clinical study protocol - university of oxford · (dtu), uk, professor da yi hu from peking...

Study Number 11232/OXTREC 51-08/Version 10 /Amendment 7/ 28th

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CLINICAL STUDY PROTOCOL

Title: The Acarbose Cardiovascular Evaluation (ACE) Trial.

A Long-term, Multicentre, Double-blind, Randomised

Parallel-group Trial to Determine Whether Reducing

Post-prandial Glycaemia can Reduce Cardiovascular-

related Morbidity and Mortality in Patients with

Established Coronary Heart Disease or Acute Coronary

Syndrome who have Impaired Glucose Tolerance.

Study Number/Version/Date: 11232 / Version 10 / Amendment 7 / July 28th

2016

Development Phase: Phase IV

Test Drug: Acarbose

Sponsoring Institution: The University of Oxford

The University Offices

Wellington Square

Oxford OX1 2JD

UK

Chief Investigator: Professor Rury Holman

Diabetes Trials Unit

Oxford Centre for Diabetes, Endocrinology and

Metabolism (OCDEM)

Churchill Hospital

Old Road

Headington

Oxford OX3 7LJ

Tel: +44 (0) 1865 857240

Confidentiality

statement:

The following confidential information is the property of the ACE Trial Steering Committee. As long as

the information contained in this protocol has not been published, it may only be used when permission

has been obtained from the ACE Trial Steering Committee. It is not possible to make reproductions of all

or sections of this protocol. Commercial use of the information is only possible with the permission of the

proprietor and is subject to a license fee.


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Acceptance of Protocol Version 10 / Amendment 7

Principal Investigator:

I have read this protocol and agree to abide by all provisions set forth therein.

I agree to comply with the International Conference on Harmonisation Tripartite Guideline on Good

Clinical Practice.

______________________________________

Print Name of Principal Investigator

______________________________________ __________________

Signature of Principal Investigator Date


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Table of Contents

1. INTRODUCTION ................................................................................................. 8

2. STUDY OBJECTIVES ........................................................................................ 9

3. INVESTIGATORS AND OTHER STUDY PARTICIPANTS ................................ 9

3.1 Honoured Advisor ....................................................................................................................................... 9

3.2 Chief Investigator ...................................................................................................................................... 10

3.3 Co-Chairs ................................................................................................................................................... 10

3.4 Steering Committee ................................................................................................................................... 10

3.5 Data Safety Monitoring Board (DSMB) .................................................................................................. 11

3.6 Endpoint Adjudication Committee .......................................................................................................... 11

3.7 Publications ............................................................................................................................................... 12

4. INVESTIGATIONAL PLAN ............................................................................... 12

4.1 Study Design and Plan .............................................................................................................................. 12

4.2 Selection of Study Population................................................................................................................... 13 4.2.1 Inclusion Criteria ............................................................................................................................... 13 4.2.2 Exclusion Criteria .............................................................................................................................. 14 4.2.3 Diabetes Diagnosed on Screening ..................................................................................................... 14

4.3 Removal of Patients from Study .............................................................................................................. 15

4.4 Premature Closure of Centre ................................................................................................................... 15

4.5 Premature Termination of Study ............................................................................................................. 15

4.6 Study Medication ...................................................................................................................................... 16 4.6.1 Study Medication to be Administered ............................................................................................... 16 4.6.2 Identity of Investigational Product(s) ................................................................................................ 16 4.6.3 Method of Assigning Patients to Treatment Groups .......................................................................... 17 4.6.4 Selection of Doses in the Study ......................................................................................................... 17 4.6.5 Timing and Titration of Dose for Each Patient .................................................................................. 17 4.6.6 Blinding ............................................................................................................................................. 18 4.6.7 Concomitant Therapy ........................................................................................................................ 18 4.6.8 Treatment Adherence ........................................................................................................................ 18 4.6.9 Assessment Periods ........................................................................................................................... 19 4.6.10 New Onset Diabetes During Study ............................................................................................... 20

4.7 Observations and Measurements: Assessment for Treatment Effects ................................................. 21 Note: patients who experience any of the non-fatal endpoints musts remain on study medication and continue

the study. Any subsequent endpoint should also be reported........................................................................... 21


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4.7.1 Screening Visit (Visit 1, -5 weeks) .................................................................................................... 21 4.7.2 Run-in Visit (Visit 2, -4 weeks) ......................................................................................................... 22 4.7.3 Randomisation Visit (Visit 3, week 0)............................................................................................... 23 4.7.4 Follow up Visits ................................................................................................................................ 24 4.7.5 Annual Visits ..................................................................................................................................... 24 4.7.6 Closeout Visit .................................................................................................................................... 25 4.7.7 Final Visit/Telephone Contact ........................................................................................................... 26

4.8 Data Quality .............................................................................................................................................. 26

4.9 Documentation .......................................................................................................................................... 27

5. ETHICAL AND LEGAL ASPECTS ................................................................... 28

5.1 Ethics Committee or Institutional Review Board................................................................................... 28

5.2 Ethical Conduct of the Study ................................................................................................................... 28

5.3 Regulatory Authority Approvals/Authorizations ................................................................................... 28

5.4 Informed Consent ..................................................................................................................................... 28

5.5 Insurance ................................................................................................................................................... 29

5.6 Confidentiality ........................................................................................................................................... 29

6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .......... 29

6.1 Description of Patient Groups for Analysis ............................................................................................ 29

6.2 Study Objectives ........................................................................................................................................ 29 6.2.1 Primary Endpoint ............................................................................................................................... 29 6.2.2 Secondary Endpoints ......................................................................................................................... 30

6.3 Statistical and Analytical Plans ................................................................................................................ 30

6.4 Interim Analysis/Analyses ........................................................................................................................ 31

6.5 Sample Size Estimation............................................................................................................................. 31 6.5.1 Event Rate ......................................................................................................................................... 31 6.5.2 Number of Patients ............................................................................................................................ 31

6.6 Health Economic Evaluation .................................................................................................................... 31 6.6.1 Resource use and costs ...................................................................................................................... 32 6.6.2 Economic outcomes ........................................................................................................................... 32 6.6.3 Cost-effectiveness .............................................................................................................................. 32 6.6.4 Analysis and presentation of economic data ...................................................................................... 33

7. ADVERSE EVENTS ......................................................................................... 33

7.1 Adverse Event Monitoring ....................................................................................................................... 33

7.2 Adverse Event Definitions ........................................................................................................................ 34 7.2.1 Adverse Event (AE)........................................................................................................................... 34


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7.2.2 Serious Adverse Event (SAE) ........................................................................................................... 34 7.2.3 Suspected Serious Adverse Reaction (SSAR) ................................................................................... 34 7.2.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................................ 34 7.2.5 Relationship to Study Medication ..................................................................................................... 35 7.2.6 Severity of the Adverse Event ........................................................................................................... 35

7.3 Collection and Reporting of Adverse Events .......................................................................................... 35

7.4 Reporting of Pregnancy ............................................................................................................................ 36

7.5 Warnings/Precautions for Acarbose ........................................................................................................ 36

7.6 Overdosage ................................................................................................................................................ 37

8. USE OF DATA AND PUBLICATION ................................................................ 37

9. APPENDIX 1 ..................................................................................................... 38

9.1 Study Flow Chart and/or Schedule Procedure ....................................................................................... 38

10. APPENDIX 2: NYHA GRADING CRITERIA FOR HEART FAILURE .......... 40

11. APPENDIX 3: OGTT PROCEDURE ............................................................. 41

12. REFERENCES .............................................................................................. 43


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Glossary and Abbreviations

2HPG

ACS

AE

ALT

CABG

CHD

CVD

2-hour post-challenge plasma glucose

Acute Coronary Syndrome

Adverse Event

Alanine Transaminase

Coronary Artery Bypass Graft

Coronary Heart Disease

Cardiovascular Disease

CRF

DSMB

DTU

Case Report Form (either paper or electronic)

Data Safety Monitoring Board

Diabetes Trials Unit

EC

ECG

eCRF

FPG

Ethics Committee

Electrocardiogram

Electronic Case Report Form

Fasting Plasma Glucose

GCP Good Clinical Practice

ICH

IFG

IGT

International Conference on Harmonization

Impaired Fasting Glucose

Impaired Glucose Tolerance

IRB

MDRD

MI

Institutional Review Board

Modification of Diet in Renal Disease

Myocardial Infarction

MRR

NAFLD

NYHA

OGTT

PCI

Medical Research Report

Non Alcoholic Fatty Liver Disease

New York Heart Association classification

Oral Glucose Tolerance Test

Percutaneous Coronary Intervention

SAE

T2DM

TIA

TMS

ULN

Serious Adverse Event

Type 2 Diabetes Mellitus

Transient Ischaemic Attack

Trial Management System

Upper Limit of Normal


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1. INTRODUCTION

The number of people worldwide with diabetes is predicted to exceed 300 million by

the year 2025, more than all of the people living currently in North America [1]. Over 90% of

those with diabetes have type 2 diabetes (T2DM), which confers a two to four times greater

risk of heart disease and stroke than in the general population and a concomitant reduction in

life expectancy of five to ten years [2]. Given that around 80% of all diabetes-related deaths

are associated with cardiovascular disease (CVD), it is of paramount importance that

everything possible is done to reduce coronary heart disease (CHD) risk in these people.

