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For peer review only
Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a multicentric,
randomised control trial - PREHAB study
Journal: BMJ Open
Manuscript ID bmjopen-2016-012876
Article Type: Protocol
Date Submitted by the Author: 01-Jun-2016
Complete List of Authors: Le Roy, Bertrand; CHU Estaing, Digestive surgery Pereira, Bruno; University Hospital CHU Clermont-Ferrand, Biostatistic unit Bouteloup, Corinne; CHU Estaing, Digestive and Liver Disease
Costes, Frederic; CHU Gabriel Montpied, Department of physiology and medical sport Richard, Ruddy; CHU Gabriel Montpied, Department of physiology and medical sport Selvy, Marie; CHU Estaing, Digestive surgery and oncological department Petorin, Caroline; Oncology Gagniere, Johan; University Hospital of Clermont-Ferrand, Digestive and Hepatobiliary Surgery Futier, Emmanuel; CHU Estaing, Department of Anesthesia Slim, Karem; CHU Estaing, Digestive surgery and oncological department Meunier, Bernard; Centre Hospitalier Universitaire de Rennes Mabrut, Jean-Yves; Hopital de la Croix-Rousse
Mariette, C.; CHU Claude Huriez, Digestive and oncological surgery Pezet, Denis; Digestive surgery
<b>Primary Subject Heading</b>:
Surgery
Secondary Subject Heading: Rehabilitation medicine, Oncology
Keywords: Prehabilitation, Gastric cancer, Oesophageal disease < GASTROENTEROLOGY, Fitness, Gastrointestinal tumours < ONCOLOGY
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Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Bertrand Le Roy, MD1, Bruno Pereira, PhD
2, Corinne Bouteloup, MD
6,9,10, Frederic Costes,
MD, PhD5, Ruddy Richard, MD, PhD
5, Marie Selvy, MD
1, Caroline Pétorin, MD
1, Johan
Gagnière, MD1, Emmanuel Futier, MD, PhD
3, Karem Slim, MD
1, Bernard Meunier, MD,
PhD7, Jean-Yves Mabrut, MD, PhD
8, Christophe Mariette, MD, PhD
4, Denis Pezet, MD,
PhD1.
(1) Digestive surgery and oncological department, Hospital Estaing, 1, place Lucie-Aubrac,
63003 Clermont-Ferrand, France
(2) Biostatistics unit (DRCI), Clermont-Ferrand University Hospital, 63003 Clermont-
Ferrand, France
(3) Department of Anesthesia, Hospital Estaing, Clermont-Ferrand University Hospital, 1
Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
(4) Digestive and oncological surgery, Hospital Claude Huriez, place de Verdun, 59037 Lille,
France
(5) Department of physiology and medical sport, Hospital, Gabriel Montpied, Clermont-
Ferrand, France
(6) University Hospital of Clermont-Ferrand, Digestive and Liver Disease Unit F-63003
Clermont-Ferrand, France
(7) Digestive surgery department, Hospital Pontchaillou, 2 rue Henri Le Guilloux, 35033
Rennes, France
(8) Digestive surgery department, Hospital Croix Rousse, 103 Grande rue de la Croix
Rousse, 69004 Lyon, France
(9) Clermont Auvergne University, University of Auvergne, Human Nutrition Unit, ECREIN,
BP 10448, F-63000 Clermont-Ferrand, France
(10) INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France
Corresponding author
Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
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63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Word count: 2840
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Administrative information
Title: Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Trial registration: NCT02780921
Protocol version: Version 4, 20 apr 2016
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY), a national public funding of research.
In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015.
A clinical research assistant will be commissioned by the sponsor (University Hospital of
Clermont-Ferrand) in order to monitor the progress of the study in accordance with the
Standard Operating Procedures implemented at the University Hospital of Clermont-Ferrand,
in accordance with the Good Clinical Practice and current French laws.
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov.
Protocol contributor
Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Study sponsor:
C.H.U. de Clermont-Ferrand
58 Rue de Montalembert
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63003 Clermont-Ferrand Cedex 1
Protocol contributors
Pr Christophe Mariette, principal investigator from Lille
Service de Chirurgie Digestive et Générale
Hôpital HURIEZ, CHRU Lille
Place de Verdun, 59037 Lille
Pr Meunier Bernard, principal investigator from Rennes
Service de Chirurgie Digestive et Générale
Hôpital Pontchaillou, CHRU Rennes
Rue Henri Le Guilloux, 35000 Rennes
Pr Jean Yves Mabrut, principal investigator from Lyon
Service de Chirurgie Digestive et Générale
Hôpital de la Croix Rousse, Hospice civils de Lyon
Grande rue de la croix rousse, 69317 Lyon
Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript.
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ABSTRACT
Introduction: Perioperative chemotherapy is the gold standard treatment of the resectable
gastroesophageal adenocarcinoma. However, 70% of patients can’t receive the complete
sequence because of a postoperative complication or a decrease of functional and nutritional
reserves. Recently, a new concept appeared in digestive surgery: the prehabilitation. This
interventional process consists of a patient preparation, between the surgical consultation and
the surgery, and is based on 3 components: 1) physical management 2) nutritional care and 3)
psychological care. Prehabilitation should decrease postoperative complications and improve
nutritional and physical status during the pre- and postoperative period. Therefore, it is
becoming essential to evaluate the effect of prehabilitation, compared to conventional care, on
the percentage of patients reaching the complete oncological treatment.
Methods and analysis: The PREHAB trial aimed to evaluate the efficacy of prehabilitation
compared to conventional care, in patients with gastroesophageal cancer with perioperative
chemotherapy. This trial is a prospective, randomised, controlled, open-blind, and
interventional study, in 4 centers. Patients (n=60 per group) will be randomly assigned for
management with either prehabilitation or conventional care. The primary outcome is the
percentage of patients reaching the complete oncological treatment decided in a
multidisciplinary tumour board. The secondary outcomes are the postoperative morbidity,
disease free survival, overall survival, feasibility of the protocol, length of stay, variation of
the functional reserve after the preoperative chemotherapy (defined by VO2peak, ventilatory
threshold and 6 min walk test), pre- and postoperative nutritional status, preoperative anxiety,
quality of life, 30- and 90 days mortality and cumulative dose of cytotoxic treatment received.
Ethics and dissemination: The study was approved by an independent medical ethics
committee (IRB00008526, CPP Sud-Est VI, Clermont-Ferrand, France) and by the competent
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French authority (ANSM, Saint Denis, France) and registered on Clinicaltrial.gov. The results
will be disseminated in a peer-reviewed journal.
Trial registration number: NCT02780921; pre-result.
Strengths and limitations of this study: The main strength of this multicentric, prospective
and randomized study is that this concept of prehabilitation has never been done on this high
postoperative morbidity surgery. The main limit is this study includes both oesophageal and
stomach cancer.
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INTRODUCTION
Perioperative chemotherapy is the gold standard treatment of the resectable and advanced
gastroesophageal adenocarcinoma. The efficacy of this strategy has been demonstrated in two
randomized studies.1 2
It reduces tumour size before surgery, treats micrometastases and
evaluates chemosensitivity. Disease free and overall survival rates were significantly
improved with perioperative chemotherapy compared to surgery alone. However, the
limitation of these studies is that among all patients requiring chemotherapy, almost 70% of
patients did not receive the complete sequence. This sequence is defined by the administration
of two to four cycles before and two to four cycles after the surgery, according to the
protocol. The major cause of absence or impossibility of realization of postoperative
chemotherapy was the presence of postoperative complication, postoperative serious asthenia
and impaired nutritional and physical status. 1 2
Poor physical condition assessed by
cardiopulmonary exercise testing, reflecting a reduced physiological reserve, is predictive of
postoperative complications. 3 4
A physical training, even during a short period and on a
various population, is beneficial in improving physical condition, cardiopulmonary function
and muscular mass of the patient.5-8
A prehabilitation over a six week period between pre-
surgical clinic appointment and surgery decreases postoperative morbidity and the hospital
stay in cardiovascular surgery, but no study has ever been performed in patients presented
with gastric or oesophageal cancer. 7 9
Prehabilitation revolves around three axes: 1) a physical training based on initial
cardiopulmonary exercise testing (VO2peak, ventilatory threshold (VT) and 6-min walk test
(6MWT)), 3 times by week, supervised by a physical therapist 2) a nutritional care to ensure
the compliance of the nutrition program and adapt the nutritional management based on
protein and energy needs and on the level of spontaneous oral intake and 2) a psychological
treatment by a psychologist to reduce preoperative anxiety. To our knowledge, no study ever
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focused on the gastroesophageal cancer. The benefit of prehabilitation in this cancer may be
particularly important because 1) this surgery is associated with a high postoperative
morbidity (40%, especially respiratory) and mortality (5%) 2) the physical and nutritional
status of these patients is often precarious (cancer cachexia, gastroesophageal obstruction),
and 3) the need to preoperative chemotherapy declines physical reserves and is associated
with a lengthening of the time between pre-surgery clinic appointment and surgery of more
than 3 months.10
Also, we hypothesize, in this parallel, of noninferiority study that with a
physical training, a personalized nutritional support and a psychologist global management
may decrease postoperative complications, increase postoperative nutritional status and so,
would results in an increase in the numbers of patients receiving their full cancer treatment.
The aim of this randomized, with parallel group, of superiority study, was to evaluate, in
patients presenting with gastroesophageal adenocarcinoma, the effect of prehabilitation
compared to conventional care, the percentage of patients reaching the complete oncological
treatment previously decided in a multidisciplinary tumour board.
METHODS AND ANALYSIS
Study setting
The present study is a prospective, randomised, controlled, open and multicentric, phase III
trial that compares prehabilitation (Prehab group) versus conventional care (control group) in
patients presenting with gastric and low oesophageal adenocarcinoma, treated by
perioperative chemotherapy. Inclusions will be perform in four French tertiary centers.
