setting: The purpose of this sub-study is the

acquisition and management of a database for the development of the algorithms. This

database must incorporate venous blood glucose measurements and interstitial glucose levels

determined by the Dexcom sensor at regular intervals, orders for insulin delivery by the

Debiotech pump and insulin levels in the blood. The database should also include insulin meal

bolus doses as well as the meal content, the reduction in insulin delivery in case of physical

activity, and the quantification of the physical activity.

SP 4 – Development of the control loop: The purpose of this sub-study is to develop the

control loop: state of the art and technology watch, study of identified research themes and

validation of algorithms on the basis of data collected in SP3.

SP 5 - Integration, qualification and overall system tests: The purpose of this sub-study is

to integrate the Diabeloop system from the components and features developed in SP2 and

SP4. The second purpose is to qualify the system in relation to the specifications given by

sub-study SP1.

SP 6 - Validation of the medical contribution: The purpose of this sub-study is to

coordinate the tests to be carried out at the different hospital centers in order to quantify the

contribution of the Diabeloop system in the treatment of diabetes.

The study presented in this protocol corresponds to sub-study 6_1, described below.

Sub-project 6 comprises 3 steps:

• SP 6_0: Initial testing of the Diabeloop algorithm over the prandial period and

physical activity

• SP 6_1: First evolution of the artificial pancreas Diabeloop prototype in the hospital

setting.

• SP 6_2: Crossover Evaluation of Glycemic Control Provided for Three Days by the

Artificial Pancreas Diabeloop Compared to Conventional Treatment by External

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Insulin Pump in Patients With Type 1 Diabetes in a Situation of Sedentarity,

Exceptional Meals and Physical Activity.

SP 7 – Evaluation of the safety and efficacy of the Artificial Pancreas: This sub-study

aims to test the safety and security of the hybrid system in the home setting with remote monitoring

with a view to obtaining CE Mark registration.

III COMPONENTS OF THE SP7 PROJECT

The Diabeloop SP7 project will be conducted with the following components:

111.1. The terminal (Smartphone)

This will be used:

• To collect data sent from the glucose sensor every 5 minutes, store the data and send it

to the control algorithm;

• To receive data input by the patient: meals, announced CHO intake, physical activity;

• As a calculation unit for the control algorithm;

• To pilot the Cellnovo insulin pump;

• To display to the user and doctor new dose recommendations, stopping of basal rate

and/or sugaring to avoid hypoglycemia.

111.2. Blood glucose control algorithm

The MPC (Model Predictive Control defined above) algorithm designed by CEA-LETI is a

software program that determines insulin doses to be delivered according to interstitial glucose

measurements, data input by the patient (meals and physical activity) and the treatment prescribed

by the doctor (usual basal rates, prandial bolus, temporary basal rate reduction for physical activity

and sugaring to avoid hypoglycemia).

111.3. The DexcomTM G5 system

The DexcomTM G5 is a continuous glucose monitor (CGM) with Bluetooth low energy

wireless communication built into the receiver. It transmits interstitial glucose levels to the

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Diabeloop algorithm in the Smartphone. Insulin administration by the Cellnovo patch pump is

controlled by the Diabeloop algorithm.

The DexcomTM G5 is designed to continuously measure glucose over a range of 40 to 400

mg/dL and can be used for a maximum of seven days. It is identical to the DexcomTM G4 Share AP

CGM except for the receiver which can be integrated in a Smartphone via a Dexcom application.

As with the G4 ShareTM , it is contraindicated in association with medicinal products

containing acetaminophen (paracetamol) since these can alter sensor performance.

The DexcomTM G5 is composed of:

- a sensor with a disposable applicator

The Dexcom sensor is a platinum electrode coated with 3 membrane layers. It uses a 2-step

process to convert glucose into an electrical signal:

glucose + O2 gluconic acid + H2O2

H2O2 2H+ + O2 + 2e-

It is validated for up to 7 days of use.

- a transmitter

This is wireless and sends glucose data to the receiver. It locks onto the sensor receptacle and when it

is correctly installed, the sensor+transmitter become water-resistant.

glucose

oxidase

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The transmitter battery has a lifetime of about 6 months. The transmitter should be replaced when the

low battery signal appears on the receiver.

- a receiver

Figure 5: DexcomTM G5 receiver

This can transmit data up to a distance of about 15 feet (≈4.572 meters) at a frequency of 2.4

GHz.

Instructions for inserting the sensor and locking in the transmitter can be found in the

appendix.

- an application for Smartphone/tablet:

The Dexcom G5 Mobile application is designed to work with a Smartphone or tablet, thereby

offering even more options to measure glycemic trends and profiles.

111.4. The Cellnovo pump

The Cellnovo insulin pump is a high precision patch pump composed of a durable pump and a

disposable insulin cartridge.

For arm 1, the Cellnovo pump will have a wireless connection to the Diabeloop system and be

controlled by the Smartphone with the Diabeloop application.

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111.5. The Kaleido external insulin pump

Following the technical incidents that occurred in arm 1 in patients equipped with the

Cellnovo pump during the closed loop, it was decided for safety reasons to replace the Cellnovo

insulin pump by the Kaleido patch pump in arm 2.

The Kaleido insulin pump is a high precision patch pump composed of a durable pump

(control unit) and a disposable insulin cartridge (consumable unit). The “consumable unit” is the

part of the pump in contact with the insulin; it is sterile and single-use. The control unit of the

pump contains the electronics that control the pump and ensure communication with the terminal

of the Diabeloop system. The pump patch is a velcro adhesive by which the skin patch is fixed to

the body of the pump.

The Kaleido pump obtained CE mark registration a year and a half ago. It is marketed in the

United Kingdom and the Netherlands and is in the process of being launched in other countries.

The design of this pump is modern and ergonomic. The technology depolyed to administer

insulin does not generate constant pressure on the insulin reservoir in the direction of the patient.

The pump is water-tight for 1 hour up to a depth of 1 meter, rated IP68 according to IEC standard

60529.

Kaleido insulin cartridges have been validated for a period of 84 hours of use. The Kaleido

cartridges contain 200 units. The accuracy of the Kaleido pump has been tested according to IEC

60601-2-24 for a basal rate of 1U/h and showed an error of -1.0%. Its dimensions are 12.5 mm x

50 mm x 35 mm and it weighs 19g. The Kaleido kit contains two pumps of different colors.

For arm 2, the Kaleido® external insulin pump will be connected to the Diabeloop system by

Bluetooth and driven by the Motorola terminal containing the Diabeloop application.

111.6. The open loop system (OL)

The open loop system consists of the patient’s usual insulin pump preprogrammed with the

usual treatment prescribed by the doctor. The patient will be fitted with a DexcomTM G5 CGM for

continous glucose measurements.

In current practice, the patient with type 1 diabetes is educated and trained to use a

triple blood glucose regulation system:

1. In basal state, that is, outside of meals and physical activity, the patient’s insulin

requirements are provided by the basal rate of insulin delivery by the pump, adapted

empirically and by trial and error by the doctor and patient. These basal rates depend

on the patient’s insulin sensitivity overall and throughout the day/night (four basal rates

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are often defined: 1st part of the night, 2nd part of the night, morning, and afternoon,

although there are wide interindividual variations).

2. At meals, an insulin bolus is necessary. The dose of insulin depends on the

carbohydrate intake. Patients trained in functional insulin therapy precisely evaluate

their carbohydrate intake and calculate the insulin dose accordingly (carbohydrates in

grams or in 10g or 20g portions) multiplied by the patient’s I/C index.

3. For physical activity away from meals, patients are advised to temporarily reduce their

basal rate.

111.7. The closed loop system (CL)

The closed loop system consists of the Cellnovo patch pump for arm 1 (Kaleido pump for arm

2) piloted by a Smartphone with the Diabeloop algorithm installed. The Smartphone communicates

with the DexcomTM G5 receiver by Bluetooth low energy allowing transmission, every 5 minutes,

of interstitial glucose levels to the Diabeloop software for calculation of insulin doses to be

administered.

The algorithm installed in the Smartphone is based on CGM data, the I/C ratio set by the

doctor, insulin sensitivity (weight, total insulin requirements), glycemic target (70-180 mg/dl), usual

preprogrammed basal rates, carbohydrate intake (high or low carbohydrate and/or fat), and physical

activity and its intensity. All of these data will be registered manually in the Smartphone by the

patient, except for the sensor data which are sent automatically to the algorithm.

The Diabeloop algorithm will serve as the basal regulation that will not be modified as long as

fasting and postprandial glucose remain within target range. If a glucose variation outside target

range is predicted within a 1-2 hour horizon, the algorithm proposes a preventive correction either

as an additional bolus, in prandial period, or a temporary basal rate reduction during other periods.

If despite this, hypoglycemia is predicted, the algorithm recommends a calibrated preventive

sugaring.

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Figure 6: Artificial Pancreas Diabeloop system

The algorithm instruction will be emitted in the Smartphone by the application and the

treatment will be implemented as follows:

Every 15 minutes, the algorithm reassesses the quantity of insulin to be delivered and may

order an adaptation of the insulin dose (bolus and/or change in basal rate according to basal or

prandial period). In the absence of an instruction, the basal rate will remain at the usual rate initially

preprogrammed by the doctor at the start of the test.

The modification of treatment recommended by the algorithm will occur automatically via the

Bluetooth signal emitted by the terminal to the Cellnovo or Kaleido pump, which simultaneously

executes the algorithm instruction (injection or basal rate modification).

In some situations, despite a temporary suspension of the basal rate, the algorithm predicts a

hypoglycemic episode with a projection horizon of a few minutes and recommends a preventive

sugaring, calibrated according to the predicted level of hypoglycemia and the patient’s settings.

Patients are then supposed to take the recommended amount of fast-acting carbohydrate as soon as

possible.

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III.6.a Configuring the regulation settings

Diabeloop is an “intelligent” system designed to continuously and automatically adapt the

optimum amount of insulin to prescribe. This contrasts with the usual insulin pumps like the

Medtronic or Roche Diabetes Care, where the patients themselves must modify the pump

flow rates according to the situation (sports, illness, stress, etc.).

With the Diabeloop system, the final user will see that his flow rates are automatically

modified according to the current and predicted blood glucose value:

- Either every 5 minutes, if a meal is announced or if the system predicts that the

hypoglycemia limit will be crossed,

- Or every 10 minutes, according to the trend of the current glucose values.

In order to secure the user and give him some control, four settings have been added to the

regulation system. The combined use of these four settings will have an effect on the insulin

doses prescribed. Therefore it is important to understand the impact that changing these

settings will have on the amount of insulin dispensed.

Thus it will be possible to change these settings independently of each other to better adjust

the behavior of the algorithm and ultimately the blood glucose balance of the patient.

In the framework of the Diabeloop SP7 clinical study, these settings will be modified

under the authority of medical staff trained in the use of the Diabeloop system.

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Figure 7: Steps to access the regulation settings (click on the red box)

III.6.b Default configuration

After receipt and initialization of the Diabeloop system with the patient’s data, the “regulation

settings” menu is accessed as described below. The system will be delivered in the following

configuration:

Table 3: Diabeloop system settings

Setting Default setting

Responsiveness during normoglycemia Normal

Responsiveness during hyperglycemia Normal

Target blood glucose 110 mg/dl

Hypoglycemia limit 70 mg/dl

Weight Data entered during initialization

This default configuration is based on experience acquired with computer simulations on

virtual patients, test bench reassessments of real patient data, and during the previous studies

SP6.0 and SP6.1. It is this default configuration that was used during study SP6.2, where for

three days, it gave very satisfactory results in all patients, with the exception of two patients

where the system was “overly reactive” from the first day.

In general, in this type of patient who is highly sensitive to the action of insulin and therefore has an

increased risk of hypoglycemia, it will be possible for the caregiver to adjust the system to be less

responsive, by selecting “low” or “very low” responsiveness, in order to reduce this risk. The

opposite can also be done in case of hyperglycemia (the caregiver will adjust responsiveness to

“high” or “very high”), with respect to responsiveness during hyperglycemia or during

normoglycemia.

Notion of convergence of the settings: the determination of the level of responsiveness that seems

most appropriate for a given patient as the study progresses (choice among five levels) should

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ultimately result in a stabilization of the “responsiveness” setting at a given level for a given patient.

This stabilization over time towards a given level of responsiveness illustrates what has been defined

as a convergence of settings (in this case, a convergence of the responsiveness settings), and this

convergence of settings will form the basis of the optimization of algorithm self-learning.

For settings involving a quantitative variable (target blood glucose and hypoglycemia limit),

stabilization of each of these settings towards a given blood glucose value should also occur as the

study progresses, corresponding to what is referred to as the convergence of these settings.

III.6.d. Notion of responsiveness

The responsiveness is the room for maneuver granted to the regulation system to correct the

glycemic balance of the patient. This type of setting corresponds to the speed at which the

algorithm will correct blood glucose levels higher than the target, either already effective or

predicted by the system. Each of these settings has five levels: very low / low / normal /

high / very high. With high responsiveness, the system will correct hyperglycemia more

quickly, increasing the risk of minor hypoglycemia within 2 hours after the hyperglycemia.

With low responsiveness, hyperglycemia will be corrected more slowly, but the risk of minor

hypoglycemia is much smaller.

Figure 8: Responsiveness to correct hyperglycemia

III.6.a Responsiveness during normoglycemia

Responsiveness during normoglycemia is a setting that will adjust only the basal rate that the

algorithm wants to prescribe. The Diabeloop system will be able to adjust the basal rate every

10 minutes in order to bring the blood glucose value back to target range. To avoid an overly

large decrease in blood glucose and hypoglycemia, we limit the prescription of this basal rate.

Responsiveness during normoglycemia can be set to five levels: very low / low / normal /

high / very high. With high responsiveness, the system will tend to correct hyperglycemia

more quickly, increasing the risk of minor hypoglycemia within 2 hours after hyperglycemia.

Conversely, a low responsiveness will correct more slowly, thereby significantly decreasing

the risk of minor hypoglycemia.

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Adjustment of the setting: responsiveness during normoglycemia

During the clinical study it will be possible to adjust this setting under the authority of the

medical staff in charge of monitoring the patient.

If it is noticed that the user has an average blood glucose value that is too high or too low

(with hypoglycemia), we recommend, before any change in the settings, to check the

reference initial daily insulin dose to make sure it is coherent with the patient’s theoretical

insulin requirements and the quantity entered in the system during initialization of the

terminal. If this value is coherent with the patient’s insulin requirements, then we recommend

adjusting the level of responsiveness during normoglycemia.

The main idea to keep in mind when adjusting the responsiveness during normoglycemia is

the following: the more I raise the level of responsiveness, the larger the dose of insulin that

will be dispensed (proportionality between the two).

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Figure 9: Comparison of 3 levels of responsiveness during normoglycemia and the impact on

blood glucose values: default situation (middle), low responsiveness (left) and high

responsiveness (right). The default graph is based on actual data from a patient in Diabeloop

SP6.2 over 3 days in closed loop. Blood glucose and insulin values were modified by hand to

illustrate the impact of changing the setting (green dashed line is blood glucose, blue line is

the amount of insulin prescribed, red line is the hypoglycemia limit and orange line is the

hyperglycemia limit).

Raising the responsiveness during normoglycemia will not necessarily increase the basal

prescription. It might turn out that the basal rate prescribed is the same as the previous

one. Raising the responsiveness during normoglycemia is equivalent to saying “I allow

my algorithm to deliver a higher basal rate if it considers it necessary to do so”.

III.6.b Responsiveness during hyperglycemia

Responsiveness during hyperglycemia is a setting that will adjust the compensation bolus

doses that the algorithm wants to prescribe. The Diabeloop system will be able to prescribe a

compensation bolus autonomously by using the meal ratios entered during the initialization

phase.

Always for the sake of safety, responsiveness during hyperglycemia is introduced to limit the

amount of insulin in the compensation bolus dose that the algorithm will want to prescribe.

Like the responsiveness during normoglycemia, the responsiveness during hyperglycemia is

defined by the speed at which the algorithm will correct hyperglycemia. Responsiveness

during hyperglycemia can be set to five levels: very low / low / normal / high / very high.

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To adjust this setting, it must be remembered that there is a proportional relationship between

the level of responsiveness and the amount of insulin dispensed: the higher the level of

responsiveness, the higher the amount of insulin in the compensation bolus.

By way of comparison, the responsiveness during hyperglycemia is the compensation factor

that diabetologists currently control for a given patient, and that no longer exists as such in

Diabeloop.

Adjustment of the setting: responsiveness during hyperglycemia

If a patient has an undesirable glycemic profile, such as too much hyperglycemia especially

“plateaus”, we recommend in consultation with the CERITD medical teams that you work on

responsiveness during hyperglycemia.

To authorize the algorithm to prescribe a larger compensation bolus you can raise this

responsiveness, which will increase the risk of minor hypoglycemia within 2 hours (Cf. Figure

11: “I raised the level of responsiveness during hyperglycemia” below).

Figure 10: Comparison of 3 settings for responsiveness during hyperglycemia: default

situation (middle), situation of low responsiveness (left) and high responsiveness (right).

Green dashed line is blood glucose, blue rectangles are the insulin boluses, blue line is basal

rate insulin injections, red line is hypoglycemia limit and orange line is hyperglycemia limit.

The data are from a patient in study SP6.2. Bolus doses and blood glucose values were

modified to illustrate the impact of changing the responsiveness during hyperglycemia.

Table 4: Insulin doses of each compensation bolus injected in the above graphs. As the doses are illegible they

are shown in tabular format.

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Prescription time Insulin dose prescribed when

responsiveness is lowered

Insulin dose prescribed for

default setting of

responsiveness

Insulin dose prescribed when

responsiveness is raised

19:33 1.2 1.55 1.9

19:43 0.6 0.6 0.9

19:53 0.5 0.4 0.7

20:03 0.4 0.3 0.5

20:13 0.3 0.2 0.3

20:23 0.2 0.1 0.15

20:33 0.1

Raising the responsiveness during hyperglycemia will not necessarily raise the

prescription of the compensation bolus. It might turn out that the compensation bolus

prescribed is the same as the previous one. Raising the responsiveness during

hyperglycemia is equivalent to saying “I allow my algorithm to deliver a larger

compensation bolus if it considers it necessary to do so”.