Equally, previously undiagnosed diabetes and impaired glucose tolerance are common in

patients with an acute myocardial infarction [3] and the Euro Heart Survey showed that

normal glucose regulation was less common than abnormal glucose regulation in patients

with coronary artery disease [4]. A meta analysis [2] of people with impaired glucose

tolerance (IGT) has shown that this prediabetic state is associated also with a substantially

increased CVD risk with some evidence that postprandial hyperglycaemia may have the

greatest deleterious effect [5]. China has one of the highest rates of new-onset T2DM in the

world today [6] and the China Heart Survey has shown that the prevalence of IGT is

significantly higher in Chinese patients with CHD, compared with those without CHD [7].

The rate of development of new-onset diabetes has been shown in patients with IGT

to be reduced by 25% with acarbose in the international STOP NIDDM trial [8], 88% in a

Chinese multicentre trial [9] and to be reduced non-significantly in a smaller Chinese study

[10]. Reductions of 31% with metformin were seen in the Diabetes Prevention Program [11]

and 77% in a Chinese multicentre trial [9]. Improved lifestyle achieved a 58% reduction in

both the Diabetes Prevention Program [11] and the Finnish Diabetes Prevention Study [12].

In a mixed population of IGT and/or IFG patients the rate of development of new-onset

diabetes was reduced by 60% with rosiglitazone therapy [13]. Epidemiological analyses of

UK Prospective Diabetes Study (UKPDS) data for patients with newly diagnosed T2DM

have confirmed that, in addition to age and gender, the potentially modifiable risk factors for

CHD include the “deadly quintet” of hyperglycaemia, a raised LDL cholesterol, a low HDL

cholesterol, hypertension and smoking [14]. Whilst the excess CHD risk seen in those with

diabetes is not explained fully by these conventional risk factors, there is increasing evidence

of the benefits that can be obtained from a number of different cardiovascular interventions.

The UKPDS showed that intensive control of glycaemia with sulphonylurea or insulin, and

with metformin in overweight patients, can reduce substantially the risk of diabetic

complications [15], although the true extent to which reducing glycaemia can impact on CVD

is still to be established. The UKPDS showed that intensive control of blood pressure with an

ACE inhibitor or a beta-blocker can also reduce substantially the risk of diabetic

complications [16]. The HPS (Heart Protection Study) [17] and the CARDS (Collaborative

Atorvastatin Diabetes Study) [18] trials have shown definitively that lowering LDL

cholesterol levels can reduce cardiovascular risk to a major extent. However, despite

confirmation that lowering glycaemic, blood pressure and LDL cholesterol levels improves

clinical outcomes substantially, the residual risk of further cardiovascular events or premature

death in people with T2DM remains unacceptably elevated.

It is clear that additional approaches to cardiovascular risk reduction are required, as

well as strategies to reduce the incidence of new-onset T2DM. The STOP NIDDM study


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demonstrated not only that acarbose can reduce the risk of T2DM in patients with IGT but

suggested also that acarbose administration to IGT patients may reduce cardiovascular

morbidity and mortality [19]. This latter suggestion is supported by a study by Hanefeld and

colleagues, which showed acarbose, can reduce the rate of intima-media thickness (IMT)

progression [20].

Despite these findings, there remains a genuine uncertainty as to whether acarbose

can reduce CVD morbidity and mortality in IGT patients with CHD. Accordingly, it is

proposed to evaluate whether these potential benefits of acarbose can be confirmed in this

population by undertaking a multicentre clinical outcome study in Chinese patients with

established CHD or an acute coronary syndrome (ACS) who also have IGT.

2. STUDY OBJECTIVES

The primary objective of the Acarbose Cardiovascular Evaluation (ACE) Trial is to

determine whether acarbose therapy can reduce cardiovascular-related morbidity and

mortality in patients with IGT who have established CHD or ACS (secondary cardiovascular

prevention).

A secondary objective of the ACE Trial is to determine if acarbose therapy can prevent or

delay transition to T2DM in this patient population (primary diabetes prevention).

3. INVESTIGATORS AND OTHER STUDY PARTICIPANTS

The ACE Trial is a multicentre trial, which will be conducted, in around 150 cardiovascular

units in Mainland China and Hong Kong. ACE is an investigator-initiated, academic study

designed by Professor Rury Holman from the University of Oxford Diabetes Trials Unit

(DTU), UK, Professor Da Yi Hu from Peking University and Professor Chang Yu Pan from

the Chinese PLA General Hospital, Beijing, China.

The trial will be sponsored, run and analysed by the DTU. The ACE Coordinating Centre,

located in the DTU, will set up and oversee a regional Project Office located in Beijing that

will handle the day-to-day operations of the trial.

Cardiovascular endpoint adjudication was performed by the University of Glasgow until July

2014. Thereafter, the ACE Steering Committee mandated that this process would be

transferred to a Chinese Cardiovascular Endpoint Adjudication Committee, led by senior

cardiologists from Peking University People’s Hospital, Beijing, and Shanghai Tenth

People's Hospital, Tongji University, Shanghai.

Diabetes endpoint adjudication will be performed by the University of Glasgow.

Health Economic Evaluation will be undertaken by the University of Oxford Health

Economic Research Centre (HERC), led by Professor Alastair Gray.

3.1 Honoured Advisor

Professor Jialun Chen, Shanghai Institute of Endocrine and Metabolic Diseases.


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3.2 Chief Investigator

The ACE Trial Chief Investigator and Chair of the study will be Professor Rury Holman.

3.3 Co-Chairs

The ACE Trial Co-Chairs will be Professor Da Yi Hu and Professor Chang Yu Pan.

3.4 Steering Committee

The ACE Steering Committee will have overall responsibility for finalising the protocol and

supervising the conduct of the study. It will meet six-monthly, or more often if necessary,

with at least one face-to-face meeting each year to consider issues raised during the progress

of the study, to review relevant information from other sources e.g. related studies, and to

consider recommendations from the Data Safety Monitoring Board (DSMB). The Steering

Committee will comprise twelve independent academics, the DTU Head of Clinical Research

and two representatives from Bayer.

The Steering Committee will oversee the operation of the study in accordance with current

Good Clinical Practice (GCP) guidelines, including production of the electronic CRFs

(eCRFs), site monitoring, data management, statistical analyses and final submission of

publications.

Steering Committee members, in alphabetical order, will be:

Juliana Chan Hong Kong Endocrinologist

Jean Louis Chiasson Canada Endocrinologist

Junbo Ge China Cardiologist

Hertzel Gerstein Canada Endocrinologist

Rury Holman UK Endocrinologist (Chair)

Da Yi Hu China Cardiologist (Co-Chair)

John McMurray UK Cardiologist

Chang Yu Pan China Endocrinologist (Co-Chair)

Lars Rydén Sweden Cardiologist

Michal Tendera Poland Cardiologist

Jaakko Tuomilehto Finland Epidemiologist

Wenying Yang China Endocrinologist

Yong Huo China Cardiologist


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UK DTU Head of Clinical Research

China/Germany Bayer Representative

China/Germany Bayer Representative

3.5 Data Safety Monitoring Board (DSMB)

The DSMB will report to the Steering Committee. It will consist of seven members with

proven DSMB experience to include a Chairman, two cardiologists, two diabetologists, a

hepatologist and a statistician, at least two of which will be practicing currently in China.

ACE will commission a statistical group independent of Bayer and the DTU to provide

confidential interim analyses for the DSMB, under the direction of the DSMB statistician.

DSMB members will remain independent of the study staff, the Steering Committee and of

Bayer. At DSMB meetings, senior ACE Coordinating staff may present the updated status of

the study to the committee but will not remain in attendance whilst the DSMB statistician

presents unmasked study data, or for any subsequent discussions.

Anybody associated with the study may write to the DSMB chairman drawing attention to

any worries they may have e.g. about the possibility of particular side-effects, or about

particular categories of patient requiring special consideration, or about any other matters that

may be relevant.

The remit of the DSMB is to:

Consider unmasked interim data and relevant information from other sources

including endpoints and serious adverse events.

Determine how frequently interim safety analyses of study data should be undertaken.

These analyses will be itemised in a statistical analysis plan (SAP), agreed in advance

with the DSMB and modified by them as appropriate during the trial.

Report to the Steering Committee following each DSMB meeting recommending

whether the trial should continue in accordance with the protocol, the protocol should

be modified or the study should be stopped.

To highlight any areas of concern with respect to the trial.

To feedback any suggestions they might have for improving the conduct of the trial.

To consider any requests for unmasking and release of interim study data and to

recommend the importance of this to the Steering Committee. The Steering

Committee will then decide whether to modify the trial (or to seek extra data). Unless

this happens or the trial is stopped, the Steering Committee, study investigators, study

staff and Bayer will remain ignorant of interim trial results.

3.6 Endpoint Adjudication Committee

The Endpoint Adjudication Committee will be responsible for reviewing and coding all

major clinical outcomes pertinent to the study, identified from adverse events, biochemistry

or electrocardiogram (ECG) results. They will also be required to adjudicate any instances


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where diabetes has been diagnosed other than by the protocol defined process. All potential

primary and secondary endpoints will be reviewed and adjudicated by two members,

independently, according to pre-determined criteria (see the Endpoint Committee Charter). If

both members agree, the event will be considered adjudicated and coded accordingly. In the

case of disagreement, the potential endpoint will be reviewed by the full endpoint committee

and adjudicated either by agreement of all committee members (usually) or, if consensus is

not reached (rarely), a majority vote.