Study objectives
In the experimental group (Prehab group), the main objective is to demonstrate an
improvement of the percentage of patients reaching the complete oncological treatment fixed
in a multidisciplinary tumour board. The secondary objectives is to evaluate the effect of the
prehabilitation on the postoperative morbidity according Dindo-Clavien classification, severe
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morbidity (Clavien >2), disease free survival (DFS), overall survival (OS), feasibility of the
protocol (number of physical sessions realized on the eighteen proposed), length of stay,
variation of the functional reserve after the chemotherapy (defined by VO2peak, VT and
6MWT), pre- and postoperative nutritional status, preoperative anxiety, quality of life (EQ-5D
survey) at the end of the treatment, 30- and 90 days mortality and cumulative dose of
cytotoxic treatment received.11
Inclusion and exclusion criteria
To be included in the study, the patient must have been operated for a gastric or oesophageal
adenocarcinoma and received perioperative chemotherapy, subscribe to the French national
health insurance system and give their written consent. Patients cannot be included in the
study for one of the following criteria: <18 years of age, need for a radiochemotherapy,
presenting with any unbalanced progressive disease (hepatic failure, renal failure (creatinine
clearance <30mL / min), respiratory failure, congestive heart failure, myocardial infarction in
the last 6 months), treated for another cancer within 5 years, except basal cell skin carcinoma
or carcinoma in situ of the cervix, presenting with cognitive disorders or major disability
making impossible to understand the study and sign the informed consent, or being
breastfeeding or pregnant. Finally, patients already included in another clinical trial, or
estimated by the investigator to not be able to be compliant with the criteria of the study, or
with legal incapacity (person deprived of liberty or subject under guardianship) will not be
enrolled in this study. Guidelines regarding stopping participation are: withdrawal of patient
consent, non-compliance of the patient, adverse event and by decision of the investigator. In
case of withdrawal from the study, the patient will be followed and managed normally in the
digestive surgery department. The exclusion period during which the patient cannot
participate in another clinical trial is 15 days before inclusion and 0 days after the end of the
study.
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Interventions
After the first visit with his surgeon, the patient will be presented at the multidisciplinary
tumour board to validate the inclusion criteria and to schedule the number of cycles of pre-
and postoperative chemotherapy. After this step, a second consultation with the surgeon will
take place to verify all inclusion and exclusion criteria and perform the randomization. For the
two groups, an initial (before chemotherapy) and final (one week before the surgery)
evaluation will be performed. The evaluation includes cardiopulmonary exercise testing
(VO2peak, VT and 6MWT), nutritional evaluation (albumin), bioelectric impedance analysis,
evaluation of physical activity and ingesta, evaluation of the level of depressive symptoms
and anxiety with the HADS survey and the quality of life (5Q-FD survey).
Study group
“Prehab” group
Exercise intervention: The total-body exercise will consist of up to one hour of supervised
exercise for at least three days per week, for a total of 18 cycles, alternating between aerobic
and resistance training. Exercise intensity will be prescribed based on the rate of the 6MWT,
VT and VO2peak. The participant will exercise in the presence of the physical therapist who
will provide corrective feedback, if necessary.
Nutrition intervention: Initially, a nutritionist will perform a medical examination run
appropriate biological tests to evaluate the nutritional status and to provide individualized care
to each patient. Individual protein requirements will be calculated as 1.2g of protein per
kilogram of body weight (adjusted body weight was used for obese patients), as per European
Society for Clinical Nutrition and Metabolism (ESPEN) guidelines regarding surgical
patients.12
Patients will be asked to consume the protein supplement within one hour of their
exercise regimen to capitalize on postexercise muscle protein synthesis.13
Then, a dietician
will assess the compliance of the nutritional support at each cycle of chemotherapy and will
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adjust it, if necessary. After the preoperative chemotherapy, a second evaluation by a
nutritionist will be performed.
Psychologist intervention: Patients will receive up to a one hour visit with a trained
psychologist who will provide techniques aiming to reducing anxiety, such as relaxation
exercises based on imagery and visualization, together with breathing exercises. Each patient
will practice these exercises with the psychologist initially and at each cycle of chemotherapy
and at home two to three times per week. The psychologist also provides suggestions on how
to enhance and reinforce patients’ motivation to comply with the exercise and nutritional
aspects of the intervention.
Control group:
The control group will be treated according to conventional care; will not receive any specific
intervention before surgery except nutritional support and physiotherapy at the surgeon’s
discretion.
Study outcomes
The primary outcome is, in patients presenting with gastric or oesophageal adenocarcinoma,
the percentage of patients in each group, receiving the full perioperative oncological
treatment, previously defined by a multidisciplinary tumour board. If a patient does not
complete a chemotherapy course (=event), he will be considered as a subject who did not
receive the full protocol (chemotherapy-surgery-chemotherapy). However, a decrease in dose
of chemotherapy or a stop of a component of chemotherapy will not be considered as an
event.
The secondary outcomes are: postoperative morbidity at 3 months according Dindo-Clavien
classification; severe morbidity at 3 months (Clavien >2); disease free survival (DFS),
survival defined by the time, in months, before recurrence at 3- and 5-years after the end of
the postoperative chemotherapy; overall survival (OS), defined by the time, in months, of the
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overall survival at 3- and 5 years after the end of the postoperative chemotherapy; feasibility
of the protocol defined by the percentage of physical sessions realized on the eighteen
proposed in the preoperative period; length (in days) of postoperative stay; difference between
the initial (before preoperative chemotherapy) and final (after preoperative chemotherapy)
VO2 at the VT (ml.min-1
.kg-1
); difference between the initial (before preoperative
chemotherapy) and final (after preoperative chemotherapy) value of VO2peak (ml.min-1
.kg-1
.);
difference between the initial (before preoperative chemotherapy) and final (after preoperative
chemotherapy) 6MWT (meters); difference between the initial (before preoperative
chemotherapy) and final (after preoperative chemotherapy) weight (Kg); difference between
the initial (before preoperative chemotherapy) and final (after preoperative chemotherapy)
albuminemia (g/l); difference between the initial (before preoperative chemotherapy) and
final (after preoperative chemotherapy) evaluation on the score of HADS survey (Hospital
anxiety and depression scale) to assess the anxiety and depression from a survey with 14
questions; difference of the score between the initial evaluation (before preoperative
chemotherapy) and at 3-months after the surgery of the quality of life defined by the EQ-5D
survey; 30- and 90 days mortality.
Methodology and study design
The trial will be performed in four centres. Patients will be recruited, treated and followed-up
at the digestive surgery department of the University Hospital of Clermont-Ferrand (France),
Lille (France), Lyon (France) and Rennes (France). After the multidisciplinary tumour board
will check all the inclusion and exclusion criteria, the PREHAB trial will be proposed by
surgeons to patients with gastric or oesophageal adenocarcinoma and concomitant
perioperative chemotherapy. Patients will be informed of the trial protocol and, on
acceptance, will be randomised in the “Prehab” group or the control group. Randomisation
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will be carried out using a dedicated centralised telephone system and accessible round the
clock. The randomisation sequence will be generated by a biostatistician using random blocks
and stratification as a function of the centers and type of cancer (œsophagus or stomach). The
trial will be open blinded because of the procedures employed and with an objective primary
endpoint. The patient will be informed of the randomisation arm throughout the trial.
Statistical considerations
Estimation sample size
According to previous works, we estimated the percentage of patients in each group, realizing
the full perioperative oncological treatment around 30% (1,2). A sample size of n=56
patients by randomized group would provide 90% statistical power to detect an absolute
difference of 30% (30% vs. 60%) for a two-sided α level of 0.05. Finally, a total of 60
patients by group will be considered. An interim analysis is planned after enrolment of the
first 60 patients using the Lan and DeMets, O’Brien-Fleming method (East software, Cytel
Inc, Cambridge, Massachusetts, USA). The type I error is fixed at 0.003 for this interim
analysis. The time schedule of enrolment has been estimated at 18 months.
Statistical analysis
Statistical analysis will be conducted on intention to treat (ITT) using Stata software, V.13
(StataCorp, College Station, Texas, USA). A two-sided p value of less than 0.05 will be
considered to indicate statistical significance (except interim analysis). Baseline
characteristics will be presented for each randomized group as the mean ± SD or the median
[interquartile range] according to the statistical distribution for continuous data, and as the
number of patients and associated percentages for categorical parameters.
Comparisons between independent groups will be analysed using the χ2 or Fisher's exact test
for categorical variables (notably unplanned readmission and primary outcome: percentage of
patients realizing the full perioperative oncological treatment) and Student t-test or Mann-
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Whitney's test for quantitative parameters (notably weight loss, BMI body mass index,
albumin, body impedance, length of stay, VO2peak, VT, 6MWT, depressive and anxious
symptoms evaluated using HADS, quality of Life according EQ-5D). The normality will be
studied by the Shapiro-Wilk test and the homoscedasticity using the Fisher-Snedecor test. The
analysis of the primary outcome will be complemented by multivariate analysis using
generalized linear mixed model (logistic for dichotomous dependent variable) to take into
account (1) fixed effects covariates retained according to univariate analysis results and
clinical relevance, and (2) random-effects (between and within centre and surgeon
variabilities). Censored data such as overall survival or event-free survival will be estimated
using Kaplan-Meier method and compared (i) by log-rank test in univariate situation and (ii)
using Cox proportional hazard model in the multivariate context. Regarding the analysis of
repeated measures, random-effect models (linear or generalised linear) will be considered to
study the fixed effects group, time-points evaluation and interaction ‘group x time’, taking
into account between and within subject variability.
In prehab group, a dose-response study will be proposed to assess (i) the impact of the
number of prehabilitation sessions really realized and (ii) the compliance prehabilitation care
(dietary and nutritional management). A particular focus will be done on lost to follow-up. A
study with the abandonment considered as a censored data will be proposed using Kaplan-
Meier estimation. If the frequency of missing data is greater than 5%, we will perform
additional analyses using imputation methods.
ETHICS AND DISSEMINATION
Approval
In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
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Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015. Any substantial change in the protocol or in the informed
consent form will be presented to both authorities as well as first inclusion and end of study.
Data monitoring will be performed per French regulations requirements. As required by the
IRB, a safety committee has been set up. The study is currently registered on the clinical trials
website under the following number: NCT02780921. The current protocol version is the firth,
since April 20th
, 2016.
Patient informed consent
According to international regulations on clinical trials, written informed consent will be
obtained from patients prior to their participation in the study (Appendices 1 and 2). Patients
will voluntarily confirm their understanding and willingness to participate in the study after
having been informed (in writing and verbally) by oncologists on all the aspects of the study.
They also will be informed about requirements regarding data protection and direct access to
their individual data. The patients will be informed that they are free to withdraw from the
study at any time at their own discretion, without necessarily giving reasons.