Your patient systematically reaches the hypoglycemia limit after each compensation bolus

dose and receives a sugaring request. In this specific case you can reduce the responsiveness

during hyperglycemia. This will reduce the size of the maximum bolus dose that the algorithm

can inject (Cf. Figure 11: “I lowered the level of responsiveness during hyperglycemia”). We

thus avoid the sudden drop in blood glucose.

III.6.c Responsiveness during normoglycemia and hyperglycemia

In view of the results of the Diabeloop SP6.2 study, we think that for the majority of patients,

these two responsiveness settings will not be modified. However it is important to be able to

act on these settings for certain types of physiologies, particularly for patients who have

sudden unexplained drops in blood glucose.

Example:

For a young person not prone to hypoglycemia, who is aware of his hypogylcemia symptoms,

and has a fairly stable lifestyle, the recommended responsiveness settings will be “normal” or

even “high” if he wants to minimize his average blood glucose and therefore reduce his risks

of complications.

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Conversely, for individuals who are unaware of their hypoglycemia and subject to rapid,

unexpected drops in blood glucose, or rapid glycemic peaks due to stress, it is recommended,

in coordination with their diabetologist, to adjust the responsiveness settings to “low”.

The freedom to be able to adjust the level of both types of responsiveness, and not just one,

allows patients with hyperglycemic plateaus (> 200 mg/dl) to administer higher doses of

insulin, without which it would be difficult to descend from these hyperglycemic plateaus.

Currently, these mechanisms are poorly understood and our physiological model cannot

therefore correctly interpret them. It is recommended for these specific glycemic profiles not

to modify the responsiveness during normoglycemia but only the responsiveness during

hyperglycemia if necessary.

Other physiological situations may also require separately modifying the responsiveness

during normoglycemia and hyperglycemia.

III.6.d Target blood glucose

According to factors inherent to type 1 diabetes (inter-patient and intra-patient variability), the

target can vary without changing the way the algorithm will work to achieve it.

An individual with the profile of an “expert patient”, i.e., with a relatively stable physiology,

hypoglycemia awareness, a healthy lifestyle, a mastery of functional insulin therapy and

carbohydrate estimation, diligent with meal and physical activity announcements, will be able

to set a target range of [100-105] mg/dl with a hypoglycemia limit of 65 mg/dl.

On the other hand, for a patient living alone, with low hypoglycemia awareness, the

diabetologist will set the target at 130 mg/dl with a hypoglycemia limit of 85 mg/dl.

These settings “mirror” the diabetologist’s recommendations given to the patient as part of

standard diabetes management with a conventional insulin pump (or multiple injections).

Today in order to adjust the insulin doses, the diabetologist refers to the patient’s physiology,

age and blood glucose profile. These same principles are taken into account in the Diabeloop

system.

To remain in a situation of normoglycemia, the algorithm will use the target blood glucose to

adjust the strategy used and thereby correct any hyperglycemia or hypoglycemia. The three

possibilities available to the algorithm are:

- Recommend sugaring if blood glucose is predicted to enter hypoglycemia range

- Calculate a basal rate to prescribe if blood glucose at time (t) is higher than the target

- Calculate a compensation bolus if blood glucose exceeds 180 mg/dl.

NB: When prescribing a compensation bolus, our algorithm takes into account the previous

events that led to a blood glucose value outside the target set by the user:

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- If a sugaring took place in the hour prior to the compensation bolus, the target blood

glucose is automatically raised by 20 mg/dl.

- If no event, such as a sugaring, took place before the compensation bolus, then the

target is not modified.

Modification of target blood glucose– Case of hyperglycemia followed by hypoglycemia

If the patient experiences hypoglycemia following a hyperglycemia, it is possible to increase

the target blood glucose.

The following example illustrates the effect that increasing the target blood glucose has on the

basal rate and the resulting alteration of the blood glucose profile.

The first graph represents the default situation: target blood glucose set at 110 mg/dl. In the

case of moderate hyperglycemia, the algorithm corrects it by temporarily increasing the basal

rate leading to hypoglycemia with a sugaring recommendation.

Figure 11: target blood glucose set at 110 mg/dl, increase in basal rate, modification of blood

glucose profile.

The second graph represents the same situation with a target blood glucose set at 120 mg/dl.

We can see that the algorithm decides to lower the amount of insulin delivered in order to

smooth the slope and ideally return to target without any hypoglycemia and/or sugaring.

Figure 12: target blood glucose set at 120 mg/dl, decrease in basal rate to return to return to

target range.

III.6.e The hypoglycemia limit

The hypoglycemia limit setting is used to determine the color displayed on the terminal. The

colors used to illustrate glycemic status are indicated below:

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- Red = hypoglycemia

- Green = normoglycemia

- Orange = hyperglycemia

Figure 13 : hypoglycemia limit

This limit determines what it called the sugaring limit at which the system makes a sugaring

recommendation because it deems the patient dangerously close to a hypoglycemic event. The

system makes a sugaring recommendation if:

- Interstitial blood glucose at time (t) is below the sugaring limit and the system predicts

that blood glucose at t+15 minutes will fall below the hypoglycemia limit that was set.

- The sugaring limit is determined by the hypoglycemia limit plus 20 mg/dl (and can

therefore range from 80 to 105 mg/dl). It cannot be configured by the medical teams

or the user. It will be automatically set when the hypo limit is modified.

- Modification of the hypoglycemia limit will be left to the user’s discretion according

to their habits. This setting can range from 60 mg/dl to 85 mg/dl.

III.6.f Weight

The last setting that can be modified by the user will be body weight. This is input during the

system initialization phase and used to calculate the sugaring factor.

A change in weight of less than 10% will not have a significant effect on the system and does

not imperatively have to be input into the system. However if weight gain or loss is more than

10%, the user must access the settings menu to input the new weight. For a patient weighing

76 kg, the allowed range of weight is therefore 68.40 kg to 83.6 kg.

III.6.g Changing the settings when average blood glucose is high

In which situations should the settings be modified:

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Figure 14: decision tree for modifying the settings when average blood glucose is too high

III.6.h Changing the settings when the patient has several hypoglycemic episodes

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Figure 15: decision tree for modifying the settings when the patient has several hypoglycemic

episodes.

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IV. STUDY OBJECTIVES

IV.1. Primary objective

The primary objective is to assess whether the Diabeloop system's regulatory algorithm

provides superior glucose control than usual insulin pump therapy over a 12-week period.

The primary endpoint will be the time spent in the 70/180 mg/dl target measured continuously for 12

weeks with Dexcom™ G5 CGM.

1V.2. Secondary objectives

Comparison day and night for 12 weeks, of glycemic control with insulin administration by the

Diabeloop system versus the usual personal algorithm of the type 1 diabetic patient:

1. Efficacy: Evaluate the superiority of glycemic control with the Diabeloop system for 12 weeks

compared to the patient's usual personal algorithm.

2. Safety: Assess night and day safety of glycemic control with the Diabeloop system versus the

patient’s usual treatment in terms of episodes of severe hypoglycemia and severe hyperglycemia.

3. Benefit: Determine the percentage of time spent in the system in functional mode, and the

acceptance of the system by patients.

Secondary endpoints:

1. Efficacy:

▪ The time spent in hypo <70 mg/dl measured continuously for 12 weeks with the DexcomTM

G5 CGM.

▪ Percentage of time spent in intervals [70-180] mg/dl, [80-140] mg/dl, > 180 mg/dl during

nights and over 24h for 12 weeks.

▪ Measurement of HbA1c at the beginning and end of each treatment period.

▪ Average blood glucose over the entire period.

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▪ Calculated risks of hypoglycemia and hyperglycemia (LBGI, HBGI) over the entire 12-

week period.

▪ Total insulin intakes during the tests.

▪ Assessment of the coefficient of variation of glycemia (Monnier et al, Diabetes Care

2016 Dec 30)

2. Safety:

▪ Number of hyperglycemic episodes defined by the American Diabetes Association (ADA):

Severe hyperglycemia > 360 mg/dl (20 mmol/l) as measured by DexcomTM G5 CGM or

significant ketosis (plasma ketone> 3 mmol/l).

▪ Number of hypoglycemic episodes, defined by any crossing of the threshold of 60 mg/dl (3.33

mmol/l), 70 mg/lL (3.9 mmol/l), and <54 mg/dl (3 mmol/l) measured by the DexcomTM G5

CGM.

▪ Number of severe hypoglycemic events requiring intervention of a third party for sugaring.

▪ Number of severe hypoglycemic events with loss of consciousness.

▪ Number of hospitalizations for severe hypoglycemia or ketoacidosis.

▪ Number of sugarings and the amount of carbohydrate ingested in the last week of each

treatment period.

▪ Number of technical incidents causing closed loop interruptions.

3. Benefit:

▪ Percentage of time spent in closed loop in functional mode.

▪ For use and acceptance, a satisfaction questionnaire is provided on the daily

management of diabetes, the change of daily life with the system and the fear of

hypoglycemia.

V - STUDY DESIGN

V.1. Type of study

National, multicenter, interventional, controlled, open-label, randomized, crossover

comparative trial.

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V.2. Study design

Figure 16: Study diagram

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The study will be conducted as a crossover trial, with two treatment sessions of 12 weeks

separated by a wash-out lasting at least 8 weeks Each session corresponds to a treatment period.

According to the order of the draw, patients will receive either the treatment prescribed by the

Diabeloop system (closed loop, CL) or the usual treatment (open loop, OL) prescribed by the

diabetologist.

In the open loop, the patient will be equipped with his usual pump preprogrammed

with his usual treatment, combined with a DexcomTM G5 CGM.

In the closed loop, the patient in arm 1 will be equipped with the Diabeloop system

composed of the Cellnovo insulin pump driven by a Smartphone containing the Diabeloop

application and connected to the DexcomTM G5 CGM via Bluetooth low energy (BLE). The

patient in arm é will be equipped with the Diabeloop system composed of the Kaleido insulin

pump driven by a Smartphone containing the Diabeloop application and connected to the

DexcomTM G5 CGM via Bluetooth low energy (BLE).

Before conducting the two sessions, OL and CL, patients will wear the DexcomTM G5

CGM combined with the Cellnovo insulin pump for two weeks.

Duration of patient participation: 68 weeks

Date of first inclusion: 30/03/2017

Inclusion duration: 7 months

Estimated end of study: May 2018

V.3. Participating centers and investigators

Twelve centers will participate in the Diabeloop SP7 study. The principal investigators are

shown in Table 2.

Table 5: DIABELOOP SP6.7 study centers

Center No. Center name Last name First name Department

1 CHSF Corbeil-Essonnes

Dr FRANC Sylvia Endocrinology and Diabetology

2 Caen CHU Prof REZNIK Yves Endocrinology and Diabetology

3

Grenoble CHU Prof BENHAMOU Pierre-Yves

Endocrinology, Diabetology, Nutritional Diseases

4

Lyon HCL Prof THIVOLET Charles

Endocrinology, Diabetology, Nutritional Diseases

5 Jean Minjoz Besançon CHU

Dr BOROT Sophie Endocrinology and Diabetology

6 Marseille CHU Prof RACCAH Denis Nutrition,

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Metabolic Diseases, Endocrinology

7 Montpellier CHU Prof RENARD Eric Endocrinology-Diabetes Team

8 Nancy CHU Prof GUERCI Bruno Endocrinology and Diabetology

9

Nantes CHU Dr CHAILLOUS Lucie

Nutrition, Metabolic Diseases, Endocrinology

10

Reims CHU Prof DELEMER Brigitte

Nutrition, Metabolic Diseases, Endocrinology

11

Strasbourg CHU Prof JEANDIDIER Nathalie

Endocrinology, Diabetology, and Metabolic Diseases

12

Toulouse CHU Prof HANAIRE Hélène

Diabetology, Metabolic Diseases, Nutrition

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V.4. Data and Safety Monitoring Board, DSMB

A Data and Safety Monitoring Board (DSMB) will be in charge of analyzing the safety

data from the pilot study and throughout the course of the trial in order to evaluate the

expected risks to which patients may be exposed.

DSMB members will receive all SAE reports and new information as soon as possible.

The DSMB is an independent group of three experienced clinical trial physicians.

Full name Contact

Prof Pierre GOURDY University Professor-Hospital

Practitioner in the Dept. of

Diabetology, Metabolic Diseases

and Nutrition at Hôpital Rangueil-

Toulouse CHU

[email protected]

Dr Gilles LE PAPE Diabetologist at CHSF, Évry [email protected]

Dr Anne-Marie

LEGUERRIER

Former Hospital Practitioenr,

Rennes CHU

anne-

marie.leguerrier@chu-

rennes.fr

The detailed reports drawn up by the DSMB will be sent to ANSM as soon as possible.

V.5. Study population

Number of subjects:

It is estimated that 60 subjects are required of which 50 usable in the analysis (Cf. § VIII.2).

5 subjects per center; 12 centers

Number of subjects included = 71

This number is greater than the estimated number because some patients will not be evaluable

due to loss of data resulting from problems with the Cellnovo pump.

Patient profile

Type 1 diabetic patients treated with external insulin pump will be recruited. Patients will

be followed for a maximum of 40 weeks. The inclusion and non-inclusion criteria are listed

below.

Inclusion criteria ▪ Type 1 diabetic patient for at least two years;

▪ Treated with external insulin pump for at least 6 months;

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▪ HbA1c ≤ 10%; measured within last 4 months in a medical analysis laboratory or equivalent;

▪ Insulin requirements ≤ 50U per day;

▪ Living in an area covered by a GSM network (Global System for Mobile Communications);

▪ Non-isolated patient, not living alone, or having a "resource" person living nearby and having a

telephone and the key to his home;

▪ Patient not considering a trip out of France during the "closed loop" period;

▪ At least 18 years old;

▪ Affiliated with Social Security;

▪ Having signed the free and informed consent form.

Non-inclusion criteria

▪ Patient presenting any serious pathology that could alter the participation in the study;

▪ Having a long-term treatment with a drug containing paracetamol;

▪ Patient under legal protection;

▪ Pregnant or likely to be pregnant;

▪ Lack of effective contraception in women of childbearing age;

▪ Breastfeeding;

▪ Psychological and / or physical condition that may affect the proper follow-up of study

procedures;

▪ Severe hypoglycemia leading to seizures or loss of consciousness in the past 12 months;

▪ Decreased awareness of hypoglycemia (Gold score > 4);

▪ Impaired renal function (creatinine clearance <30ml/min);

▪ Patient who has had a pancreas or pancreatic islet transplant;

▪ Persons with serious hearing and / or visual problems not corrected;

▪ Person refusing to 2 capillary blood glucose measurements daily.

End of study

• Withdrawal of patient consent;

• Decision by investigator in patient’s best interest;

• Patients without the ability to manage their treatment with the CGM data and Cellnovo

pump on a daily basis;

• Patients without the ability to manage their treatment with the Kaleido patch pump on

a daily basis;

• Patient lost to follow-up

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Patients who already use an external insulin pump and continuous glucose monitor can

participate in the study.

Some patients may already be equipped with a Cellnovo insulin pump and a Dexcom G5

CGM. These patients can be included in the study. However, practically speaking very few

patients are equipped with the Cellnovo pump and G5 sensor.

Randomization:

Clininfo® in Lyon will develop and supply the electronic case report from (eCRF) containing

the randomization procedure. Patients will be assigned at random to one of the two groups

(arm 1 or arm 2). Randomization will take place 24 to 48 hours before the start of the first

treatment session.

The randomization will be stratified by center.

VI - STUDY WORK FLOW

Patients selected to participate in the study will have the visits described below:

V1.1. Pre-screening visit V0

Patient screening will take place at each hospital center in the diabetology department during

a routine medical visit. The investigator will inform patients who meet the inclusion criteria of

the study objectives, duration, and conduct of the study visits and will invite them to take part

in the study. They will be given a minimum of 24 hours to think it over.

Creatinine clearance will be checked (<30ml/min).

VI.2. Inclusion visit V1

During the inclusion visit, the investigator collects the consent of the patient meeting the

criteria for inclusion and non-inclusion, signed and dated.

DexcomTM G5 sensor and CellNovo external insulin pump will be installed during this visit for a two

week run-in period to familiarize the patient with the use of the Cellnovo pump and to educate them to

best adapt their treatment with the sensor data.

Dexcom™ Share AP CGM and Cellnovo insulin pump installation, education and calibration

will be performed by a nurse according recommendations of the respective manufacturers.

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The patient will be trained in the use of the Dexcom G5 continuous glucose sensor and the CellNovo

external insulin pump by the healthcare team and/or engineer. User manuals for the pump and sensor

will be given to the patient along with a data collection booklet to be completed during the run-in

period.

The patient will be trained in:

- Use of the pump and software.

- Use of the continuous glucose monitor and software.

Patients will be advised to avoid taking paracetamol throughout the duration of the

study.

At the end of the visit, the healthcare team will assess the patient’s ability to manage his

treatment with the Cellnovo pump and DexcomTM G5 sensor, by using the assessment forms

on the use of the pump and sensor (see appendix).

Before the start of the two treatment sessions, patients will complete a “baseline”

questionnaire (see appendix) concerning their usual treatment with their external insulin

pump.

The following data will be collected:

- Demographic data (DOB, gender, family status, occupational category)

- Clinical examination (weight, height, BMI, waist circumference, SBP, DBP)

- Disease history (biological parameters, diabetes complications)

- Current treatment (insulin type and dose, basal rate)

- Glycemic targets

- FIT: portion units morning noon and evening

- Concomitant treatments

- Pregnancy test.

- HbA1c (on file if 4 months otherwise a blood sample assay)

VI.3. Pilot study (visit V1bis)

The objectives of this sub-study are:

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1. Optimize the algorithm's self-learning by evaluating the convergence of "real-

life" parameters with patient data from several weeks.

2. Experimentation with the manual "adjustments" of the "aggressiveness of the

algorithm" accessible to caregivers and / or patients

3. Check the operation of the remote monitoring system

Evaluation criteria:

1. Time spent in hypoglycemia (<50 mg/dl, <70 mg/dl), time spent in

hyperglycemia, comparison of patient parameters at the beginning and end of

closed loop therapy.

2. Operation of the platform: doctor / patient connection, synchronization of

patient data, data display, alarm transmission / reception ...