3.7 Publications

The Steering Committee will recommend a writing group for each manuscript with a lead

author and approve the production of all ACE Trial manuscripts. Writing groups will

comprise typically of three to seven individuals identified usually from trial members. The

lead author will be responsible for ensuring that the paper is written in a timely manner,

liaising with the trial statistician as necessary, and keeping the ACE Trial Manager informed

of progress. For papers involving analysis of data generated by the ACE Trial, at least one

member of the writing group will be from the DTU’s Statistics and Modelling Group.

Major publications will be authored “on behalf of the ACE Trial group” and produced in

accordance with CONSORT guidelines [21]. The first substantive ACE publication will list

all trial staff and Committee members. Individual authorship will be governed by the

international standards for publication of academic research [22]. The Steering Committee

will review and comment on drafts of papers to ensure accurate, uniform, timely and high

quality reporting of the ACE Trial and will be responsible for the final approval and

submission of all ACE publications.

4. INVESTIGATIONAL PLAN

4.1 Study Design and Plan

ACE is a double blind, randomised, multi-centre, prospective, cardiovascular intervention

trial planned to start in 2008. Six thousand five hundred patients will be randomised in

around 150 Chinese clinical centres. Recruitment will be competitive, with no cap on the

number of patients that any one site can randomise, and will close once 6500 patients in total

have been randomised.

Patients will be allocated randomly 1:1 to double blind therapy with acarbose (50 mg) or

matching placebo three times daily with meals.

Patients will be followed up until there have been 728 adjudicated primary composite

endpoints, unless the trial should be terminated earlier. All patients that cease study

medication will be followed up, if at all possible, for the full study period. All patients that

withdraw from the trial will have their vital status ascertained, if at all possible, at the end of

the trial.

Potential participants will be preselected by clinical centre investigators by reviewing

cardiology outpatient medical records and inviting any patients thought suitable to attend a

screening visit. Those who fulfill all of the inclusion criteria and violate none of the exclusion

criteria, and who have provided written informed consent, will undergo an oral glucose


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tolerance test (OGTT). Only those patients found to have impaired glucose tolerance (IGT)

will be entered into the Trial.

Enrolled patients will undergo a four-week single-blind placebo run-in period during which

time their existing therapy for coronary heart disease (CHD) will be optimised if it does not

conform already to internationally accepted guidelines for the treatment of patients with

established CHD i.e. antiplatelet therapy (unless contraindicated or not tolerated), a statin

(unless contraindicated or not tolerated) and, if considered indicated by the investigator, an

ACE inhibitor, a beta-blocker and/or antihypertensive therapy.

ACE follow up visits will be performed at one month, at two months, at four months post-

randomisation, and then every four months.

4.2 Selection of Study Population

Approximately 6,500 patients found to have IGT and with established coronary heart disease

(CHD), including those with a recent acute coronary syndrome (ACS).

4.2.1 Inclusion Criteria

1. Male or female, aged 50 years or more.

2. Definite CHD, defined as a, b or c below:

a) Previous myocardial infarction (MI) or Acute Coronary Syndrome (ACS), but not

within the last 3 months, with any two of the following:

i) Typical clinical presentation

ii) Confirmatory ECG changes

iii) Appropriate elevation of cardiac enzymes/biomarkers

If original reports are unavailable then alternative documentation e.g. discharge

summary or a clinical note from the study Investigator describing the evidence for a

previous MI will be accepted.

Note: Patients with stents are eligible.

b) Previous unstable angina (UA) or Acute Coronary Syndrome (ACS), but not within

the last 3 months, with any two of the following:

i) Typical clinical presentation

ii) Confirmatory ECG changes

iii) Either elevation of a cardiac biomarker or a >50% stenosis in ≥1 major epicardial

coronary artery shown on coronary angiography or CT angiography. Where

stenosis is reported in a qualitative manner, the categories “moderate” and

“severe” will be taken as equating to >50% stenosis.

c) Current stable angina defined as:

i) Typical clinical history with symptoms occurring within the last month, and

ii) A >50% stenosis in ≥1 major epicardial coronary artery shown on coronary

angiography or CT angiography. Where stenosis is reported in a qualitative


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manner, the categories “moderate” and “severe” will be taken as equating to

>50% stenosis.

3. Impaired glucose tolerance diagnosed on a single standard OGTT, defined as a 2-hour

plasma glucose (2HPG) value ≥7.8 but <11.1 mmol/l and a fasting plasma glucose

(FPG) <7.0 mmol/l within six months prior to enrollment.

4. Optimised cardiovascular drug therapy.

5. At least 80% adherent to single blind placebo Study Medication during the run-in period.

6. Provision of written informed consent.

4.2.2 Exclusion Criteria

1. Previous history of diabetes, other than gestational diabetes.

2. MI, unstable angina, stroke or a transient ischaemic attack (TIA) within the previous

three months.

3. Planned or anticipated coronary, cerebrovascular or peripheral arterial revascularisation

or other major surgical intervention, at the time of randomisation.

4. NYHA class III or IV heart failure. NYHA classification criteria are listed in Section 10,

Appendix 2.

5. Evidence of severe hepatic disease.

6. Evidence of severe renal impairment or an eGFR <30 ml/min/1.73m2

(derived using the

MDRD Chinese equation [23])

7. Any other condition likely to reduce adherence to the protocol e.g. alcoholism, major

active psychiatric disorder, cognitive impairment or a condition likely to markedly limit

life expectancy e.g. malignancy.

8. Pregnancy (or planned pregnancy within the next five years).

9. Concurrent participation in any other clinical interventional trial. Note: Patients who

were treated previously with an alphaglucosidase inhibitor must have at least a three-

month washout period before being randomised into the ACE trial.

10. Known intolerance to alpha glucosidase inhibitors or gastrointestinal problems.

11. Thought by the investigator for any reason to be unsuitable for participation in this

clinical study.

4.2.3 Diabetes Diagnosed on Screening

Patients diagnosed with diabetes during screening or run-in are not eligible to join the trial

and will be referred for medical care in line with local practice. Note: for the purposes of this

study any diagnosis prior to randomisation only requires a single test result in the diabetic

range and does not need to be confirmed.


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4.3 Removal of Patients from Study

Patients will be excluded from entry to the Study if they take less than 80% of their single

blind placebo run-in medication.

Once randomised, all patients should be followed wherever possible until the end of the trial

even if no longer taking study medication.

In accordance with the World Medical Association Declaration of Helsinki (1996 version), as

amended from time to time, all patients have the right to withdraw from the study at any time

and for any reason, without prejudice to his or her future medical care by the physician or

institution, and is not obliged to give his or her reasons for doing so. Without compromising

the right of patients to withdraw from the trial, every effort will be made to understand and

accommodate their concerns and avoid withdrawal wherever possible. This will include, for

instance, down-titrating Study Medication if side effects are a concern, agreeing to a Study

Medication interruption if circumstances dictate, flexibility with regard to follow up intervals

and continued automatic follow-up of patients to end of trial even if they are not taking Study

Medication.

In the event that a patient is unwilling to attend follow up visits, as outlined in 4.6.8, they

will be asked if they will permit the investigator to contact them, while the study is ongoing,

to collect as much data as possible and/or try to establish their vital status at the end of the

trial either by direct contact with them or the people that they have listed as contacts (in

person, by telephone or by letter) or through records (hospital records, public records etc.).

4.4 Premature Closure of Centre

An individual clinical centre may be closed under the following circumstances:

Failure to recruit

Non-compliance with the protocol

Non-compliance with Good Clinical Practice

Unethical practices

Should a clinical centre be closed prematurely, all study materials (except documentation that

has to remain stored at site) must be returned to the sponsor. The investigator will retain all

other documents until notification given by the sponsor for destruction.

4.5 Premature Termination of Study

ACE is an event driven trial and will continue until a total of 728 adjudicated primary events

have been accumulated. The study may be terminated at any time by the Steering Committee

if, in the opinion of the DSMB continuation of the study represents a serious medical risk to

the patients.

During the period of the study, interim analyses of primary endpoints, mortality and of any

other information that is available on major events along with any other analyses that the

Steering Committee may request, will be supplied in strict confidence, to the chairman of the

independent DSMB. In the light of these analyses, and the results of any other relevant


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studies, the DSMB will advise the Steering Committee if, in their view, the randomised

comparisons in the study have provided “proof beyond reasonable doubt” that for all, or for

some specific types, of patient, really prolonged use of either treatment is clearly indicated or

clearly contra-indicated in terms of a net difference in all-cause mortality.

The DSMB may recommend premature termination of the study if recruitment is so low that

it becomes unrealistic to consider completion of the protocol in an acceptable period of

time.

4.6 Study Medication

4.6.1 Study Medication to be Administered

At week -4, all patients who complete all screening procedures and who meet the eligibility

criteria to enter the study will be commenced on single blind once-daily placebo tablets.

At Week 0, all patients who complete all screening procedures, who meet the eligibility

criteria to enter the study and who have taken at least 80% of their single-blind placebo run-

in study medication are to be randomized into one of the following two double-blind

treatment groups:

Acarbose tablets (50 mg)

Matching placebo tablets

For selection and timing of the dose please refer to respective section of the study protocol

(4.6.5.).

Investigators will dispense Study Medication only to patients included in this trial following

the procedures set out in the study protocol.