Data collection and quality management
Experienced and trained study coordinators will be dedicated to data acquisition, coding,
security and storage, under the responsibility of investigators. Each study data will be
anonymised. Data will be collected and managed using REDCap electronic data capture tools
hosted at the University Hospital of Clermont-Ferrand.14
Research Electronic Data Capture
(REDCap) is a secure, web-based application designed to support data capture for research
studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking
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data handling and export procedures; 3) automated export procedures for seamless data
downloads to common statistical packages; and 4) procedures for importing data from
external sources. A clinical research assistant will be commissioned by the sponsor
(University Hospital of Clermont-Ferrand) in order to monitor the progress of the study in
accordance with the Standard Operating Procedures implemented at the University Hospital
of Clermont-Ferrand, in accordance with the Good Clinical Practice and current French laws.
Access to data and dissemination of results
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov.
DISCUSSION
The perioperative chemotherapy became the gold standard treatment in advanced gastric and
low œsophageal adenocarcinoma, with an improvement of DFS and OS.1 2
However, the
limitation of these studies is that, among all patients requiring chemotherapy, 70% of patients
will not receive the complete treatment sequence. In these studies, only patients in good
nutritional and physical status without postoperative complications can receive postoperative
treatment. 1 2
A meta-analysis reported that prehabilitation improved postoperative morbidity,
length of stay, nutritional and physical status.7 The PREHAB study presented here should
demonstrate if the prehabilitation increases the percentage of patients reaching the complete
oncological treatment defined in a multidisciplinary tumour board, to increase DFS and OS.
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BIBLIOGRAPHY
1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson
M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal
cancer. N Engl J Med. 2006 Jul 6;355(1):11–20.
2. Ychou M, Boige V, Pignon J-P, Conroy T, Bouché O, Lebreton G, et al. Perioperative
chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma:
an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol Off J Am Soc Clin Oncol.
2011 May 1;29(13):1715–21.
3. Hennis PJ, Meale PM, Grocott MPW. Cardiopulmonary exercise testing for the
evaluation of perioperative risk in non-cardiopulmonary surgery. Postgrad Med J. 2011
Aug;87(1030):550–7.
4. Carlisle J, Swart M. Mid-term survival after abdominal aortic aneurysm surgery
predicted by cardiopulmonary exercise testing. Br J Surg. 2007 Aug;94(8):966–9.
5. Fong DYT, Ho JWC, Hui BPH, Lee AM, Macfarlane DJ, Leung SSK, et al. Physical
activity for cancer survivors: meta-analysis of randomised controlled trials. BMJ.
2012;344:e70.
6. Kemi OJ, Wisloff U. High-intensity aerobic exercise training improves the heart in
health and disease. J Cardiopulm Rehabil Prev. 2010 Feb;30(1):2–11.
7. Valkenet K, van de Port IGL, Dronkers JJ, de Vries WR, Lindeman E, Backx FJG.
The effects of preoperative exercise therapy on postoperative outcome: a systematic review.
Clin Rehabil. 2011 Feb;25(2):99–111.
8. Jaggers JR, Simpson CD, Frost KL, Quesada PM, Topp RV, Swank AM, et al.
Prehabilitation before knee arthroplasty increases postsurgical function: a case study. J
Strength Cond Res Natl Strength Cond Assoc. 2007 May;21(2):632–4.
9. Van Adrichem EJ, Meulenbroek RL, Plukker JTM, Groen H, van Weert E.
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Comparison of two preoperative inspiratory muscle training programs to prevent pulmonary
complications in patients undergoing esophagectomy: a randomized controlled pilot study.
Ann Surg Oncol. 2014 Jul;21(7):2353–60.
10. West J, Wood H, Logan RFA, Quinn M, Aithal GP. Trends in the incidence of
primary liver and biliary tract cancers in England and Wales 1971-2001. Br J Cancer. 2006
Jun 5;94(11):1751–8.
11. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004
Aug;240(2):205–13.
12. Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P, et al. ESPEN
Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr Edinb
Scotl. 2006 Apr;25(2):224–44.
13. Campbell WW, Leidy HJ. Dietary protein and resistance training effects on muscle
and body composition in older persons. J Am Coll Nutr. 2007 Dec;26(6):696S–703S.
14. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
data capture (REDCap)--a metadata-driven methodology and workflow process for providing
translational research informatics support. J Biomed Inform. 2009 Apr;42(2):377–81.
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Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript.
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY).
Ethics approval IRB00008526 and ANSM (2015-A01733-46).
Provenance and peer review Not commissioned; externally peer reviewed.
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Appendices:
1. Informed form
2. Consent form
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Appendice 1
FORMULAIRE D’INFORMATION
Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation dans le cancer de l’estomac et de
l’œsophage
Promoteur de l’essai :
CHU de Clermont Ferrand,
58 rue Montalembert,
63003 Clermont Ferrand Cedex 1, France
Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy
Service de chirurgie digestive et hépato-biliaire
1 Place Lucie Aubrac
63003 Clermont-Ferrand
Madame, Monsieur, il vous est proposé de participer à un protocole de recherche clinique, dont le but
est de montrer qu’on peut améliorer votre récupération post opératoire et optimiser la poursuite de votre
traitement de chimiothérapie en vous préparant physiquement, psychologiquement et le plan nutritionnel avant
l’intervention. Cette prise en charge est appelée « préhabilitation » et va vous être expliquée ci-après plus en
détails.
Cependant avant de décider de prendre part à cette étude biomédicale, il est important que vous preniez
le temps de lire et de comprendre les informations suivantes concernant le déroulement de ce protocole. Cette
note d’information décrit l’objectif, les procédures, les bénéfices et les risques de l’étude. Elle explique entre
autre votre droit à vous retirer de l’étude à tout moment sans avoir à vous justifier. S’il y a quoi que ce soit dans
ce document que vous ne comprenez pas, veuillez demander à votre médecin ("investigateur") ou au personnel
de l’étude de vous l’expliquer. Prenez votre temps pour décider si vous souhaitez ou non participer à cette étude ;
parlez-en avec vos amis ou vos proches. Si vous choisissez de participer, il vous sera demandé de signer un
document intitulé « Formulaire de consentement » et ce en 2 exemplaires, dont un vous sera remis. Si vous
refusez de prendre part à l’étude, ceci n’aura aucune conséquence sur votre prise en charge médicale.
Pour pouvoir participer à cette étude vous devez être couvert par un régime de Sécurité Sociale.
Rationnel de l’étude
Vous allez être opéré de votre cancer œsogastrique dans le service de chirurgie de votre CHU.
Comme toute intervention chirurgicale, elle comporte des risques propres à chaque type d’intervention.
Ces risques peuvent induire une augmentation de votre durée d’hospitalisation, une diminution plus ou moins
longue de votre qualité de vie voire une impossibilité à poursuivre votre traitement de chimiothérapie.
Récemment des chirurgiens ont montré qu’une préparation durant 6 semaines avant l’opération, pouvait
améliorer les résultats post-opératoires sur la morbidité globale, le statut nutritionnel, le retour plus rapide aux
activités quotidiennes permettant, en autre, de réaliser tout le protocole de chimiothérapie prévu initialement.
Cette prise en charge est appelée « préhabilitation ». Elle repose sur 3 volets.
- une prise en charge physique qui consiste à réaliser des exercices cardiovasculaires 3 fois par
semaine sous surveillance médicale dans le service de médecine du sport et de réadaptation de
votre l’hôpital
Paraphe du patient
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- une prise en charge nutritionnelle qui consiste à établir avec un médecin nutritionniste et un
diététicien, un programme alimentaire pouvant conduite à une supplémentation nutritionnelle si
nécessaire
- une prise en charge psychologique avec le soutien d’un psychologue qui vous recommandera, en
autre, des tests de relaxation à réaliser à la maison.
Ce protocole a déjà montré son intérêt dans le domaine de la chirurgie cardio vasculaire ou du cancer colorectal.
Aussi, nous souhaiterions en faire de même pour la chirurgie du cancer œsogastrique d’où l’étude à laquelle nous
vous proposons de participer.
Déroulement de l’étude :
Après information par votre chirurgien et après lecture de cette note, si vous acceptez de rentrer dans l’étude, un
bilan pré-opératoire standard pour votre pathologie pourra être réalisé si nécessaire. De même vous pourrez être
amené à voir ou revoir un anesthésiste à la demande du chirurgien.
Nous vous demanderons également de bien vouloir compléter, répondre à quelques questionnaires évaluant votre
qualité de vie, vos habitudes alimentaires, vos activités quotidiennes...
Après ces évaluations et si vous répondez toujours aux critères du protocole, un tirage au sort sera réalisé afin de
déterminer dans quel groupe vous allez entrer durant vos séances de chimiothérapie pré opératoire 1) groupe
contrôle : préparation standard selon les référentiels actuels, 2) groupe préhabilitation.
Paraphe du patient
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Paraphe du patient
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La préparation standard consistera :
a) à bénéficier de séance de kinésithérapie respiratoire si nécessaire,
b) à prendre des compléments alimentaires si nécessaire soit par voie orale, soit à l’aide de sonde naso-
gastrique (sonde qui passe par les narines pour aller directement dans le tube digestif) soit par injection.
c) à évaluer votre anxiété à l’aide de questionnaires
La "préhabilitation" consistera :
a) à réaliser des exercices physiques à raison de 1h, 3 fois par semaine durant 6 semaines dans le service
de médecine du sport de votre Hôpital et ce, sous la surveillance médicale d’un kinésithérapeute.
Ces activités seront adaptées à vos propres capacités et selon vos résultats aux examens cardio
respiratoires réalisés au préalable avant tout traitement. Ils débuteront 2 mois avant votre chirurgie.
Les exercices réalisés seront de 2 types :
* des exercices d’endurance dont le but sont d’améliorer votre résistance cardio vasculaire en
réalisant du vélo et/ou de la marche,
* des exercices de renforcement musculaires (bras, épaules, poitrine, abdomen, dos hanches et
jambe) à l’aide de matériel type haltères, élastiques …...
Tous ces exercices seront actualisés au cours du temps en fonction de vos progrès, performances.
b) à suivre un programme nutritionnel élaboré avec un nutritionniste 2 mois avant votre chirurgie. Ce
dernier sera établi en fonction de vos besoins, de vos habitudes alimentaires et pourra être adapté,
modifié en cours du programme avec l’aide du diététicien qui vous rencontrera régulièrement lors de
vos
venues à l’hôpital pour vos séances de chimiothérapie. Vous reverrez également le nutritionniste à la
fin de vos 6 semaines de préhabilitation.
c) à vous rendre à des consultations de psychologies pour apprendre à gérer, contrôler votre anxiété, à
mieux appréhender votre traitement de chimiothérapie et les effets secondaires associés. Pour cela il
vous sera demandé d’assister à 3 consultations d’1h avec un psychologue qui vous apprendra des
exercices de relaxations à réaliser ensuite à votre domicile. Ces consultations auront lieu au cours des
2 mois précédents votre chirurgie
A la fin de vos séances de chimiothérapie, vous bénéficierez à nouveaux de bilans (et ce, peu importe
dans quel groupe vous êtes inclus) afin de faire le point sur :
1) votre résistance cardiorespiratoire
2) votre état nutritionnel,
3) votre niveau d’anxiété
De même il vous sera demandé de répondre à des questionnaires
Ensuite, un suivi médical 1 mois puis à la fin de votre traitement de chimiothérapie adjuvante sera
réalisé par le biais d’une consultation afin d’évaluer les suites opératoires, votre qualité de vie, votre autonomie.