This sub-study will be conducted only at the University Hospital of Grenoble and at the Hospital Center Sud-Francilien for a period of 3 to 4 weeks at home with 6 to 8 patients (3 to 4 patients per center) recruited for the closed loop / open loop crossover trial who would like to participate in the pilot study. The six to eight patients will be equipped with a new Dexcom G5 sensor and a CellNovo

insulin pump driven by a Smartphone (Android) in which the Diabeloop algorithm is

integrated.

The doses of insulin prescribed by the Diabeloop algorithm will be administered to the patient

automatically via the pump controlled by the Smartphone. Patients will be followed by a

health care team 24 hours a day via the "myDiabeloop.fr" platform as well as a team of

engineers in case of technical problems.

At the end of the pilot study, an exploratory analysis of efficacy and safety will be carried out.

A full report will be submitted to the DSMB to review the benefit / risk ratio prior to the start of

the closed loop at the other centers.

The pilot study comprises four visits: Visit A, Visit B, Visit C, Visit D

1. Visit A

Visit A is the pilot study start visit. It will take place 1 to 2 weeks after the inclusion visit.

The patient will be equipped with the Diabeloop closed loop system by the healthcare team

during a conventional hospital stay of 48 to 72 hours depending on the specific needs of the

patient. During this period of hospitalization, the healthcare team, in collaboration with the

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engineers, guarantees and validates the patient's ability to manage his Diabeloop system on

a daily basis.

Diabeloop engineers provide, in person or by telephone, at the request of the study center, the initial technical training of the patient (explanation of the handling of the pump, the Smartphone and the sensor, use of consumables, what to do in case of alarms, etc.), prior to hospitalization. This makes it possible to familiarize the patient upstream with the system, to answer questions and address possible apprehensions. This initial technical training, prepared by a delivery of the Diabeloop user manual, to assess

the patient's ability to manage his treatment autonomously, is reviewed with the engineer

during hospitalization and before discharge, in collaboration with the hospital team.

At the end of the hospitalization, the healthcare team gives the necessary consumables to the patient for a period of three or four weeks and a data collection booklet. Medical, paramedical and technical assistance are set up via remote monitoring for:




- Technical and safety monitoring.

A phone call from the healthcare team will be made within 48 hours after the start of the pilot study at

home to make sure the patient does not encounter any particular problems.

The patient is seen by his healthcare team at the study center, the first week after leaving the hospital,

then the second week and the 3rd or 4th week after leaving the hospital for the end of the pilot study.

During visit A, the healthcare team:

- Uploads the data from the pump and Dexcom sensor.

- Optimizes the patient’s treatment with these data, to test the Diabeloop system.

- Provides initial training to the patient on the use of the closed loop system with the

Diabeloop application, the DexcomTM G5 application and the Cellnovo pump.

- Assesses the patient’s ability to manage his treatment with the system, by filling out the

assessment form on the use of the system (appendix).

- Equips the patient with the Diabeloop system for a period of 4 weeks at home.

- Gives the patient the data collection booklet and consumables for each prototype.

2. Visit B

Visit B will take place 1 week after the end of visit A and will last about 1 hour.

The patient comes to the study center to optimize his treatment with the healthcare team based

on the data obtained during the previous week and according to his needs. The use of the

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system will be reviewed with the patient to make sure of his ability to manage his treatment

with the new system.

3. Visit C

Visit C will take place 1 week after visit B and will last about 1 hour.

The patient comes to the study center to optimize his treatment with the healthcare team if

necessary. The use of the system will again be reviewed.

4. Visit D

Visit D will take place no later than 2 weeks after visit C and will last about 1 hour.

The patient comes to the study center for the end of the pilot study. The healthcare team

uploads the data from the Cellnovo pump, Dexcom CGM and algorithm.

At the end of the pilot study, after the exploratory analysis of efficacy and safety and the

DSMB opinion, if readjustments to the algorithm are deemed necessary for the system to

work properly, a request for a substantial amendment will be submitted to ANSM before

continuing the trial. The substantial amendment authorization application dossier will contain

the tests performed in case of modification of the algorithm, the DSMB opinion, and the

conclusions of the exploratory analysis and their analysis.

In the event that, at the end of the pilot study, no modification is to be made and no additional

tests are required, the sponsor will inform ANSM accordingly.

5. Practical implementation of the settings

After their inclusion in the study, patients will receive initial training on the general handling of the

Diabeloop system, based on information provided by the caregivers and Diabeloop engineers and the

documents given to them. Configuration of the system will be done as follows:

1. Actual practical training will begin during their hospitalization for the start of the study. After

equipping patients with the Diabeloop system, the proper functioning of the system will be

assessed several times a day by:

a. Examination of the blood glucose curves

b. Automatic measurements of time spent in normo-, hyper- and hypoglycemia during

the previous hours, and automatic measurements of average blood glucose

Caregivers have permanent access to the blood glucose curves and to these measurements via

the remote monitoring system “MyDiabeloop “. Patients also have permanent access to their

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blood glucose curves on the screen of their dedicated smartphone. According to these results,

it will be decided to maintain the “normal” configuration or to change it and then reevaluate it

in the next few hours or day. Discharge of the patient on the 2nd or 3rd day of hospitalization

will be decided according to the results obtained.

2. Thereafter, at home, the same procedure will be monitored remotely on a daily basis via the

“Mydiabeloop” platform:




If a new setting seems useful, the caregiver will contact the patient to have him input the new

setting via his dedicated smartphone terminal. This monitoring will be carried out by the

nursing team of the national remote monitoring platform centralized at Centre Hospitalier Sud

Francien (study coordination center) in coordination with the medical teams at each study

center.

This daily monitoring can also include at any time the analysis of any Secured Information

Messages (SIM) and their solutions through direct telephone contact with the patient.

3. At each study visit, the investigator will carry out the same procedure to evaluate glycemic

data and settings.

VI.4. Randomization visit (V2)

The randomization visit will take place 1 to 3 days after the end of the run-in period (at least 1

to 3 days after visit D for patients who participated in the pilot study).

Patients with the ability to manage their daily treatment with CGM data and the Cellnovo

pump will be able to test the closed loop and the open loop. Otherwise the included patients

will be considered as a screen failure.

Patients will come to the study center to find out the order of the tests. The investigator will randomize patients via the electronic CRF (Case Report Form) into 2 arms:

- Arm 1: The patient will be closed loop in the 1st period and open loop in the 2nd period.

- Arm 2: The patient will be in open loop in the 1st period and closed loop in the 2nd

period.

The randomization will be stratified by center.

VI.5. Visits 3 (Start of 1st treatment period)

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a. Closed loop treatment period

(Arm 1):

Patients in arm 1 will be in closed loop for the 1st treatment period. Visit 3 will take place 1 to

15-30 days maximum after the randomization visit.

For the treatment period with the Diabeloop closed-loop system, the patient will be equipped with a

DexcomTM G5 glucose sensor, a smartphone with a Diabeloop application for automatic prescriptions

(basal and bolus) sent to the Cellnovo pump which delivers insulin continuously.

The patient will be admitted to the study center on D1 to test the Diabeloop home system for a period

of 12 weeks. As the patient will be in a closed loop, set-up of the Diabeloop system will be carried out

during a conventional hospitalization of 24h including overnight or 48h according to the specific needs

of each patient. As far as possible, we will try to start patients in arm 1 from a same center at

the same time during a conventional hospitalization, so as to promote group dynamics.

During this period of hospitalization, the healthcare team, including as far as possible one of the

nurses who will perform the remote monitoring, and in collaboration with the engineers if necessary,

guarantees and validates the patient's ability to manage his Diabeloop system on a daily basis.

Diabeloop engineers will provide, at the request of the study center, the initial technical training of the

patient (explanation of the handling of the pump, the smartphone and the sensor, use of consumables,

action to be taken in case of alarm, etc.), prior to hospitalization, either by telephone or face-to-face

during the inclusion or randomization visit. This makes it possible to familiarize the patient upstream

with the system, to answer questions and address possible apprehensions.

This initial technical training to evaluate the patient's ability to manage his treatment autonomously, is

reviewed during hospitalization and before discharge, in collaboration with the hospital team. This will

be assessed by using the assessment forms (see appendix).

At the end of the hospitalization, the health care team gives the necessary consumables to the patient for a period of three months and a data collection booklet. Medical, paramedical and technical assistance are set up via remote monitoring for:




▪ Technical and safety monitoring.

A phone call from the healthcare team will be made within 48 hours after the start of the home study

to make sure the patient does not encounter any particular problems.

The patient is reviewed by his or her study team, 1 week after leaving the hospital, 2 weeks later and

every 3 weeks until the end of the session.

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Data collected:

- HbA1c

- Pregnancy test

The healthcare team gives the patient the data collection booklet

b. Open loop treament period (Arm

2):

Patients in arm 2 will be in open loop for the 1st treatment period.

The open loop system consists of the patient’s usual insulin pump preprogrammed with the

patient’s usual treatment previously prescribed by the doctor. The patient will be equipped

with a DexcomTM G5 CGM for continuous interstitial glucose measurements.

The open loop start visit, visit 3, will take place 1 to 3 days after visit 2 and will last about 1

to 2 hours. The patient will be admitted to the study center on D1 for a 12-week session at home with

his usual treatment programmed into his external insulin pump combined with the DexcomTM G5 CGM.

The healthcare team guarantees and validates the patient's ability to manage his treatment with the

CGM on a daily basis (see assessment form in the appendix). She gives the necessary supplies to

the patient for a period of three months and a data collection booklet.

The patient is reviewed by the healthcare team at the study center 1 week after this visit, then

two weeks later and every 3 weeks until the end of the session.

Data collected:

- HbA1c

- Pregnancy test

The healthcare team gives the patient the data collection booklet.

VI.6. Visit 4

Closed loop treatment period (Arm 1)

Visit 4 will take place 1 week after the end of visit 3 and will last about 1 hour.

The patient in closed loop comes to the study center to optimize his treatment with the

healthcare team based on the data obtained during the previous week and according to his

needs. An exercise on the use of the system will be proposed to the patient to make sure of his

ability to manage his treatment autonomously.

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Open loop treatment period (Arm 2)

Visit 4 will take place 1 week after the end of visit 3 and will last about 1 hour. This will be a

face-to-face visit with patient.

An exercise on the use of the Dexcom G5 system will be proposed to the patient to make sure

of his ability to manage his treatment autonomously.

VI.7. Visit 5


Visit 5 will take place 2 weeks after visit 4 and will last about 1 hour.

The patient comes to the study center to optimize his treatment with the healthcare team if

necessary and to upload data from the Cellnovo pump, Dexcom CGM and algorithm. An

additional exercise on the use of the system will be proposed.



The patient comes to the study center, for an additional exercise on the use of the system and

also to upload the data from the Dexcom CGM.

VI.8. Visit 6



The patient comes to the study center to upload the data from the Cellnovo pump, Dexcom

CGM and algorithm if applicable. An additional exercise on the use of the system and an

optimization of the treatment will be proposed if necessary.



The patient comes to the study center to upload the data from the Dexcom CGM. An

additional exercise on the use of the system will be proposed if necessary.

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VI.9. Visit 7

A. Closed loop treatment period (Arm 1)


The patient comes to the study center to upload the data from the Cellnovo pump, Dexcom

CGM and algorithm if applicable. An additional exercise on the use of the system and an

optimization of the treatment will be proposed if necessary.

The patient will be asked to fill out a booklet with the number of sugarings during the last

week (week 12) of the treatment session.

The healthcare team gives the patient a survey booklet on snacks and sugaring that the patient

will fill out for 5 days during the last week of the period.

A. Open loop treatment period (Arm 2)




The patient will be asked to fill out a booklet with the number of sugarings during the last

week (week 12) of the treatment session.



VI.10. Visit 8 (End of 1st treatment period)


Visit 8 will take place 8 weeks after visit 7 and will last about 1 to 2 hours.

The patient comes to the study center for the end of the first treatment period. He will be

asked to fill out a satisfaction questionnaire and visual analogue scales (VAS).

The healthcare team will:

- Upload data from the Cellnovo pump, Dexcom CGM and algorithm.

- Remove the Diabeloop system.

- Recover the data booklets filled out by the patient

- Assay HbA1c.

Patients will keep the DexcomTM G5 CGM and take back their usual pump throughout the

duration of the wash-out period (8 weeks minimum).

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The patient comes to the study center for the end of the first treatment period. He will be

asked to fill out a satisfaction questionnaire and visual analogue scales (VAS).


- Upload data from the Dexcom CGM


- Assay HbA1c.

Patients will keep the DexcomTM G5 CGM and their usual pump throughout the duration of

the wash-out period (8 weeks minimum).

VI.11. Practical implementation of the settings

After their inclusion in the study, patients will receive initial training on the general handling of the

Diabeloop system, based on information provided by the caregivers and Diabeloop engineers and the

documents given to them. Configuration of the system will be done as follows:

1. Actual practical training will begin during their hospitalization for the start of the study. After

equipping patients with the Diabeloop system, the proper functioning of the system will be

assessed several times a day by:




Caregivers have permanent access to the blood glucose curves and to these measurements via

the remote monitoring system “MyDiabeloop “. Patients also have permanent access to their

blood glucose curves on the screen of their dedicated smartphone. According to these results,

it will be decided to maintain the “normal” configuration or to change it and then reevaluate it

in the next few hours or day. Discharge of the patient on the 2nd or 3rd day of hospitalization

will be decided according to the results obtained.

4. Thereafter, at home, the same procedure will be monitored remotely on a daily basis via the

“Mydiabeloop” platform:




If a new setting seems useful, the caregiver will contact the patient to have him input the new

setting via his dedicated smartphone terminal. This monitoring will be carried out by the

nursing team of the national remote monitoring platform centralized at Centre Hospitalier Sud

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Francien (study coordination center) in coordination with the medical teams at each study

center.

This daily monitoring can also include at any time the analysis of any Secured Information

Messages (SIM) and their solutions through direct telephone contact with the patient.

5. At each study visit, the investigator will carry out the same procedure to evaluate glycemic

data and settings.

VI.12. Wash-out period

A wash-out period of at least 8 weeks is planned between the two treatment sessions (between

visit 8 and visit 9). It will take place immediately after visit 8. Patients will keep the

DexcomTM G5 CGM and their usual insulin pump.

VI.13. Visits 9 (Start of 2nd treatment period)

Visit 9 will take place after the wash-out period.

c. Open loop treatment period

(Arm 1)

Patients in arm 1 will be in open loop for the 2nd treatment session.

Visit 9 will last 1 to 2 hours. The patient will be admitted to the study center on D1 for a second 12-

week session at home with his usual treatment programmed into the usual external insulin pump

combined with the DexcomTM G5 CGM. A practical exercise will be proposed to the patient if

necessary. An assay of HbA1c and a pregnancy test, where applicable, will be done at this

visit.

The healthcare team guarantees and validates the patient's ability to manage his treatment with the

Dexcm G5 CGM on a daily basis (see assessment form in the appendix). She gives the necessary

supplies to the patient for a period of 12 weeks.

The patient is seen by the healthcare team at the study center 1 week after this visit, then two

weeks later and every 3 weeks until the end of the session.

The healthcare team gives the patient a data collection booklet.

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d. Closed loop treatment period

(Arm 2)

Patients in arm 2 will be in closed loop for the 2nd treatment session.

Before the start of the 2nd treatment period with the Kaleido pump, the Clinical Research

Associates will visit the study centers for an information session on the use of the Kaleido

patch pump: handling of the pump, use of consumables, action to be taken in case of alarms,

and to describe all the technical and practical features of the Kaleido patch pump and the

Diabeloop system as a whole.

Study centers will contact their respective patients in order to:

- Schedule the appointment for visit 9;

- Tell the patients about the new Kaleido patch pump and explain its use;

- The engineers will provide additional information on the patch pump and/or Diabeloop

system at the request of the study center;

- Inform patients that a sample will be taken at visit 9 to measure HbA1c and that they

will receive practical training during their hospitalization.

At visit 9, the patient will be admitted to the study center on D1 of the 2nd session to test the Diabeloop

home system with the Kaleido pump for a period of 12 weeks. Set-up of the Diabeloop system will be

carried out during a conventional hospitalization of 48h according to the specific needs of each patient.

During this period of hospitalization, the patient will receive training on the Diabeloop system

consisting of the terminal, the Dexcom sensor and the Kaleido pump.

The healthcare team, in collaboration with the engineers, guarantees and validates the patient's ability

to manage his Diabeloop system on a daily basis.

The patient's ability to manage his treatment will be assessed by using the assessment forms (see

appendix).

A phone call from the health care team will be made within 48 hours after the start of the home study

to make sure the patient does not encounter any particular problems.

At the end of the hospitalization, the healthcare team gives the necessary consumables to the patient

for a period of three months, a data collection booklet and the user manual version 8 of 26/10/2017.

Medical, paramedical and technical assistance are set up via remote monitoring for:




▪ Technical and safety monitoring.

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The patient is seen by his or her study team, 1 week after leaving the hospital, 2 weeks later and every

3 weeks until the end of the session.

Data collected:

- HbA1c

- Pregnancy test

VI.14. Visit 10

Open loop treatment period (Arm 1):

Visit 10 will take place 1 week after visit 9 and will last about 1 hour. This will be a face-to-

face visit with the patient. An exercise on the use of the DexcomTM G5 system will be

proposed to the patient to make sure of his ability to manage his treatment autonomously.

Closed loop treatment period (Arm 2):

Visit 10 will take place 1 week after the end of visit 9 and will last about 1 hour.


healthcare team based on the data obtained during the previous week and according to his

needs. An exercise on the use of the system will be proposed to the patient to make sure of his

ability to manage his treatment autonomously.

VI.15. Visit 11



The patient comes to the study center, for an additional exercise on the use of the system and

also to upload the data from the Dexcom CGM.




healthcare team if necessary and to upload data from the Kaleido pump, Dexcom CGM and

algorithm. An additional exercise on the use of the system will be proposed.

VI.16. Visit 12

A. Open loop treatment period (Arm 1):


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B. Closed loop treatment period (Arm 2):


The patient comes to the study center to upload the data from the Kaleido pump, Dexcom

CGM and algorithm. An additional exercise on the use of the system and an optimization of

the treatment will be proposed if necessary.

VI.17. Visit 13






will fill out for 5 days during the last week of the period


Visit 13 will take place 3 weeks after visit 12and will last about 1 hour.