4.6.2 Identity of Investigational Product(s)

Bayer will be responsible for the packaging of the study drug and placebo according to

applicable regulatory requirements. All drug supplies must be stored in accordance with the

manufacturer’s instructions. Label text will be approved according to agreed Bayer

procedures, and a copy of the labels will be made available to study sites upon request.

For the study Acarbose tablets (Bayer ID number: BAY g 5421; trade name: Glucobay)

manufactured by Bayer HealthCare Company Ltd, China, will be used. Matching placebo

tablets will be manufactured and provided by Bayer HealthCare AG, Germany.

Run-in tablets will be packaged in aluminium-aluminium strips. Within study Acarbose and

placebo will be packaged in PVC/PVDC foil.

All Study Medication is to be stored in a securely locked, limited access area, protected from

light and at temperatures below 25˚C, until dispensed to the patient. After the drug is


July 2016 of 45

dispensed it is desirable, but not mandatory, to store at temperatures below 25oC. (Note:

Patients should be made aware that some discolouration of the tablets might occur).

4.6.3 Method of Assigning Patients to Treatment Groups

Each clinical centre will be assigned a unique three-digit centre code when they are enrolled.

Participants considered for entry to the Study at their Screening Visit (Visit 1) will be

identified by a unique within-centre serially assigned participant number, by their initials and

their date of birth. Participant numbers will be assigned automatically by the TMS and no

attempt should be made to allocate numbers outside the system.

At their Randomisation Visit (Visit 3), participants who fulfil all of the inclusion criteria,

violate none of the exclusion criteria and have demonstrated satisfactory compliance during

the run-in period, will be assigned a unique Randomisation number that will allow

subsequent identification of their randomised treatment group allocation. These

randomisation numbers will be generated by Bayer using a computerised procedure. In order

to maintain balance between treatment groups within each Clinical Centre, the randomisation

sequence will allocate patients 1:1 to acarbose or to matching placebo in permuted blocks of

an appropriate size on a centre-by-centre basis.

Any errors made concerning randomisation, such as omitting a number or dispensing

incorrect medication should be documented by the investigator in the study file and on the

eCRF.

4.6.4 Selection of Doses in the Study

The two study treatment regimens are as follows:

Treatment group Tablet content

Acarbose

Acarbose 50 mg

One tablet three times a day

No treatment

Placebo to match acarbose 50 mg tablet

One tablet three times a day

4.6.5 Timing and Titration of Dose for Each Patient

A “Start low, Go slow” dose titration scheme will be used. Patients will be instructed to

commence Study Medication by taking one tablet a day with their smallest meal during the

single-blind placebo run-in period and then for one week following allocation to randomised

Study Medication. During the second week post-randomisation they will be instructed to

increase their Study Medication by taking a second tablet with their next smallest meal.

During the third week they will be instructed to add a third tablet with their third meal and

continue with three tablets thereafter. Study medication must only be taken with meals; if

patients habitually take two meals per day then only two tablets of Study Medication per day

should be taken.

Reduction of Study Medication doses will be allowed in the event of side effects. Patients

may discontinue Study Medication temporarily e.g. for intercurrent illness or hospital


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admission. Patients who temporarily discontinue drug or reduce their dose to one tablet will

be required to repeat the “Start low, Go slow” dose titration scheme when it is restarted or up

titrated. In the event of Study Medication over-dosage, please refer to the guidelines in

Section 7.6. Note: Patients who discontinue study drug should be asked at every visit to

consider restarting it. In the case where a patient is unable to attend a clinic visit, the

drug may be mailed to the patient; contact ACPO for details.

4.6.6 Blinding

Copies of the code break will be held by the Bayer Drug Surveillance Group in China. They

will maintain a 24-hour telephone help line (010-5979 9788) should emergency unmasking of

a participant’s Study Medication become necessary. If unmasking is necessary because of a

serious, unexpected and related adverse event or if a medical emergency occurs which

requires knowledge of the exact therapy, the investigator may contact the Bayer help line.

The ACE Trial Manager must be notified of the code break as soon as possible. The date and

reason of the code break must be documented and signed and this information sent to the Co-

ordinating Centre. The patient should be withdrawn from Study Medication but be followed

up according to the protocol.

4.6.7 Concomitant Therapy

A list of concomitant medications relevant to the Study Medication (i.e. cardiac/control of

glucose) will be itemised on an eCRF. The Investigator should record if a patient on entry

and/or given is taking any of these medications in addition to Study Medication during the

course of the study.

4.6.8 Treatment Adherence

Treatment Cessation

After the Randomisation (Visit 3) patients may cease taking Study Medication for any of the

following reasons:

Voluntarily

Safety reasons

Patients diagnosed with diabetes requiring open-label acarbose therapy

Patients whose creatinine clearance falls below 25mls/min/1.73m2 (derived using the

MDRD Chinese equation [23])

Adherence will be assessed by a Study Medication tablet count at relevant visits. Patients

who discontinue Study Medication should be encouraged at every visit, wherever

appropriate, to restart it, using the “Start low, Go slow” dose titration scheme. Patients may

take a reduced dose of Study Medication if limited by side effects. For patients who become

unwilling to take any Study Medication, the reason for discontinuation must be clearly stated.

Patients who withdraw permanently from double blind Study Medication should continue to

be followed as normal and undergo all protocol determined assessments until study closeout,

provided that they have not withdrawn consent. In the event that a patient is unwilling or


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unable to attend clinic visits but has not withdrawn consent, arrangements must be made to

obtain annual and study closeout updates on the patient’s vital status and evidence of putative

study endpoints.

4.6.9 Assessment Periods

Patients with established CHD or hospitalized for ACS will be asked to consider joining the

study. They will be provided with written information about the Study and the procedures

involved. They will be given the opportunity to ask questions and given ample time to

consider participation.

Patients will be invited to a Screening Visit (Visit 1) as soon as the treating physician

considers their condition to have stabilized and asked to provide written informed consent;

those who fulfill all of the inclusion criteria and violate none of the exclusion criteria, will

have an OGTT performed. Patients found to have IGT and who continue to be eligible will

attend a Run-in Visit (Visit 2) approximately one week later and, if there are no

contraindications, be entered into the trial. (Note: Visits 1 and 2 may be conducted at the

same time if the patient has a valid OGTT result that establishes eligibility at Visit 1)

Demographic characteristics of patients screened but not able to join the trial will be recorded.

Patients with a recent MI, Unstable Angina, Stoke or TIA, may be screened once stable and

enter run-in if eligible but must not be randomised until 3 months after the

MI/UA/Stroke/TIA.

Following enrolment, patients will have a four-week single-blind placebo run-in during

which time their physician will be asked to optimise their CHD therapy if it does not conform

to international guidelines for treating patients with established CHD i.e. antiplatelet therapy

and a statin unless contraindicated or not tolerated and, if considered indicated by the

investigator, an ACE inhibitor, a beta-blocker and/or antihypertensive therapy. Visits will be

performed one, two and four months post-randomisation and subsequently every four

months. A final visit/telephone contact will be performed approximately one month after the

patient completes the study.

Patients who have not returned to site for >120 days during the pre-randomisation period (i.e.

screening and run-in) should be discontinued in the rTMS.

All routine blood samples will be analysed by the Clinical Centre’s local laboratory. The

biomarker and DNA samples will be stored in a central laboratory in China. Any analyses of

these samples will be performed in China. They can only be undertaken at the request of the

Steering Committee and with any approvals required by the Chinese Authorities.

It should be stated in the patient’s medical notes that the patient is participating in the ACE

Trial.

If a patient misses a visit they should be contacted as soon as possible to re-schedule the visit.

If a patient has missed visits, and returns to the clinic, data should be entered in the most

recent due visit. Consider carrying out any tests or procedures that were missing in the

interim. If you are unsure how to record missed data contact ACPO.


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4.6.10 New Onset Diabetes During Study

For diabetes to be diagnosed during the Study (i.e. at a study site), abnormal plasma glucose

values (a FPG ≥7.0 mmol/l and/or a 2HPG ≥11.1 mmol/l) need to be recorded on two

successive occasions.

These tests may be a FPG alone or an OGTT but must be carried out on different days.

Patients found to have an FPG value ≥7.0 mmol/l, or a two-hour plasma glucose (2HPG)

≥11.1 mmol/l after a 75g oral glucose challenge, should have an OGTT performed at their

next scheduled clinic visit to confirm possible diagnosis of diabetes.

A diagnosis of diabetes will be confirmed if there is a second abnormal plasma glucose value

(FPG ≥7.0 mmol/l and/or 2HPG ≥11.1 mmol/l). The date of diagnosis of diabetes will be

taken as the date of the first abnormal glucose value. If the OGTT does not confirm a

diagnosis of diabetes the patient will continue to be followed as normal and the process is

restarted.

A diabetes diagnosis adjudication process will be put in place to review patients who are

diagnosed as having diabetes or have been commenced on antidiabetic therapy outside the

trial.

Patients diagnosed with diabetes will remain in the Study and continue on double blind Study

Medication. They will not require an OGTT at subsequent visits but centres will continue to

record FPG as documented in section 9.1 of this protocol. Their diabetes will be treated by

adding open label metformin therapy, commencing with 250 mg daily and titrating as

necessary to 1000 mg twice daily, aiming to maintain fasting plasma glucose levels <7.0

mmol/l. In the event that FPG values are >7.0 mmol/l despite maximally tolerated metformin

therapy, additional anti-diabetic therapy should be added as deemed appropriate by the

clinician but avoiding the use of alpha-glucosidase inhibitors or prandial glucose regulators.