Le déroulement de chaque consultation comprendra un examen médical clinique, des questionnaires spécifiques
à l’étude à compléter.
Paraphe du patient
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Bénéfices et risques de l’étude
Les bénéfices potentiels pour vous de participer à cette étude pourraient être une meilleure récupération
post opératoire, une durée d’hospitalisation plus courte et surtout un retour plus rapide à vos activités du
quotidien, et peut être une meilleur tolérance de la chimiothérapie.
Ce projet ne devrait pas engendrer de risque supplémentaire pour vous si ce n’est peut être un surplus de
fatigue liée aux exercices, examens et consultations supplémentaires requis par l’essai, voire des contraintes
supplémentaires comme disponibilités, déplacements, suivi alimentaire .
Modalité de recrutement
Ce protocole sera proposé à 120 patients répondant aux critères d’inclusion et d’exclusion. Ces 120 patients
seront inclus après signature du consentement éclairé.
Traitements administrés dans le cadre de cette étude
Aucun traitement supplémentaire autre que ceux utilisés en routine pour votre prise en charge thérapeutique
ne sera nécessaire à la conduite de cette étude.
Evaluations réalisées
Nous essayerons au mieux de concilier les examens, consultations spécifiques au protocole avec vos venues
au CHU dans le cadre de votre traitement de chimiothérapie. Si des visites supplémentaires s’avéraient
nécessaires pour des questions de disponibilités, d’organisation de services sachez que cela n’induire aucun frais
supplémentaire pour vous.
De même lors de votre prise en charge, suivi, il vous sera remis des questionnaires permettant d’évaluer
votre qualité de vie, votre niveau d’anxiété ou encore votre statut physique et nutritionnel. Ces questionnaires
devront être remplis sur place et prendront au maximum une vingtaine de minutes.
Durée totale de votre participation à ce protocole
La durée totale de votre participation à cette étude sera de 6 mois.
Indemnisation
Il n’y aura aucune indemnisation dans le cadre de cette étude.
Période d’exclusion
La période d’exclusion définie dans le cadre de cette étude est de 15 jours avant votre inclusion jusqu’à
votre sortie d’étude, période pendant laquelle vous ne pourrez pas participer à un autre protocole de recherche
clinique.
Paraphe du patient
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Conservation de matériel biologique
Cette étude ne fera l’objet d’aucune conservation de matériel biologique
Protection des patients et confidentialité
Cette recherche a reçu l’avis favorable du Comité de Protection des Personnes sud est VI le
…………………………… ainsi que l’autorisation préalable de l’autorité compétente de santé datée du
………………………... Il est possible que cette recherche soit interrompue, si les circonstances le nécessitent,
par le promoteur ou à la demande de l’autorité de santé.
Votre participation à cette recherche biomédicale n'engendrera pour vous aucun frais supplémentaire par
rapport à ceux que vous auriez dans le cadre de la prise en charge standard de votre maladie.
Toutefois, pour pouvoir participer à cette recherche vous devez être affilié(e) ou bénéficier d’un régime de
sécurité sociale.
Le CHU de Clermont-Ferrand, qui organise cette recherche biomédicale en qualité de promoteur, a
contracté une assurance conformément aux dispositions législatives, garantissant sa responsabilité civile et celle
de tout intervenant auprès de la Société Hospitalière d’Assurances Mutuelles (SHAM, contrat n° 147161). Dans
le cas où votre état de santé serait altéré du fait de votre participation à l’étude, conformément à la loi de Santé
Publique n°2004-806 du 9 août 2004, vous seriez en droit de recevoir des dédommagements dans le cadre de ce
contrat d’assurance spécifique.
Dans le cadre de la recherche biomédicale à laquelle le CHU de Clermont-Ferrand (établissement
promoteur) vous propose de participer, un traitement informatique de vos données personnelles va être mis en
œuvre pour permettre d’analyser les résultats de la recherche au regard de l’objectif de cette dernière qui vous a
été présenté. A cette fin, les données médicales vous concernant et les données relatives à vos habitudes de vie,
seront transmises au Promoteur de la recherche ou aux personnes ou sociétés agissant pour son compte, en
France ou à l’étranger. Ces données seront identifiées par un numéro de code et par vos initiales. Ces données
pourront également, dans des conditions assurant leur confidentialité, être transmises aux autorités de santé
françaises, à d’autres entités du CHU de Clermont Ferrand (établissement promoteur).
Conformément aux dispositions de loi relative à l’informatique aux fichiers et aux libertés, vous disposez
d’un droit d’accès et de rectification. Vous disposez également d’un droit d’opposition à la transmission des
données couvertes par le secret professionnel susceptibles d’être utilisées dans le cadre de cette recherche et
d’être traitées.
Vous pouvez également accéder directement ou par l’intermédiaire d’un médecin de votre choix à
l’ensemble de vos données médicales en application des dispositions de l’article L. 1111-7 du code de la santé
publique. Ces droits s’exercent auprès du médecin qui vous suit dans le cadre de la recherche et qui connaît votre
identité.
Par ailleurs, vous pourrez être tenu informé des résultats globaux de cette recherche à la fin de l’étude.
Vous êtes libre d'accepter ou de refuser de participer à cette recherche. De plus vous pouvez exercer à tout
moment votre droit de retrait de cette recherche sans avoir à vous justifier. Le fait de ne plus participer à cette
recherche ne modifiera pas la qualité des soins qui vous sont prodigués. Vous pouvez demander à tout moment
des explications complémentaires sur l’étude à l’équipe soignante.
Lorsque vous aurez lu cette note d’information et obtenu les réponses aux questions que vous vous posez
en interrogeant le médecin investigateur, il vous sera proposé, si vous en êtes d’accord,
Paraphe du patient
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de donner votre consentement écrit en signant le document préparé à cet effet en accord avec le code de la
santé publique visant à protéger les personnes se soumettant à une étude biomédicale. Votre consentement écrit
n’enlève en aucun cas la responsabilité des médecins qui vous soignent
A qui devez-vous vous adresser en cas de questions ou de problèmes ?
En cas de problèmes, d’événements indésirables en cours d’essai ou de questions, vous pouvez vous
adresser aux personnes suivantes :
Vos contacts dans l’étude
Bertrand Le Roy (Coordonnateur)
Service de Chirurgie Digestive Hôpital Estaing CHU de Clermont-Ferrand
1 place Lucie et Raymond Aubrac 63003 Clermont-Ferrand cedex 1
Tel: 04 73 75 04 94 Fax : 04 73 75 19 22 bleroy@chu-
clermontferrand.fr
Brigitte Gillet (Ingénieur Hospitalier, Attaché de recherche clinique)
Service de Chirurgie Digestive Unité d'Oncologie Digestive Hôpital Estaing
CHU de Clermont-Ferrand 1 place Lucie et Raymond Aubrac
63003 Clermont-Ferrand cedex 1Tel: 04 73 75 52 26 Fax : 04 73 75 19 22 bgillet@chu-
clermontferrand.fr
Paraphe du patient sur toutes les pages
Date : ……/……/……
Signature du patient Paraphe de l’investigateur
(Précédée de la mention « Lu et compris »)
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Appendice 2
FORMULAIRE DE CONSENTEMENT DE PARTICIPATION A UNE
RECHERCHE BIOMEDICALE
Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation
dans le cancer de l’œsophage et de l’estomac
Promoteur de l’essai :
CHU de Clermont Ferrand,
58 rue Montalembert,
63003 Clermont Ferrand Cedex 1, France
Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy
Service de chirurgie digestive et hépato-biliaire
1 Place Lucie Aubrac
63003 Clermont-Ferrand
Je soussigné(e)
Mme, M
lle, M. (rayer les mentions inutiles) (nom, prénom)……………………………………………
Né(e) le ………………….…………………...
Déclare :
- que le Docteur (nom, prénom, téléphone) ……………………………………………..…………….. m’a proposé
de participer à l’étude sus nommée,
- qu’il m’a expliqué en détail le protocole,
- qu’il m’a notamment fait connaître :
• l’objectif, la méthode et la durée de l’étude
• les contraintes et les risques potentiels encourus
• mon droit de refuser de participer et en cas de désaccord de retirer mon consentement à tout moment
• mon obligation d’inscription à un régime de sécurité sociale
• que, si je le souhaite, à son terme, je serais informé(e) par le médecin investigateur de ses résultats globaux
• que je ne serais pas autorisé(e) à participer à d’autres études cliniques durant toute ma participation à ce
protocole estimée à 6 mois maximum.
• que le Comité de Protection des Personnes Sud Est VI a émis un avis favorable en date du
xx/xx/xxxx(Préciser le nom de CPP sollicité et la date d’obtention de l’avis favorable)
• que l’ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé) a délivré une
autorisation pour cette étude
• que dans le cadre de cette étude le promoteur, le CHU de Clermont-Ferrand, a souscrit à une assurance
couvrant cette recherche (contrat SHAM 147161).
- que j’ai répondu en toute bonne foi aux questions concernant mon état de santé et ma participation à d’autres
études.
Les informations relatives à l’étude recueillies par l’investigateur sont traitées confidentiellement. J’accepte que
les données enregistrées à l’occasion de cette recherche puissent faire l’objet d’un traitement informatisé
anonyme. J’ai bien noté que le droit d’accès prévu par la loi du 6 août 2004 relative à l’informatique, aux fichiers
et aux libertés s’exerce à tout moment auprès du médecin qui me suit dans le cadre de la recherche et qui connaît
mon identité. Je pourrai exercer mon droit de rectification et d’opposition auprès de ce même médecin, qui
contactera le promoteur de la recherche
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Après avoir discuté librement et obtenu réponse à toutes mes questions, j’accepte librement et
volontairement de participer à cette recherche biomédicale dans les conditions précisées dans le
formulaire d’information et de consentement.
Nom et prénom du patient :
……………………………………………………
Date :……./……./…….