The patient comes to the study center to upload the data from the Kaleido pump, Dexcom

CGM and algorithm. An additional exercise on the use of the system and an optimization of

the treatment will be proposed if necessary.



VI.18. Visit 14 (End of study)

A. Open loop treatment period (Arm 1):


The patient comes to the study center for the end of the 2nd treatment session and the end of

the study. He will be asked to fill out a satisfaction questionnaire and visual analogue scales

(VAS).


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- Upload data from the Dexcom CGM.

- Remove all study devices.


- Assay HbA1c

B. Closed loop treatment period (Arm 2):


The patient comes to the study center for the end of the 2nd treatment session and the end of

the study. He will be asked to fill out a satisfaction questionnaire and visual analogue scales

(VAS).


- Upload data from the Kaleido pump, Dexcom CGM and algorithm.

- Remove all study devices.


- Assay HbA1c

Also, at the end of the clinical study, the patient will transition to his usual insulin pump with

the same basal rates as those administered on the last day of the open loop treatment period.

VI.19. Visit schedule Arm 1

Visit Description Date of

visit

Duration

PRE-SCREENING Visit 0

(during

a usual

medical

visit)

Pre-

screening visit:

information

notice given to

patient

-1 to -7 days

before visit

V1

INCLUSION AND

RUN- IN PERIOD


Signature of

informed

consent, HbA1c

(from patient’s

file if 4


of 145


months),

pregnancy test.

Installation and

training on CGM

and Cellnovo

pump for 2-week

run-in period.

Evaluation of

patient’s ability

to manage

treatment with

the Cellnovo and

Dexcom G5.

« Baseline »

satisfaction

questionnaire.

PILOT STUDY

Visit A

(Only

concerns

CHSF

and

Grenoble

CHU)

Pilot study:

Initial training on

the Diabeloop

system.

Installation of

system for 4 to 6

weeks

1 to 2 weeks

after visit 1

Conventional hospitalization of 48 to

72 hours


treatment with

Diabeloop

system according

to patient’s

needs. Review

use of system

with the patient.

1 week after

visit A

1 hour


treatment if

necessary.

Review use of

system with the

patient.

1 week after

visit B

1 hour


pump, CGM and

2 weeks

maximum

1 hour

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algorithm. after visit C

RANDOMIZATION

Visit 2 Randomization

visit for patients

with the ability

to manage their

treatment with

the Cellnovo

pump and

Dexcom G5.

Diabeloop

system user

manual given to

patients

assigned to arm

1 and telephone

exchanges with

the engineers if

necessary.

Patients will

keep the

Cellnovo pump

and Dexcom

sensor. HbA1c

(if HbA1c at V1

≥ 3 months)

2 weeks

after visit 1

[at least 1 to

3 days after

visit D for

patients who

participated

in the pilot

study]

1 hour

ARM 1

CLOSED LOOP


the Diabeloop

system.

Installation of

system and

practical

exercises.

Evaluation of

patient’s ability

to manage

treatment.

Pregnancy test,

HbA1c. Data

collection

booklet given to

1 to 15-30

days

maximum

after visit 2

Conventional hospitalization of 24 to

48 hours

of 145


patient.


treatment if

necessary.

Review use of

system with the

patient.

1 week after

visit 3

1 hour


treatment if

necessary.

Upload data from

pump and CGM.

2 weeks

after visit 4

1 hour

Visite 6 Upload data from

pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary.

3 weeks

after visit 5

1 hour


pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary. Give

patient survey on

snacks+sugarings

to fill out in last

week at end of

session.

3 weeks

after visit 6

1 hour

Visit 8 End of closed

loop. Satisfaction

questionnaire

filled out. Data

collection

booklet

recovered.

3 weeks

after visit 7

1 to 2 hours

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Upload data from

pump, CGM and

algorithm.

Remove

Diabeloop

system. Patients

will keep the

CGM for the

wash-out period.

HbA1c


Patients will

keep the Dexcom

G5 CGM and

take back their

usual pump.

Immediately

after visit 7

8 weeks minimum

OPEN LOOP


system and

practical

exercises.

Pregnancy test,

HbA1c. Data

collection

booklet given to

patient.

8 weeks

after end of

visit 8

1 to 2 hours

Visit 10

Face-to-

face visit

Review use of

Dexcom CGM

with the patient.

1 week after

visit 9

1 hour


CGM. Review

use of Dexcom

CGM with the

patient

2 weeks

after visit 10

1 hour


CGM. Review

use of open loop

system.

3 weeks

after visit 11

1 hour

Visit 13 Upload data

from CGM.

3 weeks

after visit 12

1 hour

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Review use of

open loop

system. Give

patient survey on

snacks+sugarings

to fill out in last

week at end of

session.

Visit 14 End of open

loop.

HbA1c.

Satisfaction

questionnaire

filled out. Data

collection

booklet

recovered.

Upload data from

CGM. Remove

all study medical

devices

3 weeks

after visit 13

1 hour

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VI.20. Visit schedule Arm 2


PRE-SCREENING Visit 0 (during a

usual medical

visit)


information notice

given to patient


visit V1

INCLUSION AND

RUN- IN PERIOD


Signature of

informed consent,

HbA1c (from


months), pregnancy


training on CGM

and Cellnovo pump

for 2-week run-in

period.

Evaluation of


manage treatment

with the Cellnovo

and Dexcom G5.

« Baseline »

satisfaction

questionnaire.


PILOT STUDY

Visit A (Only

concerns CHSF and

Grenoble CHU)

Pilot study: Initial

training on the

Diabeloop system.

Installation of

system for 4 to 6

weeks. Data

collection booklet

given to patient

1 to 2 weeks after

visit 1

Conventional

hospitalization

of 48 to 72

hours


treatment with

Diabeloop system

according to


1 hour

of 145


patient’s needs.

Review use of

system with the

patient.


treatment if

necessary. Review

use of system with

the patient.



pump, CGM and

algorithm.

2 weeks maximum

after visit C

1 hour

RANDOMIZATION

Visit 2 Randomization visit

for patients with the

ability to manage

their treatment with

the Cellnovo pump

and Dexcom G5.

Patients will keep

the Dexcom sensor

and take back their

usual pump.

HbA1c (if HbA1c ≥

3 months at V1)


[1 to 3 days after

visit D for patients

who participated in

the pilot study]

1 hour

ARM 2

OPEN LOOP



exercises.

Pregnancy test,

HbA1c. Data

collection booklet

given to patient.

1 to 3 days after

visit 2

1 to 2 hours

Visit 4

Face-to-face visit

Review use of usual

pump and Dexcom

CGM system with

the patient.



CGM. Review use

of usual pump and

Dexcom CGM


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system with the

patient


CGM. Review use

of the open loop

system.



CGM. Review use

of the open loop

system. Give patient

survey on

snacks+sugarings to

be filled out during

last week at end of

session.



HbA1c.

Satisfaction



booklet recovered.

Upload data from

CGM. Remove all

study medical

devices. Diabeloop

system user manual

given to patients

assigned to arm 2

for the 2nd period in

CL and telephone

exchanges with the

engineer if

necessary.



Patients will keep

their usual pump and

Dexcom G5 CGM.

Immediately after

visit 7

8 weeks

minimum

CLOSED LOOP


the Diabeloop

system and Kaleido

8 weeks after visit 8 Conventional

hospitalization

of 48 hours

of 145


pump. Installation of


exercises.

Evaluation of


manage treatment.

Pregnancy test,

HbA1c

Data collection

booklet and user

manual V8 of

26/10/2017given to

patient.


treatment if

necessary. Review

use of system with

the patient.



treatment if

necessary.

Upload data from

pump and CGM.

2 weeks after visit

10

1 hour


pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary.

3 weeks after visit

11

1 hour


pump and CGM.

Review use of

system with the

patient.

Optimization of

treatment if

necessary. Give

patient survey on

3 weeks after visit

12

1 hour

of 145


snacks+sugarings to

be filled out during

last week at end of

session

Visit 14 End of study and

end of closed loop.

Satisfaction



booklet recovered.

Upload data from

pump, CGM and

algorithm. Remove

Diabeloop system.

Patients will keep

the CGM and pump

for the wash-out

period.

HbA1c

3 weeks after visit

13

1 to 2

hours

VI.21. Procedure for situations requiring a capillary glucose

measurement

Patients will be required to take a capillary glucose measurement in some specific situations:

- During the first 12 hours after initiating the closed loop, patients will be have to take a

capillary glucose measurement when they wake up, before and after each meal, and at

bedtime.

- Patients will be advised that paracetamol must not be taken during the entire duration of

the study. They will be given a list of medicines that contain paracetamol. However, in

the event that this occurs by mistake, they will be instructed to

o transition to manual control of the pump for 6 hours,

o measure capillary glucose 2 hours and 4 hours after taking paracetamol.

- If the patient gets symptoms of hypoglycemia, despite an interstitial glucose

measurement greater than 80 mg/dL, they must take a capillary glucose measurement.

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- If interstitial glucose value is still below 80 mg/dl 20 minutes after a sugaring, the

patient must take a capillary glucose measurement.

- If interstitial glucose value is still above 250 mg/dl 2 hours after a bolus dose of insulin,

the patient must take a capillary glucose measurement.

VI.22. Action to take in case of ketosis

When fasting blood glucose is > 2.80 g/l with no obvious explanation, the patient must use a

test strip for acetonemia (plasma test strip) or ketonuria (urine test strip).

➢ In the absence of acetone (urine or blood) the patient will be instructed to use his

simple compensation (= correction) algorithms.

➢ Acetonemia or acetonuria occurring in a context of a capillary glucose value > 2.80 g/l

means there is ketosic decompensation. Insulin must be added (with an injection pen

until the infusion set of the pump has been checked and/or changed), in the following

manner:

Example for a urine test strip

+ + 5 units of insulin

+ + + 10 units of insulin

+++ + 15 units of insulin

For plasma acetone test strips

< 0.6 mmol/L traces

0.6 to 1.5 mmol/L + + 5 units of insulin

1.5 to 3 mmol/L ++ + 10 units of insulin

> 3mmol/L +++ + 15 units of insulin

In both cases, blood glucose should be checked 2 hours later and then monitoring should be

continued in the same way until normalization of blood glucose values.

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VI.23. Study flowchart

Arm 1 Arm 2

Recruitment & consent

HbA1c assay + Creatinine + Baseline

satisfaction questionnaire

2 week run-in period

Initial training on use of CGM and pump

Evaluation of patient

Optimization of treatment with pump + CGM

Patient compliance

Randomization HbA1c at start of 1st

period

Treatment period

Closed loop 12 weeks

Diabeloop system

Treatment period

Open loop 12 weeks


Treatment period

Open loop 12 weeks


Questionnaire + VAS HbA1c at end of 1st period

Wash-out period 8 weeks minimum

Patients equipped with their usual

pump +CGM

Treatment period

Closed loop 12 weeks Diabeloop system with Kaleido pump

HbA1c at

start ane

end of

2nd

period

End of study

Satisfaction questionnaire + VAS

Final data analysis

Preliminary analysis

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VII DATA CAPTURE AND HANDLING

VII.1. Data capture

All information required by the protocol must be provided in the case report form (eCRF)

which allows real-time quality control of data by a clinical research associate.

The CRO designated by the sponsor for the electronic case report form is Clininfo in

Lyon, which provides CERITD with the eCRF together with supporting data management

software (error detection, missing forms, traceability, corrections, etc.). This electronic case

report form also allows very accurate monitoring of inclusions and thus an end-of-study

management and an improvement in data quality.

By agreeing to participate, the investigator undertakes to strictly comply with the study

protocol, Good Clinical Practice and the legislation in force. The investigator vouches for the

authenticity of the data collected in the study and accepts the legal provisions allowing the

study sponsor to set up a data quality control.

Data must be entered in the eCRF as they are obtained. Each missing data must be

justified.

The statistical analysis will only be carried out after verifying data input and coherence.

Data will be archived by the sponsor.

Patients in the study will be identified by their number and their initials on all study

documents. Named data on copies of source documents intended for study documentation will

be anonymized by appropriate means.

VII.2. Data monitoring

This trial will be monitored by a Clinical Research Associate mandated by CERITD, to

ensure the collection of accurate, complete and reliable data and compliance with Good

Clinical Practice and to provide logistical support to study centers.

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VII.3. DATA ANALYSIS

After validation of the data, the database will be frozen and sent to the company RCTs in

charge of the statistical analysis.

VIII STATISTICAL ANALYSIS PLAN

VIII.1. Statistical analysis methodology

A detailed statistical analysis plan will be drawn up before freezing the database and will

be validated by the study sponsor and the principal investigator.

Analysis sets:

• Safety set: all randomized patients who were exposed at least once during the study

• Efficacy set (modified ITT population): all randomized patients who completed the

two evaluation sessions (open loop and closed loop).

General points relating to the descriptive analyses:

All endpoints will be analyzed descriptively by session (closed loop and open loop) using the

following statistics:

• for quantitative variables: number of missing values, non-missing values, mean, standard

deviation, median, 1st quartile, 3rd quartile, minimum and maximum.

• for qualitative variables: number of missing values, non-missing values, frequencies,

percentages for each modality (excluding missing data from the denominator).

VIII.1.a. Analysis of the primary objective

The analysis will be performed on the modified ITT population.


provides superior glucose control than usual insulin pump therapy over a 12-week period.

The primary endpoint will be the time spent in the 70/180 mg/dl target measured continuously for 12

weeks with the Dexcom™ G5 CGM.

The null hypothesis tested will be: absolute intra-patient variation between the percentage of time

spent in the glycemic intervals closed loop - open loop = 0.

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The comparison of the 2 sessions will be carried out for the continuous variables using an

analysis of variance model for cross-over design (subject to compliance with the application

conditions), including the HbA1c value at the start of each period as adjustment variable. The

measurement allowing the evaluation of the primary endpoint is provided by the DexcomTM

G5 continuous glucose monitoring system, in the two situations tested: open loop and closed

loop.

In the first situation, the interstitial glucose values are transmitted to the receiver of the

DexcomTM G5 system and in the second situation, the interstitial glucose values are

transmitted to the Smartphone of the Diabeloop system, which can generate orders as a

function of these data.

This is the currently recognized and widely used tool in all artificial pancreas studies. Other

continuous glucose monitors (Abbot and Medtronic) can also be used.

A descriptive analysis of the data will also be performed for the different periods of the

crossover and for the different sequences.

VIII.1.b. Analysis of secondary objectives

The analysis will be performed on the modified ITT population.

Comparison of quantitative variables will be carried out with an analysis of variance model

for crossover design (subject to compliance with the application conditions), including

including the HbA1c value at the start of each period as adjustment variable.

For binary variables the two sessions will be compared with a conditional logistic regression

model including including the HbA1c value at the start of each period as adjustment

variable.

VIII.1.c. Preliminary analysis

In order to be able to have safety data as soon as possible, a preliminary analysis will

be conducted after the 1st cross-over period, i.e., in a parallel plan situation (closed

loop vs. open loop).

This analysis will be performed on the safety analysis set.

The criterion used for the preliminary analysis will be the time spent in hypoglycemia < 70

mg/dl.

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The null hypothesis of non-inferiority to be tested will be: variation (closed loop – open loop)

in percentage of time spent in hypoglycemia < 70 mg/dl ≥ ∆ (non-inferiority margin set at Δ

= 2.5% – as per the Scientific Committee).

An approach using a two-sided 95% confidence interval will be carried out based on the

analysis of variance model including the HbA1c value at the start of each period as

adjustment variable:

If the upper boundary of the two-sided 95% confidence interval (closed loop – open loop) is <

∆, the null hypothesis will be rejected in favor of the alternative hypothesis of non-inferiority

of the closed loop versus open loop.

If the upper boundary of the two-sided 95% confidence interval (closed loop – open loop) is <

∆ and < 0, a statistically significant difference will be demonstrated in favor of the closed

loop at a level of significance α = 0.05 (as per EMA guideline

(http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC

500003658.pdf). The level of significance will be obtained with the same analysis of variance

model.

The two groups will also be compared on the criterion of time spent in the 70 / 180 mg/dl

target using an analysis of variance model including the HbA1c value at the start of each

period as adjustment variable.

In addition to the statistical analysis on these criteria, a descriptive analysis will be performed

on the inclusion data and on the main evaluation parameters of the two groups after 12 weeks.

The results will be examined by the DSMB which can stop the study if this preliminary safety

and efficacy assessment is not conclusive.

VIII.1. d. Analysis of the pilot phase

The efficacy and safety data collected on the first 8 patients in closed loop will be examined

by the DSMB to determine whether modifications of the algorithm are necessary. In that case

an authorization application for a substantial amendment will be submitted to ANSM.

VIII.1.e. Conclusion of the study

The study will be considered positive if the following two hypotheses are demonstrated:

• Superiority of the closed loop versus open loop on time spent in the 70-180 mg/dl

target measured continuously for 12 weeks with the Dexcom ™ G5 CGM.

http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003658.pdf

http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003658.pdf

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• Non-inferiority of the closed loop versus open loop on the time spent in hypoglycemia

< 70 mg/dl measured continuously for 12 weeks with the Dexcom ™ G5 CGM.

VIII.2. Calculation of sample size

Justification of the number of subjects necessary for the primary objective of the study


provides better glucose control than usual insulin pump therapy over a 12-week period. The primary

endpoint will be the time spent in the 70/180 mg/dl target measured continuously for 12 weeks with

Dexcom ™ G5 CGM.

The results on these criteria obtained in study SP6.2 are summarized in the following table, in

each of the three test situations (sedentarity, exceptional meals, physical activity). Powers

were calculated in each situation for N=50 patients analyzed, with alpha risk=0.05, two-sided

situation.

% of time spent in 70 / 180 mg/dl target

Sedentarity group SP6.2

Exceptional meals group SP6.2

Physical activity group SP6.2

Situation Two-sided Two-sided Two-sided

Alpha 0.05 0.05 0.05

Closed loop 77.8% 80.5% 80.2%

Open loop 71.5% 54.3% 64.2%

Standard deviation 12.4% 17.8% 15.3%

Correlation 0.5 0.5 0.5

Number of patients 50 50 50

Power* 94% >99.9% >99.9% * : power calculations performed with SAS Power & Sample Size 3.1

A sample of 50 evaluable patients would be able to show, regardless of the situation of the

patient, a difference between the two groups with a statistical power greater than 94%.