Double-blind acarbose Study Medication is continued even after diabetes is diagnosed in

order to continue to evaluate the potential impact of acarbose on the primary cardiovascular

endpoint. If a patient is commenced on an alpha-glucosidase inhibitor by a non study

physician the possibility of replacing it with another antidiabetic agent. e.g. metformin should

be explored. In the event that the patient continues to take an open-label alpha-glucosidase

inhibitor, Study Medication should be discontinued.


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4.7 Observations and Measurements: Assessment for Treatment Effects

Patients should attend all visits, except the run-in visit, fasting (apart from water) from 22:00

the previous evening.

Note: patients who experience any of the non-fatal endpoints musts remain on study

medication and continue the study. Any subsequent endpoint should also be

reported.

4.7.1 Screening Visit (Visit 1, -5 weeks)

Patients who fulfil all of the inclusion and violate none of the exclusion criteria, and who

have provided written informed consent, will be asked to attend fasting for a Screening Visit

(Visit 1). Patients with a recent MI, UA, stroke or TIA may be screened once the patient is

considered stable and enter run-in, but must not be randomized until 3 months after the MI,

UA, stroke or TIA. The following actions will be completed:

Obtain written informed consent

Record eligibility criteria status

Record relevant concomitant medication

Record age, gender, alcohol consumption, smoking status and self-reported ethnic group

Record past medical history

Note: If a patient has had any tests that are required to establish eligibility as part

of standard care within the last 6 months, then the results may be used as part of

the eligibility check.

Note: Documentation of previous cardiac disease to establish eligibility should include a

thorough clinical history detailing the patients signs and symptoms, 12 lead ECGs,

cardiac markers such as CK-MB and/or troponins and details of any treatments or

procedures relevant to their disease.

Record menopausal status for women


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Undertake physical examination (full external examination with emphasis on CVD-

related issues e.g. evidence of heart failure or previous stroke)

Record height

Record waist/hip circumference

Record body weight

Record blood pressure (right arm in sitting position after five minutes rest)

Perform 12 lead ECG (read locally)

Perform 75g OGTT with 0 and 2 hour plasma samples for assay of glucose

Note: The OGTT may be omitted if the patient has had a standard oral glucose tolerance

test, demonstrating IGT within the last 6 months.

Note: For patients that have had a recent acute event, defined as AMI, Unstable Angina

or Stroke, an OGTT may be carried out at any time, at the physician’s discretion, but the

patient cannot be randomized until at least 3 months after the event occurred.

Take fasting serum sample for assay of creatinine

Take fasting serum sample for assay of lipid profile

Take EDTA whole blood sample for full blood count

Provide appropriate lifestyle advice with respect to diet, exercise and smoking

Agree date and time of next study follow up appointment

Patients may be rescreened on one occasion only, but not within one week of the first screen.

The Registration eCRF provides an option for entering the additional data for patients who

are screened a second time. If the patient has a MI/UA/Stroke/TIA after screening but before

randomization they remain eligible to join the study, but cannot be randomized until three

months after the event and undergoing a second run-in period if the first was not completed

satisfactorily. Patients who have experienced any other acute cardiac event may be screened

at any time, once the treating physician considers their condition is stable. Patients who are

screened a second time do not need to re-sign an informed consent form.

4.7.2 Run-in Visit (Visit 2, -4 weeks)

Patients who continue to be eligible will attend a Run-in Visit (Visit 2) one week later (±7

days), at which time the following assessments will be completed:

Recheck patient eligibility

Dispense single-blind run-in placebo Study Medication


All patients will commence a four-week single-blind placebo run-in and will be instructed to

take this Study Medication once a day with their smallest meal of the day. Patients requiring

CHD therapy optimisation will be prescribed additional open-label medication, titrated as

necessary during this time period. Optimised CHD therapy should include: Antiplatelet


July 2016 of 45

therapy, a statin, unless contraindicated or not tolerated, an ACE inhibitor, and a beta-

blocker and/or antihypertensive therapy, if considered indicated by the investigator.

4.7.3 Randomisation Visit (Visit 3, week 0)

Patients who continue to be eligible will be asked to attend fasting for a Randomisation Visit

(Visit 3) four weeks later, at which time the following actions will be completed:

Recheck patient eligibility

Check patient has taken at least 80% of single-blind placebo run-in study medication


Record any relevant adverse events

Record body weight


Take fasting plasma sample for assay of glucose. Patients found to have an FPG value

≥7.0 mmol/l should have an OGTT performed at their next clinic visit to confirm possible

diagnosis of diabetes. If there is clinical concern, an OGTT should be performed within

one month. If diabetes is confirmed treat, as outlined in section 4.6.10

Take fasting serum sample for assay of alanine transaminase (ALT)

Record Hepatitis B status, if available


Take fasting whole blood sample for assay of HbA1c

Take fasting serum and plasma samples for later biochemical tests (sent to central

laboratory). The maximum volume of these samples will not exceed 14ml. If these

samples are not taken, or found to be unsatisfactory, further samples cannot be taken once

patients are taking study medication.

Take whole blood sample for later molecular analyses (sent to central laboratory). The

maximum volume of these samples will not exceed 9ml. If these samples are not taken, or

found to be unsatisfactory, a further sample can be taken (but only while recruitment for

the study is ongoing).

Randomise patient and dispense four months’ double-blind Study Medication

Provide “Start low, Go Slow” instructions

Administer Quality of Life (QoL) questionnaire


If a follow up visit is delayed or missed, subsequent follow-up visits will still take place as

scheduled originally from the date of randomisation, to ensure timely completion of the

study.


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4.7.4 Follow up Visits

Follow up telephone visits 4 and 5 will be scheduled for one and two months post-

randomisation respectively. All telephone contacts must be recorded in the patient’s notes.

The following items will be addressed:


Record any Study Endpoints

(Note, perform 12 lead ECG (read locally) if it is suspected that a CV event occurred

since the last visit)

Review Study Medication and assess need for Study Medication to be titrated

Agree date and time of next appointment

Visit 6 will be scheduled four months post-randomisation with participants asked to attend

fasting. The following actions will be performed:

Check Study Medication adherence




Take fasting plasma sample for assay of glucose. Patients found to have an FPG value

≥7.0 mmol/l should have an OGTT performed at their next clinic visit to confirm possible

diagnosis of diabetes. If there is clinical concern, an OGTT should be performed within

one month. If diabetes is confirmed treat as outlined in section 4.6.10

Assess need for Study Medication to be titrated

Dispense four months’ Study Medication


Visit 6 and all subsequent scheduled study visits will be at four-monthly intervals with

participants asked to attend fasting. The assessments performed at these four-monthly visits

will be the same as at Visit 6.

4.7.5 Annual Visits

At annual visits (Visit 8, 11, 14, 17 & 20 etc. and annually thereafter) participants will be

asked to attend fasting. The following actions will be performed:






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(Note, perform 12 lead ECG (read locally) if it is suspected that a CV event occurred

since the last visit)

Record smoking status


Record alcohol consumption

Record body weight



Perform ECG (read locally)



Perform 75g OGTT with 0 and 2 hour plasma samples for assay of glucose.

Note: OGTT must be performed using the glucose sachets provided for the study.

Patients found to have an FPG value ≥7.0 mmol/l or a 2HPG ≥11.1 mmol/l should have

an OGTT performed at their next clinic visit to confirm possible diagnosis of diabetes. If

there is clinical concern, an OGTT should be performed within one month. If diabetes is

confirmed treat at outlined in section 4.6.10

Take fasting serum sample for assay of ALT




Assess need for Study Medication to be titrated

Dispense four months’ Study Medication



4.7.6 Closeout Visit

Participants will be asked to attend the closeout visit in a fasting state and the following

actions will be performed:



Collect any remaining Study Medication



Record smoking status


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Record alcohol consumption

Record body weight



Perform ECG (read locally)



Take fasting plasma sample for assay of fasting plasma glucose (FPG). If the FPG is ≥7.0

mmol/l arrange appropriate follow-up outside of the study to confirm whether the patient

has developed diabetes and, if so, receives appropriate therapy.

Take fasting serum sample for assay of ALT





Agree date and time of final visit/telephone contact (if applicable)

Thank the patient for their participation in the study and inform them that they will be

notified of the main results after they are published.

4.7.7 Final Visit/Telephone Contact

A final visit/telephone contact will be conducted only for patients who:

a) Stop taking study drug at their close-out visit

OR

b) Have stopped taking study drug within 28 days prior to their close-out visit.

This final visit/telephone contact, which should take place a minimum of 28 days after drug

discontinuation, is intended to identify any AEs, SAEs, hospitalisations or study endpoints

that have occurred in this period.

4.8 Data Quality

The ACE Co-ordinating Centre will be based in the Diabetes Trials Unit at the University of

Oxford (DTU). Co-ordinating Centre staff will set up, supervise and track the progress of the

study and establish a Chinese Project Office in Beijing to monitor and provide local support

for the Clinical Centres.


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The Chinese Project Office will assess all Clinical Centres prior to their initiation to verify

the qualifications of each investigator, check the site facilities and inform the investigators of

their responsibilities and the procedures for ensuring adequate and correct documentation.

Investigator training meetings will be held to introduce investigators and their personnel to

the study protocol, eCRF and procedures. Centre initiation visits will also be performed.