Signature
Précédée de la mention « Lu et compris » :
Nom de l’investigateur :
……………………………………………………
Date :……./……./…….
Signature :
Ce document est à réaliser en 2 exemplaires originaux, dont le premier doit être gardé 15 ans par l’investigateur,
un autre remis à la personne donnant son consentement.
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Spirit
Administrative information
Title
1
Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym
Trial registration=> Page 3
2a
Trial identifier and registry name. If not yet registered, name of intended registry
=> Page 3
2b
All items from the World Health Organization Trial Registration Data Set
Protocol version
=> Page 3
3
Date and version identifier
Funding
=> Page 3
4
Sources and types of financial, material, and other support
Roles and responsibilities
=> Page 3-4
5a
Names, affiliations, and roles of protocol contributors
=> Page 4
5b
Name and contact information for the trial sponsor
=> Page 3-4
5c
Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation
of data; writing of the report; and the decision to submit the report for publication, including whether they will
have ultimate authority over any of these activities
=> Page 3
5d
Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication
committee, data management team, and other individuals or groups overseeing the trial, if applicable (see
Item 21a for data monitoring committee)
=> Page 3
Introduction
Background and rationale
6a
Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
=> Page 7
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6b
Explanation for choice of comparators
=> Page 8
Objectives
7
Specific objectives or hypotheses
Trial design
=> Page 8
8
Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation
ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
=> Page 8
Methods: Participants, interventions, and outcomes
Study setting
9
Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be
collected. Reference to where list of study sites can be obtained Eligibility criteria
=> Page 8
10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists) Interventions
=> Page 9
11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
=> Page 10
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
=> Page 11-12
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
=> Page 11-12
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial Outcomes
=> Page 11-12
12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy
and harm outcomes is strongly recommended Participant timeline
=> Page 11-12
13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure) Sample size
=> Page 13-14
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14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations Recruitment
=> Page 13-14
15 Strategies for achieving adequate participant enrolment to reach target sample size
=> Page 14
Methods: Assignment of interventions (for controlled trials) Allocation: Sequence generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg,
blocking) should be provided in a separate document that is unavailable to those who enrol participants or
assign interventions
=> Page 14
Allocation concealment mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
Implementation
=> Page 14
16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions Blinding (masking)
=> Page 14
17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
=> Page 14
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial Methods: Data collection, management, and analysis Data collection
methods
=> NA
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
=> Page 14
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols Data management
=> Page 14
19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol Statistical methods
=> Page 14
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20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
=> Page 14
20b Methods for any additional analyses (eg, subgroup and adjusted analyses)
=> Page 14
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
=> Page 14
Methods:
Monitoring Data monitoring
21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement
of whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed
=> Page 16
21b Description of any interim analyses and stopping guidelines, including who will have access to these
interim results and make the final decision to terminate the trial Harms
=> Page 13
22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct Auditing
=> Page 13
23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
=> Page 13
Ethics and dissemination
Research ethics approval
24
Plans for seeking research ethics committee/institutional review board (REC/IRB) approval
Protocol amendments
=> Page 14-15
25
Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)
=> Page 14-15
Consent or assent
26a
Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how
(see Item 32)
=> Page 15
26b
Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
Confidentiality
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27
How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
Declaration of interests
28
Financial and other competing interests for principal investigators for the overall trial and each study site
Access to data
29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators Ancillary and post-trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
Dissemination policy
=> Page 16
31a
Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the
public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing
arrangements), including any publication restrictions
=> Page 16
31b
Authorship eligibility guidelines and any intended use of professional writers
=> Page 16
31c
Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code
=> Page 16
Appendices
Informed consent materials
32
Model consent form and other related documentation given to participants and authorised surrogates
Biological specimens
=> Appendice 1, legends page 20
33
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis
in the current trial and for future use in ancillary studies, if applicable
=>NA
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Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a multicentric,
randomised control trial - PREHAB study
Journal: BMJ Open
Manuscript ID bmjopen-2016-012876.R1
Article Type: Protocol
Date Submitted by the Author: 14-Sep-2016
Complete List of Authors: Le Roy, Bertrand; CHU Estaing, Digestive surgery Pereira, Bruno; University Hospital CHU Clermont-Ferrand, Biostatistic unit Bouteloup, Corinne; CHU Estaing, Digestive and Liver Disease
Costes, Frederic; CHU Gabriel Montpied, Department of physiology and medical sport Richard, Ruddy; CHU Gabriel Montpied, Department of physiology and medical sport Selvy, Marie; CHU Estaing, Digestive surgery and oncological department Petorin, Caroline; Oncology Gagniere, Johan; University Hospital of Clermont-Ferrand, Digestive and Hepatobiliary Surgery Futier, Emmanuel; CHU Estaing, Department of Anesthesia Slim, Karem; CHU Estaing, Digestive surgery and oncological department Meunier, Bernard; Centre Hospitalier Universitaire de Rennes Mabrut, Jean-Yves; Hopital de la Croix-Rousse
Mariette, C.; CHU Claude Huriez, Digestive and oncological surgery Pezet, Denis; Digestive surgery
<b>Primary Subject Heading</b>:
Surgery
Secondary Subject Heading: Rehabilitation medicine, Oncology
Keywords: Prehabilitation, Gastric cancer, Oesophageal disease < GASTROENTEROLOGY, Fitness, Gastrointestinal tumours < ONCOLOGY
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1
Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Bertrand Le Roy, MD1, Bruno Pereira, PhD
2, Corinne Bouteloup, MD
6,9,10, Frédéric Costes,
MD, PhD5,10
, Ruddy Richard, MD, PhD5,10
, Marie Selvy, MD1, Caroline Pétorin, MD
1, Johan
Gagnière, MD1, Emmanuel Futier, MD, PhD
3, Karem Slim, MD
1, Bernard Meunier, MD,
PhD7, Jean-Yves Mabrut, MD, PhD
8, Christophe Mariette, MD, PhD
4, Denis Pezet, MD,
PhD1.
(1) Digestive surgery and oncological department, Hospital Estaing, 1, place Lucie-Aubrac,
63003 Clermont-Ferrand, France
(2) Biostatistics unit (DRCI), Clermont-Ferrand University Hospital, 63003 Clermont-
Ferrand, France
(3) Department of Anesthesia, Hospital Estaing, Clermont-Ferrand University Hospital, 1
Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
(4) Digestive and oncological surgery, Hospital Claude Huriez, place de Verdun, 59037 Lille,
France
(5) Department of Sports Medicine and Functional Explorations, Hospital, Gabriel Montpied,
Clermont-Ferrand, France
(6) University Hospital of Clermont-Ferrand, Digestive and Liver Disease Unit F-63003
Clermont-Ferrand, France
(7) Digestive surgery department, Hospital Pontchaillou, 2 rue Henri Le Guilloux, 35033
Rennes, France
(8) Digestive surgery department, Hospital Croix Rousse, 103 Grande rue de la Croix
Rousse, 69004 Lyon, France
(9) Clermont Auvergne University, University of Auvergne, Human Nutrition Unit, ECREIN,
BP 10448, F-63000 Clermont-Ferrand, France
(10) INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France
Corresponding author
Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
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2
63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Word count: 2840
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Administrative information
Title: Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Trial registration: NCT02780921
Protocol version: Version 4, 20 apr 2016
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY), a national public funding of research.
In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015.
A clinical research assistant will be commissioned by the sponsor (University Hospital of
Clermont-Ferrand) in order to monitor the progress of the study in accordance with the
Standard Operating Procedures implemented at the University Hospital of Clermont-Ferrand,
in accordance with the Good Clinical Practice and current French laws.
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov.
Protocol contributor
Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Study sponsor:
C.H.U. de Clermont-Ferrand
58 Rue de Montalembert
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63003 Clermont-Ferrand Cedex 1
Protocol contributors
Pr Christophe Mariette, principal investigator from Lille
Service de Chirurgie Digestive et Générale
Hôpital HURIEZ, CHRU Lille
Place de Verdun, 59037 Lille
Pr Meunier Bernard, principal investigator from Rennes
Service de Chirurgie Digestive et Générale
Hôpital Pontchaillou, CHRU Rennes
Rue Henri Le Guilloux, 35000 Rennes
Pr Jean Yves Mabrut, principal investigator from Lyon
Service de Chirurgie Digestive et Générale
Hôpital de la Croix Rousse, Hospice civils de Lyon
Grande rue de la croix rousse, 69317 Lyon
Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript.
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ABSTRACT
Introduction: Perioperative chemotherapy is the gold standard treatment of the resectable
gastroesophageal adenocarcinoma. However, 70% of patients can’t receive the complete
sequence because of a postoperative complication or a decrease of functional and nutritional
reserves. Recently, a new concept appeared in digestive surgery: the prehabilitation. This
interventional process consists of a patient preparation, between the surgical consultation and
the surgery, and is based on 3 components: 1) physical management 2) nutritional care and 3)
psychological care. Prehabilitation should decrease postoperative complications and improve
nutritional and physical status during the pre- and postoperative period. Therefore, it is
becoming essential to evaluate the effect of prehabilitation, compared to conventional care, on
the percentage of patients reaching the complete oncological treatment.
Methods and analysis: The PREHAB trial aimed to evaluate the efficacy of prehabilitation
compared to conventional care, in patients with gastroesophageal cancer with perioperative
chemotherapy. This trial is a prospective, randomised, controlled, open-blind, and
interventional study, in 4 centers. Patients (n=60 per group) will be randomly assigned for
management with either prehabilitation or conventional care. The primary outcome is the
percentage of patients reaching the complete oncological treatment decided in a
multidisciplinary tumour board. The secondary outcomes are the postoperative morbidity,
disease free survival, overall survival, feasibility of the protocol, length of stay, variation of
the functional reserve after the preoperative chemotherapy (defined by VO2peak, ventilatory
threshold and 6 min walk test), pre- and postoperative nutritional status, preoperative anxiety,
quality of life, 30- and 90 days mortality and cumulative dose of cytotoxic treatment received.
Ethics and dissemination: The study was approved by an independent medical ethics
committee (IRB00008526, CPP Sud-Est VI, Clermont-Ferrand, France) and by the competent
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French authority (ANSM, Saint Denis, France) and registered on Clinicaltrial.gov. The results
will be disseminated in a peer-reviewed journal.
Trial registration number: NCT02780921; pre-result.
Strengths and limitations of this study: The main strength of this multicentric, prospective
and randomized study is that this concept of prehabilitation has never been done on this high
postoperative morbidity surgery. The main limit is this study includes both oesophageal and
stomach cancer.