Verification of statistical power for the preliminary analysis:

In order to be able to have safety data as soon as possible, a preliminary analysis will

be conducted after the 1st cross-over period, i.e., in a parallel plan situation (closed

loop vs. open loop).

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The criterion used for the preliminary analysis will be the time spent in hypoglycemia < 70

mg/dl. Non-inferiority of the closed loop versus the open loop will be demonstrated on this

criterion with a power of 96%** and the following hypotheses:

• N=25 patients / group

• First species risk α = 0.025 (one-sided situation)

• Difference closed loop – open loop = -1.5%1

• Standard deviation = 3.7%1

• Non-inferiority margin ∆ (larger loss of efficacy / safety than can be tolerated) = 2.5%

(as per the Scientific Committee considering the mean values and standard deviations

observed in study SP6.2).

1 : value observed in study SP6.2

** : power calculations performed with Nquery Advisor 4.0.

Likewise, 25 patients per group would be able to show with a statistical power of 89%* a

statistically significant difference on the criterion: time spent in 70 / 180 mg/dl target during

12 weeks, with the following hypotheses:

• First species risk α = 0.05 (two-sided situation)

• Closed loop: 78.6%2

• Open loop: 66.8%2

• Standard deviation = 12.9%2

2 : value observed in study SP6.2

* : power calculations performed with SAS Power & Sample Size 3.1

Conclusion:

In order to have at least 50 evaluable patients for the primary objective and at least 25 patients

per group for the preliminary analysis, 60 patients will be included in this study.

IX Analysis of the methodological impact of changing the Cellnovo

pump at the end of the 1st crossover period

The methodological impact of the malfunctioning of the Cellnovo pump occurs at three

levels:

1. Impact on the preliminary analysis at the end of the 1st crossover period:

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Since all patients in the closed loop group of the 1st crossover period used the Cellnovo

pump, the first expected impact is a bias in the protocol-specified preliminary analysis at the

end of the 1st crossover period, i.e., in a parallel plan situation (closed loop versus open loop).

The criterion used for this preliminary analysis will be the time spent in hypoglycemia < 70

mg/dl; the null hypothesis of non-inferiority to be tested is: variation (closed loop – open

loop) of the percentage of time spent in hypoglycemia < 70 mg/dl ≥ Δ (non-inferiority margin

Δ = 2.5% as per the Scientific Committee). Since the Cellnovo pump malfunctioning only

concerned the closed loop where this pump was used, the impact of this bias is conservative in

that it only penalizes patients in the closed loop. Thus, if the preliminary analysis leads to a

rejection of the null hypothesis and therefore a demonstration of non-inferiority of closed loop

versus open loop, this conclusion can be considered robust. Only the intensity of the observed

effect (closed loop – open loop) can be considered quantitatively biased.

2. Impact on the duration of the wash-out period:

The Cellnovo pump malfunctions will lead to the use of a different pump for the 2nd crossover

period and a wash-out period that will be extended by 1 to 3 months. In so far as all included

patients will be concerned by this extension, and hypothesizing that a 3-month wash-out will

allow a return to baseline, the extension of this wash-out period will not have an impact on the

conclusions of the study, provided that this longer wash-out does not result in an increase in

the drop-out rate. The final end-of-study analysis will include a list of patients who withdrew

from the study with the times and reasons of study withdrawal, in order to assess whether this

extension of the wash-out period had an impact.

3. Impact on the conclusions of the final analysis:

The primary objective of this final analysis is to assess whether the Diabeloop system’s

regulatory algorithm provides superior glycemic control than usual insulin pump therapy over

a period of 12 weeks. The primary endpoint is the time spent in the 70-180 mg/dl target

measured continuously for 12 weeks with Dexcom ™ G5 CGM. The null hypothesis to be

tested will be: absolute variation intra-patient between the percentage of time spent in the

glycemic intervals closed loop – open loop = 0.

Because the Cellnovo pump malfunctions occurred only in the closed loop group of the 1st

crossover period, a quantitatively larger effect is expected for patients randomized in the order

CL followed by OL, than in the sequence OL followed by CL. In other words, the expected

impact is to observe a period effect, i.e., that the closed loop – open loop effect observed in

the 1st period is quantitatively smaller than that observed in the 2nd period. If the analysis of

the period effect shows a quantitative effect, i.e., the effects observed in the two periods are in

favor of the same treatment group and do not differ in intensity, any difference observed in

favor of the closed loop group can be considered robust, because this bias has a conservative

effect, i.e., in favor of not rejecting the null hypothesis specified in the protocol. However the

possible impact in such a case could be a decrease in the expected effect of the closed loop

relative to the hypotheses used for the same size calculation, leading to a non-rejection of the

null hypothesis.

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X SAFETY ASSESSMENTS

Adverse event (Art. R.1123-46 CSP): any untoward medical occurrence in clinical

investigation subject whether or not it is related to the research or to the product which is the

subject of the research.

Should an adverse event (AE) occur, it will be recorded in the AE form of the electronic case

report form and the form will be faxed to the CERITD (Fax: 01.60.88.93.59). The CERITD

receives an instant alert by email from the eCRF as soon as such a form is filled out.

Adverse device effect (Art. R.1123-46 CSP): any untoward and unintended reaction to a

device, or any incident that could have caused a reaction if appropriate action had not been

taken, in a clinical investigation subject or in a user of the MD, or any effect related to a

defect or alteration of a IVDMD which harms the health of a research subject.

Seriousness criterion: an event/effect is serious if it meets at least one of the following

seriousness criteria:

• results in death;

• is life-threatening;

• results in persistent or significant disability/incapacity;

• requires inpatient hospitalization or prolongation of existing hospitalization;

• is a congenital anomaly/birth defect/abortion

• is considered medically important

The expected serious adverse events (SAEs) in this study are severe blood glucose

imbalance and severe hypoglycemia.

Should a serious adverse event (SAE) occur, it will be recorded in the SAE form of the

eCRF and the form will be faxed to the sponsor, CERITD within 24 hours (Fax:

01.60.88.93.59).

The CERITD receives an instant alert by email from the eCRF as soon as such a form is filled

out.

The sponsor reports the following USADEs and SAEs to ANSM (Art. R.1123-55 CSP):

▪ Suspicions of unanticipated serious adverse device effects (USADEs)

▪ IVDMD

▪ Serious AEs (SAEs) that may be related to the deployment/implementation of the MD

▪ Occurring in France or outside national territory

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USADEs and SAEs that may be related to the deployment/implementation of the MD, having

resulted in death or a life-threatening illness or injury, will be reported without delay from the

day the sponsor becomes aware of them.

In other cases the reporting time frame is 15 days.

Suspicions of unanticipated serious adverse device effects due to the medical device subject

of the research and serious adverse events likely to be related to the procedure of

implementation of the medical device subject of the research (expected and unexpected

events) will be reported by the sponsor to ANSM (French National Agency for Medicines and

Health Products Safety) and to the relevant Ethics Committee, in accordance with article

R.1123-48 of the Public Health Code.

XI - MATERIAL AND LEGAL ASPECTS

XI.1. Signed informed consent

In accordance with Good Clinical Practice and legal provisions in force, any preselected

subject will be informed beforehand by the investigator of the objectives of the study, the

study methodology, duration, constraints and foreseeable risks including if the study is

stopped early. In particular the subject will be told that he/she is entirely free to refuse to

participate in the study or to withdraw his/her consent at any time without incurring any

liability or harm thereby. A document summarizing the information provided by the

investigator will be given to the patient.

After making sure that the patient has understood the information provided, the investigator

asks the patient to provide written consent to participate in the study. If the patient accepts,

he/she will sign the informed consent form before any study procedures can begin.

XI.2. Professional secrecy, confidentiality

The investigator is bound by professional secrecy. The data collected, including the results of

the analyses, will be rendered anonymous by any appropriate means. The sponsor and its

representatives are subject to the same obligations of professional secrecy as the investigator.

This document and its appendices are given to the investigator on a confidential basis and

must only be given or disclosed to the named persons specifically involved in the trial with

the agreement or at the request of the coordinator.

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XI.3. Insurance

The CERITD is the sponsor of this research study. Pursuant to the law on biomedical research

(No. 2004-806, Art L.1121-10 CSP), the sponsor has taken out an insurance policy with

BIOMEDICINSURE for the entire duration of the research, covering its own civil liability as

well as that of any collaborator (doctor or staff involved in carrying out the research)

Company: Biomedicinsure

Address: Parc d’Innovation Bretagne Sud – CP 142

56 038 Vannes Cedex

Policy No.: 0100534514058 – 160073 - 10005

XI.4. Anonymity of study subjects

The case report form sheets will only carry the patient’s initials (first three letters of

last name and first two letters of first name) and an identification number. Only this number

will be computerized.

This study falls within the scope of the Reference Methodology (MR-001) pursuant to

the provisions of article 54 § 5 of the law of 6 January 1978 amended, relating to computer

processing, computer files and individual liberties. This change was approved by decision of 5

January 2006. CERITD, the study sponsor, signed a commitment of conformity to this

Reference Methodology on 22/10/2007, reference number 1261463.

XI.5. Quality assurance

The clinical part of the study will be conducted in accordance with Good Clinical

Practice.

XI.6. Patient compensation – Exclusion period

Compensation of patients is planned.

Subjects participating in this research study cannot simultaneously participate in other

biomedical research studies. No exclusion period is necessary after the end of this study.

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XI.7. Publications

All data collected during this study are the property of the sponsor and cannot be

communicated under any circumstances to a third party without the written permission of the

investigator.

Any publication or communication (oral or written) will be decided by mutual agreement

between the investigators and will follow international guidelines “Uniform Requirements for

Manuscripts Submitted to Biomedical Journals”

(http://www.cma.ca/publications/mwc/uniform.htm).

XI.8. Recordkeeping

All study data will be kept for a period of 15 years under the sponsor’s responsibility.

Source documents, case report forms, original copies of the informed consent forms and the

signed protocol must be kept by the investigator for a minimum of 15 years from the end of

the study.

The sponsor plans for the storage of the following documents in appropriate premises:

• Protocol with appendices, amendments.

• Case report forms (originals) with appended documents.

• Clinical study monitoring document.

• All study correspondence and administrative documents.

• Study report.

http://www.cma.ca/publications/mwc/uniform.htm

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XII - REFERENCES

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C, Avogaro A, Bruttomesso D, Filippi A, Scotton R, Magni L, Lanzola G, Di Palma F,

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http://www.ncbi.nlm.nih.gov/pubmed?term=Renard%20E%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Place%20J%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Farret%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Cobelli%20C%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Del%20Favero%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Dalla%20Man%20C%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Dalla%20Man%20C%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Avogaro%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Bruttomesso%20D%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Filippi%20A%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Scotton%20R%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Magni%20L%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Lanzola%20G%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Di%20Palma%20F%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Soru%20P%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Toffanin%20C%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=De%20Nicolao%20G%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Arnolds%20S%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Benesch%20C%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=Heinemann%20L%5BAuthor%5D&cauthor=true&cauthor_uid=24170747

http://www.ncbi.nlm.nih.gov/pubmed?term=AP@home%20Consortium%5BCorporate%20Author%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=AP@home%20Consortium%5BCorporate%20Author%5D

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infusion versus patient self-management. Diabetes Care. 2013 Dec;36(12):3882-7.

15. Phillip M, Battelino T, Atlas E, Kordonouri O, Bratina N, Miller S, Biester T, Stefanija

MA, Muller I, Nimri R, Danne T.. Nocturnal glucose control with an artificial pancreas at

a diabetes camp. N Engl J Med. 2013 Feb 28;368(9):824-33.

16. Quemerais MA, Doron M, Dutrech F, Melki V, Franc S, Antonakios M, Charpentier G,

Hanaire H, Benhamou PY; Diabeloop Consortium; Diabeloop Consortium. Preliminary

evaluation of a new semi-closed-loop insulin therapy system over the prandial period in

adult patients with type 1 diabetes: the WP6.0 Diabeloop study.Diabetes Sci Technol.

2014 Nov;8(6):1177-84)

17. Clemens AH, Chang PH, Myers RW. The development of Biostator, a Glucose Controlled

Insulin Infusion System (GCIIS). Horm Metab Res. 1977;Suppl 7:23-33

18. Shichiri M, Kawamori R, Hakui N, Yamasaki Y, Abe H. Closed-loop glycemic control

with a wearable artificial endocrine pancreas. Variations in daily insulin requirements to

glycemic response. Diabetes. 1984 Dec;33(12):1200-2.

19. Nishida K, Shimoda S, Ichinose K, Araki E, Shichiri M.What is artificial endocrine

pancreas? Mechanism and history. World J Gastroenterol. 2009 Sep 7;15(33):4105-10.

20. Renard E, Costalat G, Chevassus H, Bringer J. Artificial beta-cell: clinical experience

toward an implantable closed-loop insulin delivery system. Diabetes Metab. 2006

Dec;32(5 Pt 2):497-502

21. Hovorka R, Allen JM, Elleri D, Chassin LJ, Harris J, Xing D, Kollman C, Hovorka T,

Larsen AM, Nodale M, De Palma A, Wilinska ME, Acerini CL, Dunger DB. Manual

closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2

randomised crossover trial. Lancet. 2010 Feb 27;375(9716):743-51.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Day+and+night+closed-loop+control+in+adults+with+type+1+diabetes%3A+a+comparison+of+two+closed-loop+algorithms+driving+continuous+subcutaneous+insulin+infusion+versus+patient+self-management.

http://www.ncbi.nlm.nih.gov/pubmed/?term=Phillip%20M%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Battelino%20T%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Atlas%20E%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Kordonouri%20O%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Bratina%20N%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Miller%20S%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Biester%20T%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Stefanija%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Stefanija%20MA%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Muller%20I%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Nimri%20R%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Danne%20T%5BAuthor%5D&cauthor=true&cauthor_uid=23445093

http://www.ncbi.nlm.nih.gov/pubmed/?term=Phillip+M%2C+Battelino+T%2C+Atlas+E%2C+Kordonouri+O%2C+Bratina+N%2C+Miller+S%2C+Biester+T%2C+Stefanija+MA%2C+Muller+I%2C+Nimri+R%2C+Danne+T






http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hovorka%20R%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Allen%20JM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Elleri%20D%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Chassin%20LJ%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Harris%20J%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Xing%20D%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Kollman%20C%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Hovorka%20T%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Larsen%20AM%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Nodale%20M%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22De%20Palma%20A%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Wilinska%20ME%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Acerini%20CL%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Dunger%20DB%22%5BAuthor%5D

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XIII - APPENDICES

XIII.1. APPENDIX: SATISFACTION QUESTIONNAIRE– BASELINE

DIABETES TREATMENT SATISFACTION QUESTIONNAIRE: DTSQ

The following questions concern your current diabetes treatment. Please answer each question by

circling a single number of each scale.

1) How satisfied are you with your current treatment?

very satisfied 6 5 4 3 2 1 0 very dissatisfied

2) How often have you felt that your blood sugars have been unacceptably high recently?

most of the time 6 5 4 3 2 1 0 none of the time

3) How often have you felt that your blood sugars have been unacceptably low recently?


4) How convenient have you been finding your treatment to be recently?

very convenient 6 5 4 3 2 1 0 very inconvenient

5) How flexible have you been finding your treatment to be recently?

very flexible 6 5 4 3 2 1 0 very inflexible

6) How satisfied are you with your understanding of your diabetes?


7) Would you recommend this form of treatment to someone else with your kind of diabetes?

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yes, I would 6 5 4 3 2 1 0 no, I would definitely

8) How satisfied would you be to continue with your present form of treatment?


Please make sure you have only circled a single number for each question.

VISUAL ANALOGUE SCALE - BASELINE

definitely

recommend the

treatment

not recommend

the treatment

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VAS 1

VAS 2

VAS 3

I am extremely

dissatisfied

with the

current

treatment

I am extremely

satisfied with the

current

treatment

The current

treatment is

extremely

difficult to use

The current

treatment is

extremely easy

to use

The current

treatment is

extremely

uncomfortable to

wear

The current

treatment is

extremely

comfortable to

wear

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SATISFACTION QUESTIONNAIRE– END OF TREATMENT SESSION

DIABETES TREATMENT SATISFACTION QUESTIONNAIRE: DTSQ

The following questions concern your current diabetes treatment. Please answer each question by

circling a single number of each scale.

1) How satisfied are you with your current treatment?


2) How often have you felt that your blood sugars have been unacceptably high recently?


3) How often have you felt that your blood sugars have been unacceptably low recently?


4) How convenient have you been finding your treatment to be recently?

very convenient 6 5 4 3 2 1 0 very inconvenient

5) How flexible have you been finding your treatment to be recently?

very flexible 6 5 4 3 2 1 0 very inflexible

6) How satisfied are you with your understanding of your diabetes?


7) Would you recommend this form of treatment to someone else with your kind of diabetes?

yes, I would 6 5 4 3 2 1 0 no, I would definitely

definitely

recommend the

treatment

not recommend

the treatment

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8) How satisfied would you be to continue with your present form of treatment?