During the course of the Study, top level monitoring will be performed centrally using the

DTU’s electronic Trial Management System (TMS). A Study Monitor will conduct a site

initiation visit and conduct the first monitoring visit(s) shortly after the first patient is

screened/randomised. Monitoring visits will be conducted periodically throughout the study,

culminating in a study closeout visit. Direct access to original source data will be required to

check the accuracy of eCRF completion and for inspections/audits. The TMS will be used to

perform data capture, data validation, data and process audit, monitor protocol adherence and

facilitate statistical analyses.

Data will be entered directly onto electronic Case Report Forms (eCRFs) wherever feasible to

avoid unnecessary transcription. Mandarin or English can be used for free text entries. The

eCRFs will be completed using a laptop supplied solely for use in the ACE Study. All data

will be entered online by an ADSL or telephone dial-up Internet connection.

Data added to the TMS will be checked for internal consistency (within range and known

categories), external consistency (data is consistent with other data items known for that

patient) and trend consistency (data values have not changed by more than allowable amounts

e.g. excessive weight gain or loss which might indicate digit transposition). Study data audits

will be performed weekly. These will include checks of the number of data items obtained

from each centre, the number found to have anomalies and the number of data items overdue

to permit progress chasing.

A rule-based version of the study protocol, encapsulated within the TMS, will allow

automated checking of each patient's progress through the study. A system log will be

maintained which identifies every database edit made, the date it was made and the operator

who made the change. Data backups will be made daily with rotating on and off site storage.

4.9 Documentation

Entries made in the eCRF must be either verifiable against source documents, or have been

directly entered into the eCRF, in which case the entry in the eCRF will be considered as the

source data for verification purposes. All data necessary for the continuity of patient care

should also be maintained as normal in patients’ notes. Site staff should clearly document in a

patient’s notes that the patient is in a clinical study, and they should provide contact

information with a request that any other medical staff who might treat the patient should

contact the trial site staff. In cases where the patient retains ownership of their notes, copies

of all trial related data should be retained at site. Unless data are entered directly on to an

eCRF, they must be written in the patient’s notes (or a study file) and transferred to the

relevant eCRF at the earliest opportunity. The study file and all source data should be

retained until notification is given by the sponsor for their destruction.

If a patient has been seen by another department or institution, every effort should be made to

obtain copies of discharge summaries, cardiac biomarkers and ECGs to enable adjudication


July 2016 of 45

of events/safety data. For laboratory parameters quantitative information should be sourced,

wherever possible, rather than qualitative information.

In the event of temporary lack or delayed access to the rTMS, the use of paper CRFs is

allowed on a temporary basis. These should be sourced from ACPO.

5. ETHICAL AND LEGAL ASPECTS

5.1 Ethics Committee or Institutional Review Board

Documented approval from appropriate Ethics Committee(s) or Institutional Review Board(s)

must be obtained for all participating centres prior to study start, according to Good Clinical

Practice (GCP), local laws, regulations and organizations. When necessary, an extension,

amendment or renewal of the Ethics Committee approval must also be obtained. Ethics

Committees must supply upon request, a list of the Ethics Committee members involved in

the vote and a statement to confirm that the Ethics Committee is organized and operates

according to GCP and applicable laws and regulations.

Modifications to the study protocol will not be implemented without the agreement of the

Steering Committee and appropriate ethical approval.

5.2 Ethical Conduct of the Study

The procedures set out in this protocol, pertaining to the conduct, evaluation, and

documentation of this study, are designed to ensure that the sponsor and investigator abide by

GCP Guidelines. The study will also be carried out in keeping with applicable local law(s)

and regulation(s). This may include an inspection by the sponsor representatives and/or

Regulatory Authority representatives at any time. The investigator must agree to the

inspection of study-related records by the Regulatory Authority/sponsor representatives, and

must allow direct access to source documents to the Regulatory Authority/sponsor

representatives.

5.3 Regulatory Authority Approvals/Authorizations

Regulatory Authority approvals/authorizations/notifications, where required, must be in place

and fully documented prior to study start.

5.4 Informed Consent

Written and verbal versions of Informed Consent will be presented to the patient, detailing no

less than: the research objective, the methodology and duration, the anticipated benefits and

the limits and risks associated. It will be clearly stated that the patient is free to withdraw

from the study at any time for any reason without prejudice to future care, and with no

obligation to give the reason for withdrawal. Written Informed Consent must be obtained

before any study specific procedure takes place. If a patient is illiterate, he/she can nominate

someone to sign on their behalf and the patient can make a mark beside the signature, such a

process should be clearly documented. A copy of the signed Informed Consent will be given

to the patient. The original signed form will be retained at the study site.


July 2016 of 45

5.5 Insurance

All patients participating in the study will have insurance coverage arranged by the sponsor,

which is in line with applicable laws and/or regulations.

5.6 Confidentiality

All records identifying the patient will be kept confidential and, to the extent permitted by the

applicable laws and/or regulations, will not be made publicly available. The patient will be

identified only by their date of birth, initials and a unique patient ID number on the eCRF.

All documents will be stored securely and kept in strict confidence in compliance with the

Data Protection Act.

Study findings stored on a computer will be stored in accordance with local data protection

laws. The patients will be informed in writing that representatives of the sponsor, Ethical

Committees, Institutional Review Boards or Regulatory Authorities may inspect their

medical records to verify the information collected, and that all personal information made

available for inspection will be handled in strictest confidence and in accordance with local

data protection laws.

When the results of the study are published, the patient’s identity will remain confidential.

The investigator will maintain a list to enable patients’ records to be identified.

6. STATISTICAL METHODS AND DETERMINATION OF SAMPLE

SIZE

6.1 Description of Patient Groups for Analysis

All patients will be analysed according to the randomised treatment that they first received

i.e. the primary population for analysis is intention-to-treat (ITT), irrespective of whether

they took randomised Study Medication. Patients lost to follow-up will be censored at their

last contact point. Patients who do not have an event in the given study period will be

censored at their last follow-up visit. Further analyses to be undertaken will include Valid

Case (Per Protocol) and Safety Analyses.

6.2 Study Objectives

6.2.1 Primary Endpoint

This will be a composite cardiovascular outcome defined as the time after randomisation to

the first occurrence of any one of the following:

Cardiovascular death

Non-fatal MI

Non-fatal stroke


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Hospitalisation for unstable angina

Hospitalisation for heart failure

6.2.2 Secondary Endpoints

Transition to type 2 diabetes confirmed by two successive diagnostic plasma glucose

values (FPG ≥7.0 mmol/l and/or 2HPG ≥11.1 mmol/l), with no intervening non-

diagnostic values.

All cause mortality.

Each of the components of the primary composite cardiovascular outcome will also be

analysed individually, both as first and as total events.

MACE composite cardiovascular outcome, defined as the time after randomisation to the

first occurrence of any one of the following:

Cardiovascular death

Non-fatal MI

Non-fatal stroke

Proportion of patients with an impaired renal function as evidenced by:

A reduced eGFR (<30 ml/minute/ 1.73 m2) estimated using the Chinese

MDRD formula [23]

A doubling of the baseline plasma creatinine level

A halving of the baseline eGFR

Resource use, costs and cost effectiveness.

6.3 Statistical and Analytical Plans

The primary outcome will be evaluated by time-to-event analysis methods using a log-rank

test. It will be performed using an intent-to-treat approach, and will be supplemented by per-

protocol and on-treatment analyses. Given that secondary outcome, the progression to

diabetes, can be established in all patients only at the 4-month visits (that is, the endpoint is

interval-censored), the log-rank test for this endpoint will be based on a discrete time

proportional odds model [Cox et al 1989]. Evaluations of baseline characteristics, safety

assessments, and additional measurements during the trial (including treatment

interruption/discontinuation, lifestyle evaluation, and use of concomitant medications) will be

based on appropriate summary statistics. The effects of demographic and other baseline

characteristics on the primary outcomes will be explored using appropriate multivariate

methods. Full details of analyses to be performed will be itemised in a separate Statistical

Analysis Plan (SAP).


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6.4 Interim Analysis/Analyses

No interim analyses are planned, other than those commissioned by the Data Safety and

Monitoring Board.

6.5 Sample Size Estimation

6.5.1 Event Rate

The event rate for the original primary cardiovascular (MACE) outcome was estimated to be

3.5% per year for the population to be enrolled.

6.5.2 Number of Patients

Sample size calculations assumed a relative risk reduction of 20% in the primary composite

endpoint event rate with acarbose, an accrual period of 18 months, a minimum follow up of 4

years and an alpha of 5%. A total of 7,268 patients (3634 per group) were be required to

obtain 90% power with a total of 904 participants having an adjudicated primary event. To

allow for a possible 3% loss-to-follow up, a total of 7500 patients were planned be

randomised. No allowance was been made in this calculation for discontinuation of Study

Medication.

The sample size was reviewed by the ACE Steering Committee when they met face-to-face

on 15 February 2014. At that time the Committee noted that the substantially extended

recruitment period meant that sufficient patient years of follow up to achieve a total of 904

participants with an adjudicated primary event could be accumulated with fewer patients

randomised and revised the target down from 7,500 to 6,500. As the trial remained event

driven with the 904 primary event target unchanged, no adjustment was required for the

power calculations.