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INTRODUCTION
Perioperative chemotherapy is the gold standard treatment of the resectable and advanced
gastroesophageal adenocarcinoma. The efficacy of this strategy has been demonstrated in two
randomized studies.1 2
It reduces tumour size before surgery, treats micrometastases and
evaluates chemosensitivity. Disease free and overall survival rates were significantly
improved with perioperative chemotherapy compared to surgery alone. However, the
limitation of these studies is that among all patients requiring chemotherapy, almost 70% of
patients did not receive the complete sequence. This sequence is defined by the administration
of two to four cycles before and two to four cycles after the surgery, according to the
protocol. The major cause of absence or impossibility of realization of postoperative
chemotherapy was the presence of postoperative complication, postoperative serious asthenia
and impaired nutritional and physical status. 1 2
Poor physical condition assessed by
cardiopulmonary exercise testing, reflecting a reduced physiological reserve, is predictive of
postoperative complications. 3 4
Physical training, even during a short period and on a various
population, is beneficial in improving physical condition, cardiopulmonary function and
muscular mass of the patient.5-8
Prehabilitation over a six week period between pre-surgical
clinic appointment and surgery decreases postoperative morbidity and the hospital stay in
cardiovascular surgery, but no study has ever been performed in patients presented with
gastric or oesophageal cancer. 7 9-11
Prehabilitation revolves around three axes: 1) physical training based on initial
cardiopulmonary exercise testing (VO2peak, ventilatory threshold (VT) and 6-min walk test
(6MWT)), 3 times by week, supervised by a physical therapist 2) nutritional care to ensure the
compliance of the nutrition program and adapt the nutritional management based on protein
and energy needs and on the level of spontaneous oral intake and 2) psychological treatment
by a psychologist to reduce preoperative anxiety. To our knowledge, no study ever focused on
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the gastroesophageal cancer. The benefit of prehabilitation in this cancer may be particularly
important because 1) this surgery is associated with a high 90-day morbidity (40%, especially
respiratory) and 90-day mortality (5%) 2) the physical and nutritional status of these patients
is often precarious (cancer cachexia, gastroesophageal obstruction), and 3) the need to
preoperative chemotherapy declines physical reserves and is associated with a lengthening of
the time between pre-surgery clinic appointment and surgery of more than 3 months.12
Also,
we hypothesize, in this parallel, of noninferiority study that with physical training, a
personalized nutritional support and a psychologist global management may decrease
postoperative complications, increase postoperative nutritional status and so, would results in
an increase in the numbers of patients receiving their full cancer treatment. The aim of this
study was to compare the percentage of patients reaching the complete oncological treatment
previously decided in a multidisciplinary tumour board in the group with prehabilitation to
the group with conventional care, in patients with gastroesophageal adenocarcinoma.
METHODS AND ANALYSIS
Study setting
The present study is a prospective, randomised, controlled, open and multicentric, phase III
trial that compares prehabilitation (Prehab group) versus conventional care (control group) in
patients presenting with gastric and low oesophageal adenocarcinoma, treated by
perioperative chemotherapy. Inclusions will be perform in four French tertiary centers (Figure
1).
Study objectives
In the experimental group (Prehab group), the main objective is to demonstrate an
improvement of the percentage of patients reaching the complete oncological treatment fixed
in a multidisciplinary tumour board. The secondary objectives is to evaluate the effect of the
prehabilitation on the postoperative morbidity according Dindo-Clavien classification and the
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Comprehensive Complication Index (CCI), severe morbidity (Clavien >2), disease free
survival (DFS), overall survival (OS), feasibility of the protocol (number of physical sessions
realized on the eighteen proposed), length of stay, variation of the functional reserve after the
chemotherapy (defined by VO2peak, VT and 6MWT), pre- and postoperative nutritional status,
preoperative anxiety, quality of life (EQ-5D survey) at the end of the treatment, 30- and 90
day mortality and cumulative dose of cytotoxic treatment received.13
Inclusion and exclusion criteria
To be included in the study, the participant is scheduled for surgical intervention of gastric or
oesophageal adenocarcinoma and received perioperative chemotherapy, subscribe to the
French national health insurance system and give their written consent. Patients cannot be
included in the study for one of the following criteria: <18 years of age, need for a
radiochemotherapy, treated for another cancer within 5 years, except basal cell skin
carcinoma or carcinoma in situ of the cervix, presenting with cognitive disorders or major
disability making impossible to understand the study and sign the informed consent, or being
breastfeeding or pregnant. Finally, patients already included in another clinical trial, or
estimated by the investigator to not be able to be compliant with the criteria of the study, or
with legal incapacity (person deprived of liberty or subject under guardianship) will not be
enrolled in this study. Guidelines regarding stopping participation are: withdrawal of patient
consent, non-compliance of the patient, adverse event and by decision of the investigator. In
case of withdrawal from the study, the patient will be followed and managed normally in the
digestive surgery department. The exclusion period during which the patient cannot
participate in another clinical trial is 15 days before inclusion and 0 days after the end of the
study.
Interventions
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After the first visit with his surgeon, the patient will be presented at the
multidisciplinary tumour board to validate the inclusion criteria and to schedule the
number of cycles of pre- and postoperative chemotherapy. After this step, a second
consultation with the surgeon will take place to verify all inclusion and exclusion
criteria and perform the randomization. For the two groups, an initial (before
chemotherapy) and final (one week before the surgery) evaluation will be performed.
The evaluation includes an exercise capacity evaluation by 1) an incremental
symptom-limited cardiopulmonary exercise test on a cycloergometer according to
international recommendations in order to determine VO2peak, and the ventilator
threshold (VT) and, 2) 6 minute walk distance (6MWT) performed according to the
ATS recommendations.14, 15
Moreover, the patients will be assessed for a nutritional
evaluation (albumin), bioelectric impedance analysis, evaluation of physical activity
and ingesta, evaluation of the level of depressive symptoms and anxiety with the
HADS survey and the quality of life (5Q-FD survey).
Study group
“Prehab” group
Exercise intervention: The total-body exercise will consist of up to one hour of supervised
exercise for at least three days per week, for a total of 18 sessions, alternating between aerobic
and resistance training. Exercise intensity will be prescribed based on the target heart rate
obtained at VT during the initial CPET. The participant will exercise in the presence of the
physical therapist who will provide corrective feedback, if necessary.
Nutrition intervention: Initially, a nutritionist will perform a medical examination run
appropriate biological tests to evaluate the nutritional status and to provide individualized care
to each patient. Individual protein requirements will be calculated as 1.2g of protein per
kilogram of body weight (adjusted body weight was used for obese patients), as per European
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Society for Clinical Nutrition and Metabolism (ESPEN) guidelines regarding surgical
patients.16
Patients will be asked to consume the protein supplement within one hour of their
exercise regimen to capitalize on postexercise muscle protein synthesis.17
Then, a dietician
will assess the compliance of the nutritional support at each cycle of chemotherapy and will
adjust it, if necessary. After the preoperative chemotherapy, a second evaluation by a
nutritionist will be performed.
Psychologist intervention: Patients will receive up to a one hour visit with a trained
psychologist who will provide techniques aiming to reducing anxiety, such as relaxation
exercises based on imagery and visualization, together with breathing exercises. Each patient
will practice these exercises with the psychologist initially and at each cycle of chemotherapy
and at home two to three times per week. Once performed, the exercices at home will be
marked on diaries. The psychologist also provides suggestions on how to enhance and
reinforce patients’ motivation to comply with the exercise and nutritional aspects of the
intervention.
Control group:
The control group will be treated according to conventional care; will not receive any specific
intervention before surgery except nutritional support and physiotherapy at the surgeon’s
discretion.
Study outcomes
The primary outcome is, in patients presenting with gastric or oesophageal adenocarcinoma,
the percentage of patients in each group, receiving the full perioperative oncological
treatment, previously defined by a multidisciplinary tumour board. If a patient does not
complete a chemotherapy course (=event), he will be considered as a subject who did not
receive the full protocol (chemotherapy-surgery-chemotherapy). However, a decrease in dose
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of chemotherapy or a stop of a component of chemotherapy will not be considered as an
event.
The secondary outcomes are: postoperative morbidity at 3 months according Dindo-Clavien
classification and Comprehensive Complication Index (CCI); severe morbidity at 3 months
(Clavien >2); disease free survival (DFS), survival defined by the time, in months, before
recurrence at 3- and 5-years after the end of the postoperative chemotherapy; overall survival
(OS), defined by the time, in months, of the overall survival at 3- and 5; feasibility of the
protocol defined by the percentage of physical sessions realized on the eighteen proposed in
the preoperative period; length (in days) of postoperative stay; difference between the initial
(before preoperative chemotherapy) and final (after preoperative chemotherapy) VO2 at the
VT (ml.min-1
.kg-1
); difference between the initial and final value of VO2peak (ml.min-1
.kg-1
.);
difference between the initial and final 6MWT (meters); difference between the initial and
final weight (Kg); difference between the initial and final albuminemia (g/l); difference
between the initial and final evaluation on the score of HADS survey (Hospital anxiety and
depression scale) to assess the anxiety and depression from a survey with 14 questions;
difference of the score between the initial evaluation and at 3-months after the surgery of the
quality of life defined by the EQ-5D survey; 30- and 90 days mortality.
Methodology and study design
The trial will be performed in four centres. Patients will be recruited, treated and followed-up
at the digestive surgery department of the University Hospital of Clermont-Ferrand (France),
Lille (France), Lyon (France) and Rennes (France). After the multidisciplinary tumour board
will check all the inclusion and exclusion criteria, the PREHAB trial will be proposed by
surgeons to patients with gastric or oesophageal adenocarcinoma and concomitant
perioperative chemotherapy. Patients will be informed of the trial protocol and, on
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acceptance, will be randomised in the “Prehab” group or the control group. Randomisation
will be carried out using a dedicated centralised telephone system and accessible round the
clock. The randomisation sequence will be generated by a biostatistician using random blocks
and stratification as a function of the centers and type of cancer (œsophagus or stomach). The
trial will be open blinded because of the procedures employed and with an objective primary
endpoint. The patient will be informed of the randomisation arm throughout the trial.