Please make sure you have only circled a single number for each question.

of 145


VISUAL ANALOGUE SCALE- END OF TREATMENT SESSION

VAS 1

VAS 2

VAS 3

I am extremely

dissatisfied

with the

system used

for the last 3

months

I am extremely

satisfied with the

system used for

the last 3

months

The system

used for the

last 3 months is

extremely

difficult to use

The system used

for the last 3

months is

extremely easy

to use

The system used

for the last 3

months is

extremely

uncomfortable to

wear

The system used for

the last 3 months is

extremely

comfortable to wear

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ASSESSMENT FORM ON USE OF DEXCOM CGM

Co

mp

eten

ce a

cqu

ired

Co

mp

eten

ce

un

der

sto

od

bu

t n

eed

s p

ract

ice

Still

nee

ds

pra

ctic

e

1. Inserts a new sensor

□ □ □ 2. Sets date and time on receiver

□ □ □ 3. Notes down the serial number of the transmitter

□ □ □ 4. Performs a calibration

□ □ □ 5. Is aware of the frequency of calibrations

□ □ □ 6. Checks receiver battery level

□ □ □ 7. Reconnects receiver and transmitter in case of necessity

□ □ □ 8. Does not forget to recharge the receiver (at least every 3

days) □ □ □ 9. Understands and interprets the icons on the receiver

screen (calibration, loss of connection, trend arrows) □ □ □ 10. Checks the sensor expiry date

□ □ □ 11. Sets the receiver alarms

□ □ □ 12. Masters the alarms

□ □ □ 13. Understands the importance of the loss of connection

alarms and the “system” alarms □ □ □

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14. Uses the Dexcom Studio software

□ □ □ 15. Uses the CGM to optimize treatment

□ □ □

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ASSESSMENT FORM ON USE OF CELLNOVO PUMP

Co

mp

eten

ce a

cqu

ired

Co

mp

eten

ce

un

der

sto

od

bu

t n

eed

s p

ract

ice

Still

nee

ds

pra

ctic

e

1. Charges the pump battery every 3 days or when the battery level is low □ □ □

2. Sets the date and time on the tablet (terminal)

□ □ □ 3. Fills the pump reservoir and changes the catheter

□ □ □ 4. Knows how to prime the catheter of the pump

□ □ □ 5. Sets the basal rate of the pump on the terminal during

initialization □ □ □ 6. Checks, corrects, adds or deletes basal rate programs

□ □ □ 7. Sets a temporary basal rate

□ □ □ 8. Checks time spent and time remaining of the temporary

basal rate and knows how to cancel a temporary basal rate

□ □ □ 9. Understands the difference between the bolus functions

and the bolus calculator □ □ □ 10. Uses the bolus calculator and performs an insulin bolus

□ □ □ 11. Understands the importance of delivering all bolus doses

via the pump (not using the injector pen) □ □ □ 12. Programs the correction factor, the carbohydrate ratio,

and the target blood sugar □ □ □ 13. Is capable of using the different types of bolus, if needed

(e.g. extended bolus, biphasic bolus, etc…) □ □ □

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14. Understands the status screen: insulin still to be delivered, insulin already delivered □ □ □

15. Stops an insulin bolus in the process of delivery

□ □ □ 16. Verifies insulin being delivered by the pump

□ □ □ 17. Sets the alerts/alarms on the terminal

□ □ □ 18. Changes the alert/alarm settings on the terminal

□ □ □

ASSESSMENT FORM ON USE OF DIABELOOP SYSTEM

of 145


Co

mp

eten

ce a

cqu

ired

Co

mp

eten

ce

un

der

sto

od

bu

t n

eed

s p

ract

ice

Still

nee

ds

pra

ctic

e

1. Understands the principle of a closed loop system

□ □ □ 2. Uses the smartphone (launches the application, checks

battery level) □ □ □ 3. Initializes algorithm (inputs age, weight, height, U/P,

meals, basal, bolus, sugarings, etc…) □ □ □ 4. Pairs the different components of the system

(sensor/smartphone/pump) □ □ □ 5. Recharges smartphone every night

□ □ □ 6. Makes sure smartphone, transmitter and pump are

always close (≤3m) to avoid problems with connection □ □ □ 7. Starts and stops a closed loop

□ □ □ 8. Understands the information on the Diabeloop

application screen (e.g. current basal rate, bolus delivered…)

□ □ □ 9. Knows how to navigate the application (e.g. check the

history) □ □ □ 10. Announces a meal and confirms the bolus delivery

□ □ □ 11. Announces a physical activity and understands the

requested adjustment of treatment (e.g. sugaring) □ □ □ 12. Understands the information messages of the

application □ □ □ 13. Understands the error messages of the application

□ □ □ 14. Understands the graphic displays on the screen

□ □ □

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15. Checks the sound volume of the alarms

□ □ □ 16. Knows the system’s procedures in case of hypoglycemia

or hyperglycemia □ □ □ 17. Knows how to manually input a bolus, TBR or sugaring

□ □ □ 18. Knows about the remote monitoring platform and knows

how to reach the care team □ □ □ 19. Knows the procedure for uploading data (in case the

patient cannot come to the site) □ □ □

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XII.2. APPENDIX: Inserting the Dexcom sensor and locking the

transmitter

Once the sensor is inserted, all that’s left is to insert the transmitter.

Hold the sensor receptacle in one hand and place two fingers of the

other hand above the collar

With your thumb, push the piston completely down to insert the

needle applicator and the sensor.

Do not lift the collar when you push down the piston.

Place two fingers below the collar and pull back (to remove the

needle and applicator).

Press the tabs on each side of the sensor receptacle.

Tilt the applicator towards the front to remove it from your body.

The sensor receptacle is still attached.

Place the transmitter in the sensor

receptacle: flat side facing down and

small end away from the transmitter lock.

Put your finger on the transmitter and lift the lock (2

clicks).

Make a rotating movement to remove the lock.

You can hold the sides of the receptacle with one

hand.

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Calibration

After 2 hours of initialization, the screen will display a request for 2

capillary glucose values:

• Click C to delete the message

• Ask the patient to wash their hands and take two capillary

glucose measurements.

The following steps are done twice:

• Click OK to access the menu

• Select « Input blood sugar value » and click OK

• Input the value from a fingertip blood sample and click la OK

• Confirm the value by clicking OK

• The following screens appear:

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XIII.3. APPENDIX: List of studies carried out with the Diabeloop algorithm

DIABELOOP Sub-study 6-0 INITIAL TESTING OF THE DIABELOOP ALGORITHM OVER

THE PRANDIAL PERIOD AND PHYSICAL ACTIVITY RCB ID: 2012-A01489-34.

PROTOCOL – SYNOPSIS

Coordinating Investigator: Dr. Guillaume CHARPENTIER

Principal Investigators: Prof Pierre-Yves BENHAMOU for meals and Dr Sylvia FRANC for

physical activity

Investigators:

1. Dept. of Endocrinology and Diabetology, Centre Hospitalier Sud Francilien, Corbeil-

Essonnes (91): Dr Sylvia FRANC, Dr Guillaume CHARPENTIER

2. Dept. of Endocrinology, Diabetology and Nutritional Diseases, CHU de Grenoble (38): Prof

Pierre-Yves BENHAMOU. Dr. DEBATY Isabelle.

3. Dept. of Endocrinology and Diabetology, Hôpital Rangueil - CHU de Toulouse: Prof Hélène

HANAIRE, Dr MELKI, Dr Françoise LORENZINI, Dr Nelly PUECH-BRET Dr Claire THALAMAS

(CIC), Dr Angélica VACCARO (CIC).

Sponsor: Centre d’Etudes et de Recherches pour l’Intensification du Traitement du Diabète

(CERITD). Bioparc Génopôle Evry- Corbeil. Campus 3 – Bâtiment 5. 1, rue Pierre

Fontaine- 91058 EVRY CEDEX

Methodology: National, multicentric, interventional, controlled, open label.

Primary objective: To assess whether the Diabeloop algorithm provides better glycemic control

than the usual “manual” algorithm of a type 1 diabetic patient on pump therapy, during meals

roughly assessed by the patient, and during and after physical activity qualified as “moderate” or

“intense” by the patient.

Primary endpoint:

Time spent in glucose reference intervals.


Meals:

• To assess the efficacy and safety of a prandial algorithm informed of carbohydrate intake

by the patient either quantitatively, semi-quantitatively or not specified.

• To determine the efficacy of 2 primer levels: 50% and 75%, on postprandial AUC and

occurrence of postprandial hypoglycemia.

• To assess whether one primer level is more adapted to a standard meal, a meal low in

carbohydrate or a meal high in carbohydrate.

• To assess the efficacy and safety of a prandial algorithm detecting meal carbohydrate

intake, with bolus omitted.

Endpoints:

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• Measurement of interstitial glucose sensor and capillary glucose 2h, 3h and 4h

postprandial and AUC, in each situation tested, to evaluate efficacy and safety (time spent

in hypoglycemia);

• Comparison of interstitial glucose sensor and capillary glucose measured 2h, 3h and 4h

postprandial and AUC, in conditions of identical meals, for each primer level (50 or 75%);

• Comparison of interstitial glucose sensor and capillary glucose measured 2h, 3h and 4h

postprandial and AUC, in conditions of identical meals, for each primer level, in the three

configurations: quantitative, semi-quantitative carbohydrate intake and bolus omitted.

Physical activity:

• To assess the efficacy and safety of a physical activity algorithm informed of intensity of

the activity (intense or moderate).

Endpoints:

• Measurement of AUC during the physical activity, the next two hours, then until meal time,

during dinner, and throughout the night

• Time spent in hypoglycemia (< 0.70 g/l)

• Number of sugarings and amount of carbohydrate ingested

Main inclusion criteria:

• Patients with type 1 diabetes treated by external insulin pump;

• HbA1c < 8.5%;

• At least 18 years old;

• Having signed the free and informed consent form;

• Affiliated with Social Security.

For the Grenoble and Toulouse centers:

• Patient practicing either functional insulin therapy or a fixed meal plan.

For the CHSF:

• Patient able to perform moderate or intense activity during 40 minutes.

Main non-inclusion criteria:

• Patient with type 2 diabetes;

• Any serious disease that could interfere with the study;

• Insulin resistance or obesity (BMI > 30 kg/m2 and/or insulin requirement > 2 U/kg/day);

• Patient under legal protection

Study work flow:

GRENOBLE & TOULOUSE CENTERS:

Grenoble and Toulouse will test the prandial algorithm with several carbohydrate intakes and a primer of 50%

or 75% of the total bolus. Patient groups are described as follows:

Group I: patients have a meal with the usual carbohydrate intake. The meal bolus is according to

the current treatment.

Group II: patients have a meal with a "low" carbohydrate intake (50% reduction in carbohydrate

intake).

Group III: patients have a meal with a "high" carbohydrate intake (50% increase in

carbohydrate intake).

Group IV: patients of group IV have a meal with the usual carbohydrate intake but their bolus

will be omitted.

Inclusion visit V1: The study will be proposed to patients meeting the inclusion criteria. After

signing the informed consent form, the investigator will assign a group for each patient. The

dates of visits V2, V3 and V4 will be scheduled during the inclusion visit.

Visit V2: This visit will take place 24 hours before visit V3. Installation, calibration and education

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of two Dexcom G4 ™ glucose sensors will be performed by a nurse according to the

manufacturer’s recommendations. The patient will keep the two sensors until the end of the study

(end of V4).

Visit V3 (patient control): The patient is admitted to the CIC at 9:00. The patient will be fitted

with two Dexcom™ G4 sensors and his usual insulin pump programmed with the usual algorithm.

The meal will be served at 13:00 and the patient will leave the site at 18:00. In the case where a

corrective bolus at 10:00 was not given, the meal can be served at 12:00. Bolus will be

administered 10 min before the meal for all patients. Capillary glucose measurements will be

taken every hour from 12:00 to 18:00 and in case of hypoglycemia or hyperglycemia. Additional

capillary glucose measurements can be taken if necessary.

Visit V4 (algorithm test): The patient is admitted to the CIC at 9:00. The patient will be fitted

with his usual insulin pump programmed with the usual algorithm and two Dexcom™ G4 sensors.

Sensor measurements will be entered by the LETI engineer on the computer on which the test

algorithm is installed. The same meal taken at the “patient control” visit will be served at the

“algorithm test” visit and at the same time. The meal and type of meal will be announced or not

in the algorithm software, depending on the phase of the study. From that time onward, the

algorithm will propose insulin doses every 15 min until 18:00. Capillary glucose will be measured

every hour from 12:00 to 18:00, in case of hypoglycemia or hyperglycemia, and when the

sensors are removed. Additional capillary glucose measurements can be taken if necessary.

CHSF:

This center will test the glycemic control algorithm during physical activity of moderate (50%

VO2max) or high intensity (75% VO2max) for 40 minutes on a bicycle ergometer. Three groups

will be created for the different situations:

Group A: Patients in group A will practice an average physical activity (50% VO2max) with a

temporary basal rate reduction according to their usual algorithm (usually 50% reduction during

the test and for the next 2 hours).

Group B: Patients in group B will practice an intense physical activity (75% VO2max) with a

temporary basal rate reduction according to their usual algorithm (usually 80% reduction during

the test and for the next 2 hours).

Group C: Patients in group C will practice an average physical activity (50% VO2max) but

without a concomitant temporary basal rate reduction.

Inclusion visit V1:

The study will be proposed to patients meeting the inclusion criteria. After signing the informed

consent form, the investigator will assign a group for each patient. The dates of visits V2 and V3

will be scheduled during the inclusion visit.

Visit V2: This visit will last one day. The patient will be admitted at 8:00 and equipped with two

Dexcom™ G4 sensors and a heart rate monitor. For groups A and B, sensor data will be masked

so as not to influence the patient or care team. For Group C without basal rate reduction during

the physical activity test, sensors will not be masked so that preventive sugaring can be done if

necessary.

A calibrated meal is served at 11:30. The patient’s insulin dose will be administered according to

his usual algorithm. The physical activity test will begin 3 hours after the meal. It will be carried

out on a bicycle ergometer for 40 minutes at an intensity qualified by the patient as moderate

(50% VO2max) or intense (75% VO2max), after first implementing his usual algorithm, which

generally is as follows:

o Moderate (Group A): 50% basal rate reduction throughout the test and for 2 h afterwards.

o Intense (Group B): 80% basal rate reduction throughout the test and for 2 h afterwards.

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At the end of this test the patient can return home. He must keep the two sensors until the next

morning. He will be asked to eat a calibrated dinner meal with administration of his usual insulin

dose as per the usual FIT settings. He must make a note of any hypoglycemic episode or

sugaring. Interstitial glucose measurements by the sensor will be continuously registered until the

next morning.

Capillary glucose will be measured before and 2 hours after the meal, in case of hypoglycemic or

hyperglycemic episodes, at 4 am to check blood glucose, and before the physical activity test.

Visit V3: 24-hour hospitalization

The same test will be repeated for each patient during this visit. The insulin pump will be

controlled by the doses proposed by the algorithm after manual validation by the investigator.

These will continue until the next morning, and the patient will spend overnight in the hospital.

The same meals as at the “Patient control” visit will be served at the same times.

Total number of subjects: 18 of which 6 patients at CHSF and 12 in Grenoble and Toulouse

Study start date : early March 2013

Inclusion period: 3 months

Total study duration: 4 months

Safety criteria: Clinical collection of serious adverse events, especially severe hypoglycemia

and ketoacidosis

End of study:

• Withdrawal of patient consent

• Decision by investigator in patient’s best interest

1. Results on the performance of the Diabeloop prandial algorithm

12 adult type 1 diabetics (9 men, mean age 35.6 (±12.7) years, duration of diabetes 19.8

(±12.7) years; HbA1c 7.3 ±0.8% were included. Time spent in target was 84.5 ± 20.8% (test

day) versus 69.2 ± 33.9% (control day) (p= 0.11). Time spent in hypoglycemia <70mg/dl was

0.2 ± 0.8% (test day) versus 4.4 ± 8.2% (control day). Blood glucose at the end of the test (5h)

was 127.5 ± 40.1 (test day) versus 146 ± 53.5 mg/dl (control day) (p=0.25). The insulin doses

did not differ, and no differences were observed between the 50% or 75% priming boluses.

Conclusion: In a semi-closed loop configuration, with manual primer bolus (25 or 50%

reduction), the Diabeloop algorithm V1 performed as well as manual bolus determination in the

postprandial period, without an excess risk of hypoglycemia. This allows the conduct of controlled

trials.

2. Results on the physical activity algorithm

The percentage of time spent in the range [70-180mg/dl] was equivalent for all tests controlled

by the patient or by the Diabeloop algorithm: in the afternoon following the physical activity:

57±20% vs 70±30% p=0.30, dinner (75±24% vs 76±30%) and night (66±28% vs 84±16%).

This was also true for the time spent <70mg/dl (afternoon: 12±21% vs 15±31%, dinner: 4±6%

vs 5±11%, night: 17±17% vs 6±11%). During test C, one patient required 5 successive

moderate sugarings, whether the test was controlled by herself or by the Diabeloop algorithm.

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Conclusion: This pilot evaluation shows that the Diabeloop algorithm allows an acceptable

control of the insulin pump during physical activity. However, in the more complex situation of an

unanticipated physical activity, consideration should be given to further amplifying the preventive

sugaring function.

DIABELOOP Sub-study 6.1.A

Validation of the Artificial Pancreas Diabeloop algorithm in the hospital

RCB ID: 2013-A01657-38

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PROTOCOL – SYNOPSIS

Coordinating Investigator: Prof Eric Renard (Montpellier CHU)

Principal Investigators: Dr Guillaume Charpentier (CHSF), Prof Pierre-Yves Benhamou.

Investigators:

1. Dept. of Endocrinology and Diabetology, Centre Hospitalier Sud Francilien, Corbeil-Essonnes

(91): Dr Guillaume CHARPENTIER, Dr Sylvia FRANC, Dr Ahmed DAOUDI

2. Dept. of Endocrinology, Diabetology and Nutritional Diseases, CHU de Grenoble (38): Prof

Pierre-Yves BENHAMOU. Dr LABLANCHE Sandrine

3. Endocrinology-Diabetes team, CHU de Montpellier: Prof Eric RENARD, Dr Anne FARRET

Sponsor: Centre d’Etudes et de Recherches pour l’Intensification du Traitement du Diabète

(CERITD). Bioparc Génopôle Evry- Corbeil. Campus 3 – Bâtiment 5. 1, rue Pierre

Fontaine- 91058 EVRY CEDEX

Methodology: National, multicentric, interventional, randomized, controlled.

Medical device being evaluated: Artifical Pancreas Diabeloop (Medtronic insulin pump, Dexcom G4

sensor and Nexus 5 Smartphone containing the glucose control algorithm).

Mode of use: insulin delivery in semi-closed loop

Number of centers: 3

Number of persons participating in the study:

Number planned: 17

Number analyzed : 16

Publication: in preparation

Duration of the study:

Date of first inclusion: 26/05/2014

Date of end of participation of last person included in the study: 04/02/2015

Primary objective: To assess whether the DIABELOOP algorithm provides non-inferior glycemic

control than usual insulin pump therapy.