The sample size was reviewed again by the ACE Steering Committee when they met by

teleconference on 19 May 2016. As event rates for the primary composite cardiovascular

outcome remained much lower than originally anticipated, they agreed to reduce the power of

the study from 90% to 85%. This decision reflected the increasing participant and site

fatigue, and financial constraints. Revised power calculations, using the formula published by

Stuart Pocock et al. [24], showed that 728 participants with a confirmed primary composite

cardiovascular outcome would be required for 85% power.

6.6 Health Economic Evaluation

An economic evaluation will be performed, to assess the cost-effectiveness of acarbose

compared with placebo. The evaluation will consist of three main elements:

collection of resource use information and unit costs;

collection of outcome data appropriate to economic evaluation; and


July 2016 of 45

calculation of within-trial and extrapolated cost-effectiveness.

6.6.1 Resource use and costs

Resource use will be recorded on eCRFs, consisting mainly of number, type and dose of

medications including trial therapy; number of hospital clinic visits; and in-patient

hospitalisations associated with complications/adverse events. The duration of

hospitalisations will be recorded on the eCRF, and whether the patient underwent

angiography, angioplasty, coronary artery bypass grafting or other major procedure.

Unit costs will be then attached to these resource items, using published national average

costs, tariff averages for procedures, and drug costs to the Chinese Health Service prevailing

at the end of the study, to derive a cost per patient for each year or part of year in the study.

6.6.2 Economic outcomes

For the purposes of the economic evaluation, outcomes will be defined and measured in

terms of:

number of primary endpoints

number of fatal primary endpoints

quality adjusted life years

To assess quality of life, the EQ-5D in official Chinese language version will be administered

at randomisation, at annual visits and at closeout. Descriptive information from the EQ-5D

questionnaire will be reported and analysed in the form of distributions across response levels

on each question at each survey point, and published valuation tariffs will be used to attach

quality of life valuation to each reported health state and calculate quality adjusted survival.

6.6.3 Cost-effectiveness

Cost-effectiveness will be estimated as the net costs of therapy with acarbose compared with

placebo expressed as a ratio of the net effectiveness of acarbose compared with placebo.

Effectiveness will be measured in terms of life-years gained and quality adjusted life years

(QALYS) gained, first within trial, and secondly over lifetime using a parametric

extrapolation model that will estimate time to events, primarily from trial data.

Within trial cost-effectiveness will be reported as the incremental cost per:

Primary endpoint averted

Fatal primary endpoint averted

Quality adjusted life year gained

Lifetime cost-effectiveness will be in terms of:

Life years gained


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Quality adjusted life years gained.

6.6.4 Analysis and presentation of economic data

The primary analysis of all economic data will be on an intention-to-treat basis. Mean values

and 95% confidence intervals will be reported for each component of resource use and cost

and for total costs and effectiveness. Uncertainty around the cost-effectiveness ratios reported

will be estimated using the non-parametric bootstrap, and reported using the cost-

effectiveness plane and the cost-effectiveness acceptability curve.

All costs and outcomes will be discounted to present values at recommended annual rates in

the baseline analyses, with a range of discount rates used in the sensitivity analyses.

Sensitivity analyses will be performed on all aspects of the economic evaluation, which are

subject to uncertainty. Missing data will be handled by multiple imputations.

When the EQ-5D is administered, a small number of additional questions will be asked about

household type, household income and expenditure, health insurance status, and expenditure

on hospital visits and admissions. These data will be reported descriptively, and used as

control variables in multivariate analyses of costs, outcomes and cost-effectiveness.

7. ADVERSE EVENTS

7.1 Adverse Event Monitoring

As acarbose is already licensed in China for the treatment of IGT, ACE is a Phase IV trial. As

such, there is no requirement to collect adverse events routinely. However, an adverse event

(AE) will be recorded where study medication is reduced or stopped as a result of the adverse

event if the adverse event is thought to be related to study medication administration.

Serious Adverse Events (SAEs), including SSARs and SUSARs, that are thought to be

possible Study Endpoints (SEs) will not be reported as SAEs during the trial.

SAEs, SSARS and SUSARS that are not thought to be possible Study Endpoints will be

reported by the Investigator to the Sponsor, CFDA and EC according to the relevant

regulations.

Possible Study Endpoints (including those that are SAEs SSARs or SUSARs) will be

reported to the Diabetes Endpoint Adjudication Committee or the Cardiovascular Endpoint

Adjudication Committee as rapidly as possible.

The DSMB will review all Study Endpoints (unadjudicated and adjudicated) and all reported

SAEs by allocated therapy at least twice yearly.


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7.2 Adverse Event Definitions

7.2.1 Adverse Event (AE)

An adverse event (AE) is any undesirable medical event occurring to a patient in a clinical

trial, whether or not related to the trial product(s). An AE will be recorded where study

medication is reduced or stopped as a result of the adverse event and where the adverse event

is thought to be related to study medication administration.

7.2.2 Serious Adverse Event (SAE)

A serious adverse event or serious adverse drug reaction is any untoward medical occurrence

that results in:

Death.

A life threatening* experience.

Hospitalisation: any adverse event leading to hospitalisation or prolongation of

hospitalisation will be considered as Serious, UNLESS the admission results in a hospital

stay of less than 12 hours or the admission is pre-planned i.e. elective or scheduled

surgery arranged prior to the start of the study.

A persistent or significant disability/incapacity (disability means a substantial disruption

of a person’s ability to conduct normal life’s functions).

A congenital anomaly/birth defect.

Important medical events that may not result in death, be life threatening*, or require

hospitalisation may be considered a serious adverse event when, based upon appropriate

medical judgment, they may jeopardise the patient and may require medical or surgical

intervention to prevent one of the outcomes listed in this definition.

* The term life threatening in the definition of serious adverse event refers to an event in

which the patient was at risk of death at the time of the event. It does not refer to an event

that hypothetically might have caused death if it was more severe.

7.2.3 Suspected Serious Adverse Reaction (SSAR)

This is defined as a serious adverse reaction, the nature or severity of which is consistent with

the known study treatment information (e.g. Summary of Medicinal Product Characteristics

(SmPC), Investigator Brochure (IB) or Investigator Medicinal Product Dossier (IMPD)).

7.2.4 Suspected Unexpected Serious Adverse Reaction (SUSAR)

This is defined as a serious adverse reaction, the nature or severity of which is not consistent

with the known study treatment information. A serious event or reaction is not defined as a

SUSAR when:

‘it is serious but expected’ or it does not fit the definition of an SAE, whether expected or not.


July 2016 of 45

7.2.5 Relationship to Study Medication

Probable: Good reasons and sufficient documentation to assume a causal

relationship.

Possible: A causal relationship is conceivable and cannot be dismissed.

Unlikely: The event is most likely related to aetiology other than the trial

product.

7.2.6 Severity of the Adverse Event

The severity of adverse events should be graded as follows:

Mild: usually transient in nature and generally not interfering with normal

activities.

Moderate: sufficiently discomforting to interfere with normal activities

Severe: prevents normal activities.

7.3 Collection and Reporting of Adverse Events

Adverse event data will be collected from the first trial-related activity after the patient

provides informed consent up until 28 days after the last administration of study medication.

AEs that meet the definition listed in Section 7.2.1 of this protocol (and where study

medication is reduced or stopped as a result of the adverse event and where the adverse event

is thought to be related to study medication administration), SAEs, SSARs, SUSARs and

events thought to be Study Endpoints will be captured on Adverse Event/SAE or

Cardiovascular Event eCRFs that collect detailed data on the event including an assessment

of causality and standard safety data, and will be reported according to the timelines detailed

below.

All SAEs that are also thought to be Study Endpoints will be reported to the Cardiovascular

Endpoint Adjudication Committee as rapidly as possible.

All SAEs that are considered to be related to study drug (SSARs and SUSARS), including

Study Endpoints, will be reported via the standard paper forms to the Safety Officer within

24hrs of the site staff being aware of the event and will be forwarded to the Beijing ADR

centre by the Safety Officer, via the electronic system in the required timeline. The Endpoint

eCRF will collect detailed data on the event and also includes an assessment of causality, to

enable Study Endpoints that are considered to be Serious Adverse Drug Reactions to be

reported.

New-onset diabetes during the study will not be considered an adverse event but will be

reviewed by the Diabetes Endpoint Adjudication Committee as rapidly as possible.


July 2016 of 45

The DSMB will review all safety data, including Study Endpoints (unadjudicated and

adjudicated) and all reported SAEs by allocated therapy at least twice yearly.

SAEs, SSARs and SUSARs that are not thought to be possible Study Endpoints will be

reported by the Investigator to the Sponsor, CFDA and EC according to the relevant

regulations.

The sponsor will report all SSARs and SUSARs to:

1) Beijing ADR immediately, ideally within 3 days in the event of death; within 15 days

for all other events.

2) Bayer Global Pharmacovigilance within 24 hrs in the event of death or a life-

threatening event, within 2 working days for all others.

3) An Annual Safety Report (ASR) will be submitted to Beijing ADR and to the Oxford

Tropical Research Ethics Committee (OXTREC).

4) Local occurring SSARs and will be reported to the HK regulatory authorities as

follows;

Fatal or life-threatening unexpected Adverse Drug Reactions (ADRs) should be

reported as soon as possible but no later than 7 calendar days after first knowledge by

the sponsor that a case qualifies, followed by as complete a report as possible within 8

additional calendar days. Other serious, unexpected ADRs that are not fatal or life

threatening should be reported as soon as possible but no later than 15 calendar days

after first knowledge by the sponsor that the case meets the minimum criteria for

expedited reporting.