Statistical considerations
Estimation sample size
According to previous works, we estimated the percentage of patients in each group, realizing
the full perioperative oncological treatment around 30%.1,2
A sample size of n=56 patients by
randomized group would provide 90% statistical power to detect an absolute difference of
30% (30% vs. 60%) for a two-sided α level of 0.05. Finally, a total of 60 patients by group
will be considered. An interim analysis is planned after enrolment of the first 60 patients
using the Lan and DeMets, O’Brien-Fleming method (East software, Cytel Inc, Cambridge,
Massachusetts, USA). The type I error is fixed at 0.003 for this interim analysis. The time
schedule of enrolment has been estimated at 18 months.
Statistical analysis
Statistical analysis will be conducted on intention to treat (ITT) using Stata software, V.13
(StataCorp, College Station, Texas, USA). A two-sided p value of less than 0.05 will be
considered to indicate statistical significance (except interim analysis). Baseline
characteristics will be presented for each randomized group as the mean ± SD or the median
[interquartile range] according to the statistical distribution for continuous data, and as the
number of patients and associated percentages for categorical parameters.
Comparisons between independent groups will be analysed using the χ2 or Fisher's exact test
for categorical variables (notably unplanned readmission and primary outcome: percentage of
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patients realizing the full perioperative oncological treatment) and Student t-test or Mann-
Whitney's test for quantitative parameters (notably weight loss, BMI body mass index,
albumin, body impedance, length of stay, VO2peak, VT, 6MWT, depressive and anxious
symptoms evaluated using HADS, quality of Life according EQ-5D). The normality will be
studied by the Shapiro-Wilk test and the homoscedasticity using the Fisher-Snedecor test. The
analysis of the primary outcome will be complemented by multivariate analysis using
generalized linear mixed model (logistic for dichotomous dependent variable) to take into
account (1) fixed effects covariates retained according to univariate analysis results and
clinical relevance, and (2) random-effects (between and within centre and surgeon
variabilities). Censored data such as overall survival or event-free survival will be estimated
using Kaplan-Meier method and compared (i) by log-rank test in univariate situation and (ii)
using Cox proportional hazard model in the multivariate context. Regarding the analysis of
repeated measures, random-effect models (linear or generalised linear) will be considered to
study the fixed effects group, time-points evaluation and interaction ‘group x time’, taking
into account between and within subject variability.
In prehab group, a dose-response study will be proposed to assess (i) the impact of the
number of prehabilitation sessions really realized and (ii) the compliance prehabilitation care
(dietary and nutritional management). A particular focus will be done on lost to follow-up. A
study with the abandonment considered as a censored data will be proposed using Kaplan-
Meier estimation. If the frequency of missing data is greater than 5%, we will perform
additional analyses using imputation methods.
ETHICS AND DISSEMINATION
Approval
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In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015. Any substantial change in the protocol or in the informed
consent form will be presented to both authorities as well as first inclusion and end of study.
Data monitoring will be performed per French regulations requirements. As required by the
IRB, a safety committee has been set up. The study is currently registered on the clinical trials
website under the following number: NCT02780921. The current protocol version is the firth,
since April 20th
, 2016.
Patient informed consent
According to international regulations on clinical trials, written informed consent will be
obtained from patients prior to their participation in the study (Appendices 1 and 2). Patients
will voluntarily confirm their understanding and willingness to participate in the study after
having been informed (in writing and verbally) by oncologists on all the aspects of the study.
They also will be informed about requirements regarding data protection and direct access to
their individual data. The patients will be informed that they are free to withdraw from the
study at any time at their own discretion, without necessarily giving reasons.
Data collection and quality management
Experienced and trained study coordinators will be dedicated to data acquisition, coding,
security and storage, under the responsibility of investigators. Each study data will be
anonymised. Data will be collected and managed using REDCap electronic data capture tools
hosted at the University Hospital of Clermont-Ferrand.18
Research Electronic Data Capture
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(REDCap) is a secure, web-based application designed to support data capture for research
studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails for tracking
data handling and export procedures; 3) automated export procedures for seamless data
downloads to common statistical packages; and 4) procedures for importing data from
external sources. A clinical research assistant will be commissioned by the sponsor
(University Hospital of Clermont-Ferrand) in order to monitor the progress of the study in
accordance with the Standard Operating Procedures implemented at the University Hospital
of Clermont-Ferrand, in accordance with the Good Clinical Practice and current French laws.
Access to data and dissemination of results
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov.
DISCUSSION
The perioperative chemotherapy became the gold standard treatment in advanced gastric and
low œsophageal adenocarcinoma, with an improvement of DFS and OS.1 2
However, the
limitation of these studies is that, among all patients requiring chemotherapy, 70% of patients
will not receive the complete treatment sequence. In these studies, only patients in good
nutritional and physical status without postoperative complications can receive postoperative
treatment. 1 2
A meta-analysis reported that prehabilitation improved postoperative morbidity,
length of stay, nutritional and physical status.7 The PREHAB study presented here should
demonstrate if the prehabilitation increases the percentage of patients reaching the complete
oncological treatment defined in a multidisciplinary tumour board, to increase DFS and OS.
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BIBLIOGRAPHY
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M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal
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2. Ychou M, Boige V, Pignon J-P, Conroy T, Bouché O, Lebreton G, et al. Perioperative
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Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript.
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY).
Ethics approval IRB00008526 and ANSM (2015-A01733-46).
Provenance and peer review Not commissioned; externally peer reviewed.
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Figure:
1. CONSORT diagram: Flow chart
Appendices:
1. Informed form
2. Consent form
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Consort diagram: Flow chart
Figure 1
254x190mm (72 x 72 DPI)
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Appendice 1
FORMULAIRE D’INFORMATION Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation dans le cancer de l’estomac et de
l’œsophage Promoteur de l’essai :
CHU de Clermont Ferrand, 58 rue Montalembert, 63003 Clermont Ferrand Cedex 1, France Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy Service de chirurgie digestive et hépato-biliaire 1 Place Lucie Aubrac 63003 Clermont-Ferrand
Madame, Monsieur, il vous est proposé de participer à un protocole de recherche clinique, dont le but
est de montrer qu’on peut améliorer votre récupération post opératoire et optimiser la poursuite de votre traitement de chimiothérapie en vous préparant physiquement, psychologiquement et le plan nutritionnel avant l’intervention. Cette prise en charge est appelée « préhabilitation » et va vous être expliquée ci-après plus en détails.
Cependant avant de décider de prendre part à cette étude biomédicale, il est important que vous preniez
le temps de lire et de comprendre les informations suivantes concernant le déroulement de ce protocole. Cette note d’information décrit l’objectif, les procédures, les bénéfices et les risques de l’étude. Elle explique entre autre votre droit à vous retirer de l’étude à tout moment sans avoir à vous justifier. S’il y a quoi que ce soit dans ce document que vous ne comprenez pas, veuillez demander à votre médecin ("investigateur") ou au personnel de l’étude de vous l’expliquer. Prenez votre temps pour décider si vous souhaitez ou non participer à cette étude ; parlez-en avec vos amis ou vos proches. Si vous choisissez de participer, il vous sera demandé de signer un document intitulé « Formulaire de consentement » et ce en 2 exemplaires, dont un vous sera remis. Si vous refusez de prendre part à l’étude, ceci n’aura aucune conséquence sur votre prise en charge médicale.
Pour pouvoir participer à cette étude vous devez être couvert par un régime de Sécurité Sociale. Rationnel de l’étude
Vous allez être opéré de votre cancer œsogastrique dans le service de chirurgie de votre CHU. Comme toute intervention chirurgicale, elle comporte des risques propres à chaque type d’intervention. Ces risques peuvent induire une augmentation de votre durée d’hospitalisation, une diminution plus ou moins longue de votre qualité de vie voire une impossibilité à poursuivre votre traitement de chimiothérapie. Récemment des chirurgiens ont montré qu’une préparation durant 6 semaines avant l’opération, pouvait améliorer les résultats post-opératoires sur la morbidité globale, le statut nutritionnel, le retour plus rapide aux activités quotidiennes permettant, en autre, de réaliser tout le protocole de chimiothérapie prévu initialement. Cette prise en charge est appelée « préhabilitation ». Elle repose sur 3 volets.
- une prise en charge physique qui consiste à réaliser des exercices cardiovasculaires 3 fois par semaine sous surveillance médicale dans le service de médecine du sport et de réadaptation de votre l’hôpital Paraphe du patient
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- une prise en charge nutritionnelle qui consiste à établir avec un médecin nutritionniste et un diététicien, un programme alimentaire pouvant conduite à une supplémentation nutritionnelle si nécessaire
- une prise en charge psychologique avec le soutien d’un psychologue qui vous recommandera, en
autre, des tests de relaxation à réaliser à la maison. Ce protocole a déjà montré son intérêt dans le domaine de la chirurgie cardio vasculaire ou du cancer colorectal. Aussi, nous souhaiterions en faire de même pour la chirurgie du cancer œsogastrique d’où l’étude à laquelle nous vous proposons de participer.
Déroulement de l’étude : Après information par votre chirurgien et après lecture de cette note, si vous acceptez de rentrer dans l’étude, un bilan pré-opératoire standard pour votre pathologie pourra être réalisé si nécessaire. De même vous pourrez être amené à voir ou revoir un anesthésiste à la demande du chirurgien. Nous vous demanderons également de bien vouloir compléter, répondre à quelques questionnaires évaluant votre qualité de vie, vos habitudes alimentaires, vos activités quotidiennes... Après ces évaluations et si vous répondez toujours aux critères du protocole, un tirage au sort sera réalisé afin de déterminer dans quel groupe vous allez entrer durant vos séances de chimiothérapie pré opératoire 1) groupe contrôle : préparation standard selon les référentiels actuels, 2) groupe préhabilitation. Paraphe du patient
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Paraphe du patient
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La préparation standard consistera : a) à bénéficier de séance de kinésithérapie respiratoire si nécessaire, b) à prendre des compléments alimentaires si nécessaire soit par voie orale, soit à l’aide de sonde naso-
gastrique (sonde qui passe par les narines pour aller directement dans le tube digestif) soit par injection. c) à évaluer votre anxiété à l’aide de questionnaires
La "préhabilitation" consistera :
a) à réaliser des exercices physiques à raison de 1h, 3 fois par semaine durant 6 semaines dans le service de médecine du sport de votre Hôpital et ce, sous la surveillance médicale d’un kinésithérapeute. Ces activités seront adaptées à vos propres capacités et selon vos résultats aux examens cardio respiratoires réalisés au préalable avant tout traitement. Ils débuteront 2 mois avant votre chirurgie.
Les exercices réalisés seront de 2 types : * des exercices d’endurance dont le but sont d’améliorer votre résistance cardio vasculaire en
réalisant du vélo et/ou de la marche, * des exercices de renforcement musculaires (bras, épaules, poitrine, abdomen, dos hanches et
jambe) à l’aide de matériel type haltères, élastiques …...