Primary endpoint:

Percentage of time spent in reference glucose range 70-180 mg/dl

Pathology studied: Type 1 diabetes

Inclusion criteria

• Type 1 diabetic patient treated with external insulin pump;

• Patient without imbalanced diabetes (HbA1c < 8.5 %);

• Patient with good venous access;

• Patient practicing functional insulin therapy or fixed meal plan;

• Patient able to perform two tests of physical activity of 30 minutes (one event in each treatment

period);

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• Affiliated with Social Security;

• At least 18 years old;

• Having signed the free and informed consent form.

Non-inclusion criteria

• Patient with type 2 diabetes;

• Any serious disease that could interfere with the study;

• Insulin resistance or obesity (BMI > 30 kg/m2 and/or insulin requirement > 2 U/kg/day);

• Patient under legal protection;

• Woman pregnant or likely to be.


• To assess whether the DIABELOOP algorithm provides superior glycemic control than the

usual insulin pump therapy.

• To check in the Diabeloop system data that at each step, the information and instructions were

correctly transmitted and executed by the system: from the Dexcom™ G4 CGM to the

Smartphone (Algorithm).

Secondary endpoints of study SP6.1.A:

• Percentage of time spent in tight blood glucose range 80-140 mg/dl

• Percentage of time spent below 70 mg/dl and above 180 mg/dl

• Average blood glucose over the entire period and sub-periods: prandial, rest and physical

activity

• Variability of standard deviations and index (low blood glucose, high blood glucose, blood

glucose risk index) over the entire period and sub-periods: prandial, rest and physical activity

• Total insulin intakes during the tests

• Number of hypoglycemic episodes

• Number of technical incidents

• Comparison of Diabeloop system files with the files of the patient’s usual system.

Study work flow:

1. Test of Diabeloop software interface on a Smartphone: The objective was to test data

transmission from the Dexcom™ G4 sensor to the Smartphone containing the Diabeloop

altorithm. This sub-study was conducted only in center 1 (Centre Hospitalier Sud Francilien in

Evry 91) and center 3 (Grenoble CHU) over one day from 8:00 to 18:00 in 2 patients (1

patient/center) recruited for the closed loop/open loop crossover study and who agreed to

participate in this ancillary study.

The ancillary study visit (V0 bis) took place after collecting the patient’s consent. The patient

kept his usual insulin pump with his usual algorithm. He was fitted with the Dexcom™ G4

sensor linked to the Smartphone integrating the Diabeloop algorithm.

This ancillary study had no therapeutic impact. At this visit we checked that data from the

Dexcom™ G4 sensor were registered in the algorithm. Dose recommendations were displayed

via the Smartphone. The treatment prescribed by the Diabeloop algorithm was not administered

to the patient.

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2. Conduct of study SP6.1.A

This is a crossover study with two 24-hour hospitalizations separated by a wash-out period of at

least 1 week.

Inclusion visit Vo: The investigator collected the consent of the patient meeting the criteria for

inclusion and non-inclusion, randomized the patient to know the order of the tests and prescribed

Novorapid® insulin to the patient.

Visit V1 to install sensors: Two Dexcom™ G4 sensors were installed during an outpatient visit

two days before each 24-hour hospitalization. Patients were instructed to keep the sensors until the end

of each treatment period.

1st 24-hour hospitalization visit: According to the order of the draw, for 24 hours the patient had

either his usual treatment, or the treatment prescribed by the Diabeloop algorithm.

2nd 24-hour hospitalization visit: For the second hospitalization, the patient had either the

treatment prescribed by the Diabeloop algorithm, or the usual treatment prescribed by the

diabetologist.

The two hospitalizations were separated by a wash-out period of 1 to 2 weeks.

During each treatment period the patient was equipped with a Medtronic Paradigm VeoTM pump

which replaced his usual pump (except if the patient already had a Medtronic pump), an Actigraph (to

measure movement) and an Actiheart (to measure heart rate). The latter two devices evaluated physical

activity during the one-half hour physical activity step test during hospitalization.

During the open loop period, sensor data was masked so as not to influence the patient or the

investigator and to have results that were truly representative of the real-world setting without

continuous glucose monitoring. The patient monitored his blood glucose by capillary blood glucose

measurements before any compensation bolus or sugaring, as for his usual treatment.

During the semi-closed loop period, a Dexcom receiver was connected to the Smartphone by a cable

and the second was available to the doctor. Neither of the two sensors was masked during this period.

Statistical analysis: Fourteen DT1 patients (12 men, 2 women, age: 47.0 ± 9.9 years, weight: 75.9 ±

11.9 kg, duration of diabetes: 23.6 ± 11.7 years , HbA1c: 7.4 ± 0.7% ) were analyzed in a randomized

crossover trial including two 24-hour sessions starting at 10:00, either equipped with a standard

"Medtronic Veo" insulin pump preprogrammed with their usual treatment (OL, open loop) or

equipped with the Diabeloop system (CL, closed loop) with the MPC predictive algorithm. The

Dexcom G4 Platinum sensor was masked to the patient (OL) or connected to a Smartphone containing

the algorithm. Insulin doses proposed by the algorithm were administered manually to the patient

every 15 minutes. Each session included three standardized meals (70g CHO at 12:00 and 19:00, 40g

CHO at 08:00) and 30 minutes of moderate physical activity at 16:00. Bolus was delivered 10 minutes

before the meal as decided by the patient or after announcing the meal in the algorithm. Glycemic

control was evaluated based on the CGM data.

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Performance assessment: Overall glycemic control was similar in the two sessions with a percentage

of time spent in 70-180 mg /dl of 66.0 ± 20.8% (CL) vs 59.1 ± 21.8% (OL) and average blood glucose

was 151 ± 27 vs 141 ± 43 mg / dl, respectively.

Safety assessment: the percentage of time spent < 70 mg / dl was lower in closed loop: 3.9 ± 3.7% vs

13.5 ± 13.6%, more specifically from 23:00 to 7:00: 0.0 ± 0.2% vs 21.6 ± 27.8% (p = 0.0002 ). The

number of patients with at least one event < 70mg /dl between 23:00 and 07:00 the next day was 1/14

in CL versus 8/14 in OL (p =0065)

Conclusion: This first clinical evaluation in the hospital of the Diabeloop algorithm demonstrated

ease of use and safety of the system, including a significant reduction in nocturnal hypoglycemia.

Continuous improvements to the algorithm will focus on improving the minimization of

hyperglycemia.

Safety criteria: Clinical collection of serious adverse events, especially severe hypoglycemia and

ketoacidosis

Date of report: 21/07/2015

DIABELOOP Sub-study 6.2

Crossover evaluation of glycemic control provided for three days by

Artificiel Pancreas Diabeloop compared to conventional treatment by external insulin pump in patients with type 1 diabetes in a situation of

sedentarity, exceptional meals and physical activity RCB ID: 2015-A01294-45

Synopsis of protocol SP6.2

Title

Crossover Evaluation of Glycemic Control Provided for Three Days by the

Artificial Pancreas Diabeloop Compared to Conventional Treatment by

External Insulin Pump in Patients With Type 1 Diabetes in a Situation of

Sedentarity, Exceptional Meals and Physical Activity.

RCB ID 2015-A01294-45

Sponsor CERITD – campus 3, bâtiment 5. 1, rue Pierre Fontaine 91058 Evry Cedex

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Coordinating Investigators

Sub-study SP6.2.1 – Sedentarity. Prof Yves Rreznik

Sub-study SP6.2.2 – Exceptional meals. Prof Hélène Hanaire

Sub-study SP6.2.3 – Physical activity. Dr Sylvia Franc

Methodology National, multicenter, interventional, controlled, open-label, randomized, comparative crossover trial.

Medical

device being

evaluated

Experimental group: Diabeloop system (closed loop) composed of a

DexcomTM Share AP sensor (Dexcom Inc., San Diego, CA) + Cellnovo

Smartphone (handset) uploaded with the Diabeloop algorithm + Cellnovo

patch pump.

Control group: Usual system (open loop) composed of the patient’s

conventional insulin pump preprogrammed with the usual algorithm

prescribed by the doctor + DexcomTM Share AP sensor.

Objectives

Primary objective:

To assess non-inferiority of nocturnal blood glucose control with the

Diabeloop system compared to the usual algorithm of a type 1 diabetic patient

treated with an external insulin pump in three different situations: sedentarity,

exceptional meals and physical activity.

Primary endpoint:

Percentage of time spent in tight glucose control range 80-140 mg/dl during

the night, measured continuously during 3 days with the DexcomTM Share AP

CGM.


• For the study as a whole and for each sub-study:

1. To assess whether the DIABELOOP algorithm provides superior

nocturnal blood glucose control than the conventional external

insulin pump therapy.

2. To compare blood glucose results obtained with the Diabeloop

system and the patient’s usual algorithms:

a. During the entire study duration (72 hours)

b. During the 3 daily meals

c. During daily physical activity

• To demonstrate better efficacy of the system on the 3rd day “D3”

versus 1st day “D1” according to different periods of the day, during

closed loop versus open loop.

• To assess efficacy and safety of a prandial algorithm informed of the

type of meal (high fat and/or protein): low or high carbohydrate intake

and low or high fat intake.

• To assess efficacy and safety of a physical activity algorithm according

to the intensity of the test (intense or moderate).

Secondary endpoints:

• Percentage of time spent in reference glucose range 70-180 mg/dl,

during the night measured continuously during 3 days with the

Dexcom CGM.

• Percentage of time spent in glucose range 70-180 mg/dl on D3 versus

D1 during the closed loop period compared to D3 versus D1 during the

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open loop period.

• Time spent in glucose range < 70 mg/dl and > 180 mg/dl

• Average blood glucose over the entire period and per sub-period:

sedentarity, meals, physical activity.

• Calculated risks of hypoglycemia and hyperglycemia (LBGI, HBGI)

over the entire period and per sub-period: sedentarity, meals, physical

activity.

• Number of sugarings and amount of carbohydrate ingested.

• Number of hypoglycemic events, defined by any crossing of the

threshold of 70 mg/dL (3.9 mml/L), and < 54 mg/dL (3 mmol/l)

measured by the Dexcom CGM.

• Total insulin intakes during the tests.

• Mean peak postprandial blood glucose according to meal and time of

occurrence.

• Number of technical incidents causing closed loop interruptions.

• Comparison of glucose sensor values 2h, 3h and 4h postprandial and

AUC in identical meal conditions, to evaluate efficacy and safety (time

spent in hypoglycemia, hypeglycemia and normoglycemia).

• Mean blood glucose nadir after physical activity and time of

occurrence.

• Measurement of AUC during physical activity, the next two hours,

then until meal time, during dinner and throughout the night.

Population 9 centers; 3 centers/situation; 4 subjects/center.

36 patients evaluable

Inclusion

criteria

▪ Type 1 diabetic patient for at least one year or C-peptide nonevaluable,

treated by external insulin pump for at least 6 months;

▪ 7.5 %< HbA1c <9.5 %;

▪ Patient practicing functional insulin therapy;

▪ For the physical activity situation, patient must be able to perform

one or more physical activities every day during 3 days in each

treatment session;

▪ Patient aged 18 years or older;

▪ Patient affiliated with Social Security;

▪ Having signed the free and informed consent form.

Non-inclusion

criteria

▪ Patients with type 2 diabetes;

▪ Any serious pathology that could alter the participation in the study;

▪ Patient with insulin resistance defined as insulin requirements > 1.5

U/kg/day;

▪ Patient unaware of their hypoglycemia;

▪ Patient under legal protection;

▪ Woman pregnant or likely to be.

Déroulement de l’étude

The study will be conducted as a crossover trial, with two 72-hour

hospitalizations separated by a wash-out period of at least one week. Each

hospitalization is a treatment period. According to the order of the draw,

patients will be provided with either the Diabeloop system or the usual

system:

In both treatment periods:

• Patients in a situation of sedentarity or physical activity will be

equipped with an ActiGraph (measuring movement) and an ActiHeart

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( measuring heart rate);

• Meals and physical activities will be similar in both periods;

• The same blood glucose meter (Medtronic Contour Next Link) will

be used throughout the duration of the study.

• Capillary blood glucose will be measured: before the bolus and 2 hours

after a meal, before the physical activity, in case of hypo or hyper-

glycemic episodes and when the patient and / or investigator deem it

necessary.

Study visits are described below:

1. Inclusion visit V1: The investigator collects the consent of the patient

meeting the inclusion and non-inclusion criteria, signed and dated. He

randomizes the patient to know the order of the tests.

The patient will be equipped with the DexcomTM Share AP sensor at this visit

for a 2-week run-in period to familiarize the patient to best adapt their

treatment with the sensor data.

2. Ancillary study (visit V1bis): Test of algorithm/system interface:

This study will test data transmission from the Dexcom™ Share AP sensor to

the Diabeloop algorithm uploaded on the Cellnovo Smartphone (handset).

This sub-study will be conducted only in center 5 (Grenoble CHU) and center

7 (Centre Hospitalier Sud Francilien in Evry 91) over one day from 8:00 to

18:00 in 2 patients or more if necessary (1 patient/center) recruited for the

closed loop/open loop crossover trial and who agreed to participate in this

ancillary study.

The patient will be equipped with a new Dexcom sensor and a CellNovo

insulin pump driven by its Smartphone containing the Diabeloop algorithm. The doses of insulin prescribed by the Diabeloop algorithm will be administered to

the patient automatically via the pump controlled by the Smartphone under the

supervision of a doctor and in the presence of an engineer.

3. Visits to install sensors V2 and V4 :

The patient will be equipped with a new Dexcom™ Share AP sensor 48 hours

before starting the open loop or closed loop according to the randomization.

The ActiHeart will be calibrated during this visit(centers participating in SP6.2.1 and SP6.2.3)

4. 72-hour hospitalizations V3 and V5 (CL or OL):

According to the order of the draw the patient will either be in OL or CL and

according to the study center, in a situation of: sedentarity, exceptional

meals or physical activity . 1. 2. 3. 4. 4.1 Situation of sedentarity:

The patient will be admitted to the study center before 8:00 and will remain in

the hospital in a secured setting for 3 days.

Meals (breakfasts, lunches and dinners) will be varied, reproducible, taken at

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fixed times and in a maximum of 30-45 minutes. The bolus for each meal will

be administered at the same time in both periods. 4.2 Situation of exceptional meals

This phase of the study will focus on variations in meals. The patient will be

admitted to the study center before 8:00 as a semi-outpatient, spending the

night in the hospital and eating lunch and dinner outside accompanied by

someone from the healthcare team.

Exceptional meals will be:

- High in protein and fat for dinner,

- Low in fat and difficult to calibrate carbohydrate at lunch,

- High in carbohydrate and fat for breakfast (with various pastries and

jam).

Meals will be taken at fixed times and will be varied, but reproducible and

identical in the two treatment sessions. The general nature of the meals will be

left free to choose according to the patient’s preferences.

The bolus will be administered at the same time in both treatment periods, and

the amount of carbohydrate ingested will be estimated and recorded by a nurse

or dietician from the study center.

4.3 Situation of physical activity

This phase of the trial will be based on varied daily physical activity tests. The

patient will be admitted to the study center before 8:00 as a semi-outpatient,

spending the night in the hospital and practicing physical activities on the

outside accompanied by someone from the healthcare team.

One or more daily physical activities will be practiced at a fixed time with an

intensity (moderate or intense) estimated by the patient.

Physical tests will be reproducible during the two treatment periods (practiced

at same time for the same duration), and will vary according to the patient’s

preferences.

Diabeloop SP6.2.3 will use the temporary basal rate reduction algorithms

previously validated by the Diabrasport study (RCB ID: 2009-A01136-51) in

the case where the physical activity is practiced away from meals.

Patients will be asked to follow the procedure described below (see Practical

Guide to the Diabeloop SP6.2.3 study):

- Reduce their basal rate by 50% or 80% according to intensity of exercise,

30 to 60 min before beginning the physical activity practiced 3 hours

after the meal.

- Reduce the meal bolus if the physical activity is practiced within 3 hours

after the meal.

Physical activities can be alternated from one day to the next, for example:

• 1st day: running

• 2nd day: Nordic walking

• 3rd day: biking Meals (breakfasts, lunches and dinners) will be varied, taken at fixed times

and in a maximum of 30-45 minutes. The bolus for each meal will be

administered at the same time in both periods and if possible will be similar

between the two periods.

Safety

criteria

Clinical collection of adverse events, especially severe hypoglycemia and

ketoacidosis

Early end of • Withdrawal of patient consent

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Conduct of study SP6.2

Following the conclusions of study SP6.1, substantial improvements were made to the

Diabeloop algorithm, leading to a version V2 which, among other things, contained a shorter

reassessment loop, every 10 minutes, as well as parameters from the Howorka model, and the

addition, in case of a “mismatch”, of a decision tree mimicking the decision-making of a

diabetologist in case of a “non-physiological” situation, especially in case of unexplained

hyperglycemia. This algorithm can then take over from the basic MPC algorithm, thus

avoiding the automatic return to the reference basal rate.

study ▪ Decision by investigator in patient’s best interest

Duration of

patient

participation

6 to 8 weeks

Inclusion

duration

6 months

Study start November 2015

End of study September 2016

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In terms of meal announcements, it is possible for patients to input a meal and, if they practice

functional insulin therapy, to announce the quantity of carbohydrate. They can also announce

“exceptional” meals, such as meal high in fat and/or protein, as well as physical activity with

selection of its duration and intensity.

Furthermore, the algorithm’s control of the Cellnovo insulin pump has been completely

automated via a wireless connection between the dedicated Smartphone and the pump. The

Smartphone is also connected to the DexcomTM G4 CGM by Bluetooth low energy. The

Diabeloop system, thus automated and improved, was evaluated in study SP6.2 (clinical trial

registry NCT NCT02627911), whose primary objective was to assess non-inferiority of

nocturnal blood glucose control with the Diabeloop system compared to the usual algorithm

of a type 1 diabetic patient treated with an external insulin pump in three different situations:

sedentarity, exceptional meals and physical activity. Secondary objectives, for the study as a

whole and for each sub-study, were to compare the glycemic results obtained with the

Diabeloop system versus the usual algorithms of the patient:

a. During the entire study duration (72 hours)

b. During the 3 daily meals

c. During daily physical activity

and to demonstrate better efficacy of the system on the 3rd day “D3” versus 1st day “D1”

according to different periods of the day, during closed loop versus open loop.