In addition, at the end of the trial a brief summary of local non-serious ADRs and

serious ADRs that are expected will also be submitted.

5) The Sponsor will provide the ASR, which includes all Serious Adverse Drug

Reactions, to the sites. Sites will submit the ASR to their Ethics Committee, if

required.

7.4 Reporting of Pregnancy

Pregnancy occurring during a clinical investigation, although not considered a serious

adverse event, must be reported within the same timelines as a SAE on a Pregnancy

Monitoring Form. The patient should stop the study medication but continue to attend

follow–up visits until the end of the trial. The outcome of a pregnancy should be followed up

carefully and any abnormal outcome of the mother or the child should be reported as an SAE

if it meets the SAE definition in 7.2.2.

7.5 Warnings/Precautions for Acarbose

In this trial, annual ALT monitoring will be performed. These ALT levels will be reviewed

by the DSMB as asymptomatic elevation of liver enzymes, sometimes even to a clinically


July 2016 of 45

relevant degree (up to three times the upper limit of normal), has been observed very rarely

but was generally reversible on ceasing treatment

Other precautions

Regular treatment with acarbose should not be interrupted without the doctor’s

knowledge, as this may lead to a rise in blood glucose.

Acarbose does not cause hypoglycaemia in patients treated with diet alone. Should

signs of hypoglycaemia occur during acarbose therapy as a result of the lower insulin

requirement in patients being treated with insulin, sulfonylureas or metformin, glucose

(not table sugar [cane sugar]) should be taken.

Possible treatment with acarbose should be included in the patient’s records as well as

their inclusion in the ACE Trial.

7.6 Overdosage

If acarbose is taken with drinks and/or meals containing carbohydrates (polysaccharides,

oligosaccharides, disaccharides), overdose may lead to meteorism, flatulence and diarrhoea.

If an overdose of acarbose is taken in the absence of food, excessive intestinal symptoms are

not to be expected.

In the event of overdose, no drinks or meals containing carbohydrates (polysaccharides,

oligosaccharides, disaccharides) should be consumed for the next 4 - 6 hours.

8. USE OF DATA AND PUBLICATION

During the Trial all data derived from the Trial will be held by the Diabetes Trials Unit

(DTU) but with access for Bayer to any data required for safety and regulatory purposes.

At the time database lock occurs, Bayer will provide the DTU with an electronic file

containing the full randomisation codes for upload to the TMS. The DTU will undertake the

planned analyses and prepare and submit manuscripts for publication and presentations to

academic meetings, as agreed by the Steering Committee. Bayer will have the right to

comment on these but the final editorial control remains with the Steering Committee.

Following publication of the main trial results, a copy of the database will be transferred to

Bayer.

Study data will be archived in the DTU in the data warehouse and each site will receive a CD

with their site’s data in PDF or html format.


July 2016 of 45

9. APPENDIX 1

9.1 Study Flow Chart and/or Schedule Procedure

Screening Run-in Randomisation

One month

telephone

call

Two month

telephone

call

Four

monthly

Annual

visits

Close

out

Final

Visit/Telephone

Contact

Visit 1 Visit 2

±7 days

Visit 3

± 7 days

Visit 4

± 7 days

Visit 5

± 7 days

Visits 6, 7,

9, 10, 12,

13, 15, 16,

18, 19 & 21

± 14 days

Visits 8, 11,

14, 17 & 20

± 14 days

+ 28 days

-5 weeks -4 weeks 0 weeks 4 weeks 8 weeks

Informed consent x

Check Eligibility x x x

Demographics x

Medical history x

Physical examination x x x

Waist and hip

circumference x x x

Height x

Body weight x x x x

Smoking status x x x

Alcohol consumption x x x

Menopausal status x x x

Concomitant medication x x x x

Issue Study Medication x x x x

Randomisation x

Issue “start low, go

slow” instructions x

Titrate Study Medication x x x x

Study medication

adherence x x x x x x


July 2016 of 45

Lifestyle advice x

AE/SAE enquiry x x x x x x x

Endpoint enquiry x x x x x x

Blood pressure x x x x x

ECG x x x

Fasting plasma glucose* x x x

OGTT* x x

Serum ALT* x x x

Serum creatinine* x x x

Hepatitis B status

(HBsAg) ***

x

x

Lipid profile* x x x x

Full blood count* x

HbA1c x x x

Blood volume per visit

(blood samples for local

analysis) (ml)

8.5 8.5 3.5 8.5 8.5

Serum and plasma

samples for later

biochemical tests**

x

Volume of whole blood

taken for later

biochemical tests (ml)

14

Whole blood sample for

later molecular analyses §

x

Volume of whole blood

for later molecular

analyses (ml)

9

Completion of QoL

questionnaires x x x

* local assay; ** store centrally; *** If available § If samples for molecular analysis are not taken, or found to be unsatisfactory, a further sample can be taken (but only whilst recruitment for the study is ongoing).


July 2016 of 45

10. APPENDIX 2: NYHA GRADING CRITERIA FOR HEART FAILURE

Class Patient Symptoms

Class I (Mild) No limitation of physical activity. Ordinary physical activity does

not cause undue fatigue, palpitation, or dyspnea (shortness of

breath).

Class II (Mild) Slight limitation of physical activity. Comfortable at rest, but

ordinary physical activity results in fatigue, palpitation, or

dyspnea.

Class III

(Moderate)

Marked limitation of physical activity. Comfortable at rest, but less

than ordinary activity causes fatigue, palpitation, or dyspnea.

Class IV (Severe) Unable to carry out any physical activity without discomfort.

Symptoms of cardiac insufficiency at rest. If any physical activity

is undertaken, discomfort is increased.


July 2016 of 45

11. APPENDIX 3: OGTT PROCEDURE

For ALL OGTT tests performed within the study, the trial-specific sachets provided by trial

must be used. Commercially produced sachets containing 82.5g of dextrose monohydrate

powder are used for the OGTTs. The sachets are distributed to sites by the ACPO.

Note: the OGTT to establish eligibility, may be omitted if the patient has had a standard oral

glucose tolerance test within the last 6 months that demonstrated IGT.

This test should not be carried out on patients who are known to be diabetic.

The day before the OGTT, the participant must:

1 Eat a normal diet on the day prior to the test and refrain from drinking alcohol, in

the evening they should refrain from doing any strenuous exercise.

2 Fast from 22.00 hours on the evening prior to the test. The participant may only

drink water after 22.00 hours of the evening prior to the test..

3 Refrain from smoking the morning of the test.

The day of the test:

1 As the patient is fasting, the test should be scheduled for early in the morning.

2 The participant must be seated or lying down for the whole period of the test.

3 Prepare the OGTT drink by dissolving the contents of the trial-specific sachet in

300ml warm water (20-30oC is preferred). Note: a range of 250ml – 300ml is

permissible; < 250ml or > 300ml will affect the result.

4 Collect a fasting sample (basal) using the local procedure for collecting venous

blood samples. This sample will be time zero. Then, ask the patient to drink the

glucose drink, the drink should be consumed at a steady rate over 4-5 minutes.

5 After 120 minutes collect another venous blood sample according to local

procedure. This will be time 120min.

6 A finger stick blood glucose measurement is recommended for the safety of the

patients at the termination of OGTT.

a. If glucose < 3.1mmol/L or there are symptoms of hypoglycaemia;

administer a light carbohydrate snack (~15g of carbohydrate)

Re-test after 30 mins

Repeat if necessary until glucose > 4.0mmol/L; then discharge from clinic

b. If glucose ≥ 3.1mmol/L and there are no signs of hypoglycaemia;

discharge from clinic

7 A light meal or snack is also recommended before the patients leave the clinic.

8 If the participant vomits while drinking the glucose drink, the test should be

stopped. A finger stick blood glucose measurement should be obtained and the

investigator should follow the procedure outlined in 6. The investigator should

then reschedule an OGTT as soon as possible (on a different day).


July 2016 of 45

Processing samples for the OGTT

To ensure an accurate result, it is critical that the OGTT blood samples are processed as soon

as possible after sampling. Ideally, the OGTT samples should be separated immediately after

each patient visit due to the time-critical biochemical reaction. If this is not possible the

samples should be stored on ice prior to processing.

For the plasma glucose test, there are three options for the storage of OGTT blood samples

prior to analysis depending on the local laboratory procedures.

(A) The use of fluoride containing tubes (the most accurate and preferred option).

The samples should be spun and sent to the local laboratory for analysis within one hour.

For sites where processing times exceed one hour, the Investigator should store the whole

blood samples immediately after collection on crushed ice or on a 4oC ‘cold tray’ until

analysis. The whole process must be completed as soon as possible with an absolute time

limit of 4 hours.

(B) The use of tubes with an anticoagulant other than fluoride, for example heparin.

These samples must be spun and sent to the local laboratory for analysis within one hour.

(C) The use of tubes without anticoagulant.

This last option should only be used if options A and B above are not possible. The blood

is collected in tubes without anticoagulant and must be sent to the local laboratory for

analysis within one hour. The local laboratory should use appropriate

adjustment for the difference between plasma and whole blood.

Send processed labeled samples to the local hospital laboratory for testing.

As soon as the participant’s test results are available, enter the data onto the ‘Oral Glucose

Tolerance Test’ eCRF and add a printed copy of the results to the participant’s study file for

future monitoring purposes.


July 2016 of 45

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