The study involved two 72-hour treatment periods for each patient, in a randomly assigned

order, during which the diabetes was treated either with the semi-automated Diabeloop system

combining the DexcomTM G4 sensor, Cellnovo pump and Smartphone integrating the

Diabeloop V2 software and connected to the DexcomTM G4 and Cellnovo pump. The patient

nevertheless had to announce his meals and physical activities via the Smartphone. Or the

patient controlled his diabetes himself as usual, but with his conventional insulin pump and a

DexcomTM G4 sensor.

Study SP6.2 comprised three sub-studies in order to test the system in a “sedentary” situation,

but also in common daily life situations in which diabetes is very difficult to control, even by

“expert“ patients, i.e., unusual or heavy meals, or strenuous or repeated physical activities.

Patients spent 3 nights in the hospital.

1. SP6.2.1 involved the “sedentary” situation, in the hospital setting, with calibrated meals and

no major physical activity. 14 patients were recruited for this sub-study at the centers in Caen,

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Nancy and Strasbourg. The principal investigator for this sub-study was Prof Yves Reznick

(Caen).

2. SP6.2.2 involved the exceptional meals situation: a standard breakfast was served for the 3

days, lunch was taken in a cafeteria, and above all, dinners were at gastronomic restaurants: a

Japanese restaurant the first evening, Italian restaurant the second evening, and a gastronomic

French restaurant the third evening. 11 patients took part in this sub-study carried out at the

centers in Toulouse, Montpellier and Grenoble. The principal investigator was Prof Hanaire

(Toulouse).

3. SP6.2.3 involved the repeated physical activity situation on a bicycle ergometer:

a. On D1 in the afternoon, 45 min of intense physical activity (75% of VO2max)

b. On D2 in the afternoon, 45 min of moderate physical activity (50% of VO2max)

c. On D3, in the morning, 30 min of moderate physical activity and in the afternoon, 45 min of

intense physical activity

12 patients were recruited for this sub-study carried out at the centers in Corbeil, Marseille

and Besançon. The principal investigator was Dr Franc (Corbeil).

Performance assessment - study SP6.2:

Descriptive analysis:

Thirty-eight DT1 patients (age: 49.9±14.5 years, duration of diabetes: 25.1 ± 13.6 years,HbA1c: 7.8 ±

0.7%) were analyzed out of the 42 patients included in a randomized crossover trial involving two

sessions of 72 hours starting at 10:00, either equipped with their conventional insulin pump

preprogrammed with their usual treatment (open loop) and augmented with a continuous glucose

monitor, or equipped with the Diabeloop system (closed loop: CL) with the Cellnovo insulin pump,

the Dexcom G4 Platinum sensor connected to a Smartphone containing the algorithm. Meals and

physical activity were announced to the algorithm via the Smartphone and the insulin doses

calculated by the algorithm were administered to the patient automatically by the Cellnovo patch

pump. Glycemic control was assessed on the CGM data.

1. Overall results: Overall glucose control was superior in closed loop with a percentage of time spent in [80-140] mg/dl of 61.1%[56.1;66.7] vs. 27.4% [19.2;39.0]. Statistical tests reached the level of significance for non-inferiority and superiority of the closed loop compared to the open loop (p < 0.0001) during the night (23:00 to 7:00). The percentage of time spent in [70-180] mg/dl for the 3 nights was 76.0% [81.9;90.3] in CL vs. 58.0%

[48.2;69.8] in OL; p<0.0001). The percentage of time spent in [70-180] mg/dl during 72 hours was

79.0% [75.6;82.5] in CL versus 60.8% [55.2;67.0] in OL (p < 0.0001). Average blood glucose during 72

hours was 138.7 [133.5;144.2] mg/dl in CL versus 156.5 [148.5;165.0] mg/dl in OL, p< 0.0001. In both

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cases the closed loop reached statistical significance for non-inferiority and superiority compared to

the open loop.

2. Situation of sedentarity: The percentage of time spent in [80-140] mg/dl for the 3 nights was 58.7% [50.9;67.7] in CL versus 45.2% [25.2;81.0] in OL, with a non-significant difference between the two groups for non-inferiority and also for superiority p=0.3406. The percentage of time spent in [70-180] mg/dl for the 3 nights was 82.2% [75.9;89.1] in CL versus

72.7% [53.6;98.7] in OL, p=0.4061, and during 72 hours it was 76.9% [71.6;82.6] in CL versus 70.5%

[60.1;82.7] in OL, p=0.2602. Average blood glucose during 72 hours was 136.6 [128.1;145.7]mg/dl in

CL versus 145.0 [132.9;158.3] md/dl in OL, p=0.13. In both cases the tests of superiority and non-

inferiority did not reach statistical significance.

3. Situation of exceptional meals:

The percentage of time spent in [80-140] mg/dl for the 3 nights was 58.4% [49.7;68.7] in CL versus 14.7% [7.6;28.6] in OL, or significantly 3 times higher in closed loop versus open loop during the night (23:00 to 7:00 (p < 0.0001). The percentage of time spent in [70-180] mg/dl for the 3 nights was 85.2% [77.7;93.4] in CL versus

40.7% in (p<0.0001), and during 72 hours it was 80.2% [73.9;87.1] in CL versus 51.7% [43.1;62.0] in

OL (p<0.0001). Average blood glucose during 72 hours was 141.7 [131.7;152.4]mg/dl in CL versus

169.7[153.7;187.5] mg/dl in OL, p=0.003. In both cases the closed loop reached statistical significance

for superiority compared to the open loop.

4. Situation of physical activity:

The percentage of time spent in [80-140] mg/dl for the 3 nights was 66.6% [57.8;76.9] in CL versus 30.9% [17.2;55.3] in OL, significantly two times higher in closed loop compared to open loop during the night (23:00 to 7:00) (p < 0.0076). The percentage of time spent in reference range [70-180] mg/dl for the 3 nights was 90.8%

[83.8;98.4] in CL versus 66.1% [48.7;89.7] in OL (p<0.0368) and during 72 hours it was 79.8%

[74.2;85.7] in CL versus 61.8% [52.7;72.5] in OL (p<0.0021). Average blood glucose during 72 hours

was 138.0[129.4;147.1]mg/dl in CL versus 155.8[142.8;170.0] mg/dl in OL, p=0.0037. In both cases

the closed loop reached statistical significance for non-inferiority and superiority compared to the

open loop.

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All patients Sedentarity situation

Exceptional meals

situation Physical activity situation

Closed loop Open loop

Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Time spent in 80-140 during the 3 nights

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 61.1 27.4 58.7 45.2 58.4 14.7 66.6 30.9

95% CI [56.1;66.7] [19.2;39.0] [50.9;67.7] [25.2;81.0] [49.7;68.7] [7.6;28.6] [57.8;76.9] [17.2;55.3]

Ratio CL/OL 2.233 1.299 3.968 2.159

95% CI [1] [1.600;3.116

]

[0.749;2.253

]

[2.118;7.434] [1.245;3.744

]

Non-inferiority? Yes No Yes Yes

Superiority? Yes No Yes Yes

p value (difference) p<.0001 p=0.3406 p<.0001 p=0.0076

Table 6: Analysis of primary endpoint - study SP6.2

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Exceptional meals



Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Time spent in 70-180 during the 3 nights

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 86.0 58.0 82.2 72.7 85.2 40.7 90.8 66.1

95% CI [81.9;90.3] [48.2;69.8] [75.9;89.1] [53.6;98.7] [77.7;93.4] [28.7;57.6] [83.8;98.4] [48.7;89.7]

Ratio CL./OL 1.482 1.131 2.095 1.374

95% CI [1] [1.238;1.774

]

[0.840;1.521

]

[1.493;2.939

]

[1.021;1.849

]



Table 7: Time spent in 70-180 during the 3 nights - Diabeloop SP6.2.

of 145



Exceptional meals



Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Time spent in 70-180 during 72 hours

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 79.0 60.8 76.9 70.5 80.2 51.7 79.8 61.8

95% CI [75.6;82.5] [55.2;67.0] [71.6;82.6] [60.1;82.7] [73.9;87.1] [43.1;62.0] [74.2;85.7] [52.7;72.5]

Ratio CL/OL 1.298 1.091 1.553 1.290

95% CI [1] [1.182;1.426

]

[0.934;1.274

]

[1.302;1.853

]

[1.105;1.506

]



Table 8: Time spent in 70-180 during 72 hours – Diabeloop SP6.2

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Exceptional meals



Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Average blood glucose during entire 72 hour period

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 138.7 156.5 136.6 145.0 141.7 169.7 138.0 155.8

95% CI [133.5;144.2

]

[148.5;165.0

]

[128.1;145.7

]

[132.9;158.3

]

[131.7;152.4

]

[153.7;187.5

]

[129.4;147.1

]

[142.8;170.0

]

Ratio CL/OL 0.886 0.942 0.835 0.886

95% CI [1] [0.845;0.930

]

[0.870;1.019

]

[0.763;0.913

]

[0.818;0.958

]


p value (difference) p<.0001 p=0.1328 p=0.0003 p=0.0037

Table 9: Average blood glucose during 72 hours – Diabeloop SP6.2

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Exceptional meals



Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Delta of time spent in 70-180 (D2-D1)

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 3.1 -6.4 1.7 -19.7 4.6 -7.6 2.9 8.1

95% CI [-1.0;7.1] [-11.8;-1.0] [-4.9;8.4] [-28.6;-10.8] [-3.0;12.1] [-17.7;2.6] [-3.8;9.5] [-0.8;17.0]

Delta CL/OL 9.4 21.4 12.2 -5.2

95% CI [1] [2.1;16.7] [9.4;33.4] [-1.6;25.9] [-17.3;6.8]

Superiority? Yes Yes No No

p value (différence) p=0.0128 p=0.0010 p=0.0810 p=0.3831

Table 10: Delta of time spent in 70-180 (D2-D1)

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Exceptional meals



Closed loop

Sedentarity

Open loop

Sedentarity

Closed loop

Exceptional

meals

Open loop

Exceptional

meals

Closed loop

Physical

activity

Open loop

Physical

activity

Delta of time spent in 70-180 (D3-D1)

Non missing 36 36 13 13 10 10 13 13

Missing 0 0 0 0 0 0 0 0

Geometric mean 6.2 -1.0 7.2 -10.2 9.4 -7.7 1.9 15.0

95% CI [1.6;10.8] [-7.4;5.5] [-0.4;14.7] [-20.9;0.5] [0.8;18.0] [-19.9;4.5] [-5.6;9.5] [4.3;25.7]

Delta CL-OL 7.1 17.4 17.1 -13.1

95% CI [1] [-1.4;15.7] [3.3;31.5] [1.0;33.2] [-27.2;1.0]

Superiority? No Yes Yes No

p value (difference) p=0.0982 p=0.0173 p=0.0376 p=0.0682

Table 11: Delta of time spent in 70-180 (D3-D1)

Projet Diabeloop SP7 Version 2.2 du 24/03/2017 Numéro ID RCB : 2016-A01198-43 Ce document strictement confidentiel est la propriété du CERITD. Copyright CERITD. Toute reproduction est strictement interdite.

Results of safety assessment - study SP6.2:

Percentage of time spent >180mg/dl during the 3 nights:

1. All situations combined: 6.4% [4.2;9.5] in CL vs. 16.0% [10.4;24.7] in OL, p=0.003. CL is

significantly superior to OL.

2. Situation of sedentarity: 6.6% [3.4;13.0] in CL vs. 9.2[4.5;18.7] in OL, p=0.3981(Test non

significant).

3. Situation of exceptional meals: 9.4% [4.4;20.2] in CL vs. 34.2% [15.2;77.0] in OL , p=0.0055. CL is


4. Situation of physical activity: 4.1% [2.1;8.1] in CL vs. 13.1% [6.4;26.8] in OL, p=0.0046. CL is


Percentage of time spent < 70mg/dl during the 3 nights:

1. All situations combined: 1.9% [1.5;2.4] in CL vs. 2.7% [1.9;4.0] in OL, p=0.0665.

2. Situation of sedentarity: 2.2% [1.5;3.3] in CL vs. 2.9% [1.5;5.4] in OL, p=0.4508.

3. Situation of exceptional meals: 1.5% [1.0;2.4] in CL vs. 2.8% [1.3;5.7] in OL, p=0.1281.

4. Situation of physical activity: 1.9% [1.3;2.8] in CL vs. 2.5% [1.4;4.8] in OL, p=0.3723.

Percentage of time spent < 70mg/dl during 72 hours:

1. All situations combined: 2.1% [1.7;2.7] in CL vs. 2.7% [1.9;3.7] in OL, p=0.1301 (Test non

significant).

2. Situation of sedentarity: 3.1% [2.2;4.6] in CL vs. 3.1% [1.8;5.3] in OL, p=0.9332 (Test non

significant).

3. Situation of exceptional meals: 1.4% [0.9;2.2] in CL vs. 2.5% [1.3;4.7] in OL, p=0.561 (Test non

significant).

4. Situation of physical activity: 2.1% [1.5;3.1] in CL vs. 2.5% [1.4;4.3], p=0.5433 (Test non

significant).

Intercurrent events analyzed on all included subjects:


Parameter: CL OL Total Hyperglycemia > 3g 12 39 51 Asymptomatic hypoglycemia <= 0.7 g/l 29 24 53 Symptomatic hypoglycemia 58 75 133

Serious adverse events (SAEs):

An expected serious adverse event occurred in patient 2.CLAAN at center 2 Nancy CHU. The SAE occurred on Sunday 21/02/2016 while the patient was at home, before beginning the two

treatment sessions closed loop and open loop. Therefore the SAE is not related to the Diabeloop

system.

Medical device vigilance incidents occurring during the study:

No major system events or malfunctions life threatening to the patient occurred during the study. During the study, three main types of events occurred in different patients who wanted to continue

the study with the equipment:

- Loss of connection pump/Smartphone resolved by reinitializing communication.

- Loss of connection with Dexcom receiver resolved by reinitializing communication with the

receiver.

- Malfunction of the Diabeloop application, resolved by restarting regulation.

None of these events was associated with severe hyperglycemia or severe hypoglycemia. In total,

167 minor medical device vigilance events were identified. Resolution of these events took an

average of 10 to 15 minutes according to whether or not the engineer was routinely informed of the

event.

All the medical device vigilance events are detailed below:

1. Medical device vigilance - Smartphone

During the study, 176 medical device vigilance (MVG) events associated with the Smartphone occurred in 21 different patients who wished to continue with the equipment. None was associated with severe hyperglycemia or severe hypoglycemia. These 176 MVG events included: - 132 MVG related to a loss of connection. - 39 MVG related to a malfunction of the application. - 1 MVG related to the investigator’s dedicated remote monitoring Smartphone. - 1 MVG related to a Smartphone bug. - 1 MVG related to shutdown of the application - 1 MVG related to disconnection of the system.

- 1 MVG related to a bolus injection without preliminary confirmation.

2. Medical device vigilance - Pump

During the study 125 MVG events were identified:


- 121 MVG related to the Cellnovo pump in 28 patients who wished to continue with the equipment. - 4 MVG related to the usual pump in 3 patients who wished to continue with the equipment. No event was associated with severe hyperglycemia or severe hypoglycemia. These 121 MVG events with the Cellnovo pump included: - 77 MVG related to teletransmission between pump/Smartphone. - 6 MVG related to spontaneous shutdown of the DIABELOOP application. - 38 MVG related to the Cellnovo pump (cartridge empty, pump stopped, detection of

occlusion…).

3. Medical device vigilance - Sensor

During the study, 40 medical device vigilance (MVG) events associated with the Dexcom sensor

occurred in 13 patients who wished to continue with the equipment. None was associated with

severe hyperglycemia or severe hypoglycemia. Among these 40 events, 28 were associated with

teletransmission between the Dexcom receiver and the Smartphone.

4. Medical device vigilance - ActiHeart

During the study, 5 medical device vigilance (MVG) events associated with the electrodes used to

install the ActiHeart occurred in 5 patients who wished to continue with the equipment. None was

associated with severe hyperglycemia or severe hypoglycemia. The electrodes caused a skin reaction

in these patients.

5. Medical device vigilance - ActiGraph

No MVG events associated with the ActiGraph occurred during the study.

Patient satisfaction:

At the end of the study patients filled out three visual analogue scales (VAS) on the Diabeloop system: a. Satisfaction with the system: OL: 6.8 (±2.5) vs. CL: 8.5 (2.2) ; CL-OL 1.72[0.71;273] p=0.0016. b. Ease of use of the system: OL: 7.7(±2.1) vs. CL: 8.4(±1.5) ; CL-OL 0.74[0.71;273] p=0.1386.

c. Comfort of the system: OL: 6.4(±2.6) vs. CL: 7.2(±2.4) ; CL-OL 0.70[-0.23;1.63] p=0.1346.

Diabetes treatment satisfaction questionnaire DTSQ:

DTSQs OL: total score (/36) DTSQs CL: total score (/36) DTSQs OL-CL 95%CI 26.0 (±5.5) 31.0 (±5.5) -4.83 [-7.28; -2.38] P=0.0003


The statistical test showed that patients were satisfied with the Diabeloop system compared to the

usual system (open loop).

Conclusion:

In various situations such as intensive physical activity, exceptional meals or sedentarity, the Diabeloop system doubled the time spent in tight glucose range 80-140mg/dl during the night, decreased the time spent in hypoglycemia and hyperglycemia during the night, and reduced average blood glucose compared to conventional insulin pump therapy. In the repeated heavy meal situation, the Diabeloop system nearly quadrupled the time spent in tight glucose range 80-140mg/dl during the night and decreased average blood glucose compared to the conventional treatment. In the repeated intensive physical activity situation, the Diabeloop system doubled the time spent in

80-140mg /dL during the night and decreased average blood glucose during 72 hours compared to

the open loop, without increasing the risk of hypoglycemia.

On the other hand, medical device vigilance events comprised a large number of technical incidents

mainly related to communication problems between the Dexcom sensor with a Bluetooth connector

and the Cellnovo pump using ANT+ radio service. This problem will be resolved since the new

generation of Cellnovo pumps will be equipped with Bluetooth. The communication between the

Dexcom sensor and the pump will be compatible and the risk of interference from other radio waves

will be very low.

chu grenoble alpes - rendre l’insouciance et la qualité de vie · 2019. 3. 20. · diseases, chu...

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