Tous ces exercices seront actualisés au cours du temps en fonction de vos progrès, performances. b) à suivre un programme nutritionnel élaboré avec un nutritionniste 2 mois avant votre chirurgie. Ce
dernier sera établi en fonction de vos besoins, de vos habitudes alimentaires et pourra être adapté, modifié en cours du programme avec l’aide du diététicien qui vous rencontrera régulièrement lors de vos
venues à l’hôpital pour vos séances de chimiothérapie. Vous reverrez également le nutritionniste à la fin de vos 6 semaines de préhabilitation.
c) à vous rendre à des consultations de psychologies pour apprendre à gérer, contrôler votre anxiété, à
mieux appréhender votre traitement de chimiothérapie et les effets secondaires associés. Pour cela il vous sera demandé d’assister à 3 consultations d’1h avec un psychologue qui vous apprendra des exercices de relaxations à réaliser ensuite à votre domicile. Ces consultations auront lieu au cours des 2 mois précédents votre chirurgie
A la fin de vos séances de chimiothérapie, vous bénéficierez à nouveaux de bilans (et ce, peu importe dans quel groupe vous êtes inclus) afin de faire le point sur :
1) votre résistance cardiorespiratoire 2) votre état nutritionnel, 3) votre niveau d’anxiété
De même il vous sera demandé de répondre à des questionnaires Ensuite, un suivi médical 1 mois puis à la fin de votre traitement de chimiothérapie adjuvante sera
réalisé par le biais d’une consultation afin d’évaluer les suites opératoires, votre qualité de vie, votre autonomie. Le déroulement de chaque consultation comprendra un examen médical clinique, des questionnaires spécifiques à l’étude à compléter.
Paraphe du patient
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Bénéfices et risques de l’étude
Les bénéfices potentiels pour vous de participer à cette étude pourraient être une meilleure récupération post opératoire, une durée d’hospitalisation plus courte et surtout un retour plus rapide à vos activités du quotidien, et peut être une meilleur tolérance de la chimiothérapie.
Ce projet ne devrait pas engendrer de risque supplémentaire pour vous si ce n’est peut être un surplus de
fatigue liée aux exercices, examens et consultations supplémentaires requis par l’essai, voire des contraintes supplémentaires comme disponibilités, déplacements, suivi alimentaire .
Modalité de recrutement
Ce protocole sera proposé à 120 patients répondant aux critères d’inclusion et d’exclusion. Ces 120 patients seront inclus après signature du consentement éclairé. Traitements administrés dans le cadre de cette étude
Aucun traitement supplémentaire autre que ceux utilisés en routine pour votre prise en charge thérapeutique ne sera nécessaire à la conduite de cette étude. Evaluations réalisées
Nous essayerons au mieux de concilier les examens, consultations spécifiques au protocole avec vos venues au CHU dans le cadre de votre traitement de chimiothérapie. Si des visites supplémentaires s’avéraient nécessaires pour des questions de disponibilités, d’organisation de services sachez que cela n’induire aucun frais supplémentaire pour vous.
De même lors de votre prise en charge, suivi, il vous sera remis des questionnaires permettant d’évaluer
votre qualité de vie, votre niveau d’anxiété ou encore votre statut physique et nutritionnel. Ces questionnaires devront être remplis sur place et prendront au maximum une vingtaine de minutes.
Durée totale de votre participation à ce protocole
La durée totale de votre participation à cette étude sera de 6 mois. Indemnisation
Il n’y aura aucune indemnisation dans le cadre de cette étude.
Période d’exclusion La période d’exclusion définie dans le cadre de cette étude est de 15 jours avant votre inclusion jusqu’à
votre sortie d’étude, période pendant laquelle vous ne pourrez pas participer à un autre protocole de recherche clinique. Paraphe du patient
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Conservation de matériel biologique Cette étude ne fera l’objet d’aucune conservation de matériel biologique
Protection des patients et confidentialité Cette recherche a reçu l’avis favorable du Comité de Protection des Personnes sud est VI le
…………………………… ainsi que l’autorisation préalable de l’autorité compétente de santé datée du ………………………... Il est possible que cette recherche soit interrompue, si les circonstances le nécessitent, par le promoteur ou à la demande de l’autorité de santé.
Votre participation à cette recherche biomédicale n'engendrera pour vous aucun frais supplémentaire par rapport à ceux que vous auriez dans le cadre de la prise en charge standard de votre maladie.
Toutefois, pour pouvoir participer à cette recherche vous devez être affilié(e) ou bénéficier d’un régime de sécurité sociale.
Le CHU de Clermont-Ferrand, qui organise cette recherche biomédicale en qualité de promoteur, a contracté une assurance conformément aux dispositions législatives, garantissant sa responsabilité civile et celle de tout intervenant auprès de la Société Hospitalière d’Assurances Mutuelles (SHAM, contrat n° 147161). Dans le cas où votre état de santé serait altéré du fait de votre participation à l’étude, conformément à la loi de Santé Publique n°2004-806 du 9 août 2004, vous seriez en droit de recevoir des dédommagements dans le cadre de ce contrat d’assurance spécifique.
Dans le cadre de la recherche biomédicale à laquelle le CHU de Clermont-Ferrand (établissement
promoteur) vous propose de participer, un traitement informatique de vos données personnelles va être mis en œuvre pour permettre d’analyser les résultats de la recherche au regard de l’objectif de cette dernière qui vous a été présenté. A cette fin, les données médicales vous concernant et les données relatives à vos habitudes de vie, seront transmises au Promoteur de la recherche ou aux personnes ou sociétés agissant pour son compte, en France ou à l’étranger. Ces données seront identifiées par un numéro de code et par vos initiales. Ces données pourront également, dans des conditions assurant leur confidentialité, être transmises aux autorités de santé françaises, à d’autres entités du CHU de Clermont Ferrand (établissement promoteur).
Conformément aux dispositions de loi relative à l’informatique aux fichiers et aux libertés, vous disposez
d’un droit d’accès et de rectification. Vous disposez également d’un droit d’opposition à la transmission des données couvertes par le secret professionnel susceptibles d’être utilisées dans le cadre de cette recherche et d’être traitées.
Vous pouvez également accéder directement ou par l’intermédiaire d’un médecin de votre choix à l’ensemble de vos données médicales en application des dispositions de l’article L. 1111-7 du code de la santé publique. Ces droits s’exercent auprès du médecin qui vous suit dans le cadre de la recherche et qui connaît votre identité.
Par ailleurs, vous pourrez être tenu informé des résultats globaux de cette recherche à la fin de l’étude. Vous êtes libre d'accepter ou de refuser de participer à cette recherche. De plus vous pouvez exercer à tout
moment votre droit de retrait de cette recherche sans avoir à vous justifier. Le fait de ne plus participer à cette recherche ne modifiera pas la qualité des soins qui vous sont prodigués. Vous pouvez demander à tout moment des explications complémentaires sur l’étude à l’équipe soignante.
Lorsque vous aurez lu cette note d’information et obtenu les réponses aux questions que vous vous posez en interrogeant le médecin investigateur, il vous sera proposé, si vous en êtes d’accord,
Paraphe du patient
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de donner votre consentement écrit en signant le document préparé à cet effet en accord avec le code de la santé publique visant à protéger les personnes se soumettant à une étude biomédicale. Votre consentement écrit n’enlève en aucun cas la responsabilité des médecins qui vous soignent A qui devez-vous vous adresser en cas de questions ou de problèmes ?
En cas de problèmes, d’événements indésirables en cours d’essai ou de questions, vous pouvez vous adresser aux personnes suivantes :
Vos contacts dans l’étude
Bertrand Le Roy (Coordonnateur) Service de Chirurgie Digestive Hôpital Estaing CHU de Clermont-Ferrand 1 place Lucie et Raymond Aubrac 63003 Clermont-Ferrand cedex 1 Tel: 04 73 75 04 94 Fax : 04 73 75 19 22 [email protected]
Brigitte Gillet (Ingénieur Hospitalier, Attaché de recherche clinique) Service de Chirurgie Digestive Unité d'Oncologie Digestive Hôpital Estaing CHU de Clermont-Ferrand 1 place Lucie et Raymond Aubrac 63003 Clermont-Ferrand cedex 1Tel: 04 73 75 52 26 Fax : 04 73 75 19 22 [email protected]
Paraphe du patient sur toutes les pages
Date : ……/……/…… Signature du patient Paraphe de l’investigateur (Précédée de la mention « Lu et compris »)
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Appendice 2
FORMULAIRE DE CONSENTEMENT DE PARTICIPATION A UNE RECHERCHE BIOMEDICALE
Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation dans le cancer de l’œsophage et de l’estomac
Promoteur de l’essai :
CHU de Clermont Ferrand, 58 rue Montalembert, 63003 Clermont Ferrand Cedex 1, France Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy Service de chirurgie digestive et hépato-biliaire 1 Place Lucie Aubrac 63003 Clermont-Ferrand
Je soussigné(e) Mme, Mlle, M. (rayer les mentions inutiles) (nom, prénom)…………………………………………… Né(e) le ………………….…………………... Déclare : - que le Docteur (nom, prénom, téléphone) ……………………………………………..…………….. m’a proposé
de participer à l’étude sus nommée, - qu’il m’a expliqué en détail le protocole, - qu’il m’a notamment fait connaître :
• l’objectif, la méthode et la durée de l’étude • les contraintes et les risques potentiels encourus • mon droit de refuser de participer et en cas de désaccord de retirer mon consentement à tout moment • mon obligation d’inscription à un régime de sécurité sociale • que, si je le souhaite, à son terme, je serais informé(e) par le médecin investigateur de ses résultats globaux • que je ne serais pas autorisé(e) à participer à d’autres études cliniques durant toute ma participation à ce
protocole estimée à 6 mois maximum. • que le Comité de Protection des Personnes Sud Est VI a émis un avis favorable en date du
xx/xx/xxxx(Préciser le nom de CPP sollicité et la date d’obtention de l’avis favorable) • que l’ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé) a délivré une
autorisation pour cette étude • que dans le cadre de cette étude le promoteur, le CHU de Clermont-Ferrand, a souscrit à une assurance
couvrant cette recherche (contrat SHAM 147161). - que j’ai répondu en toute bonne foi aux questions concernant mon état de santé et ma participation à d’autres
études. Les informations relatives à l’étude recueillies par l’investigateur sont traitées confidentiellement. J’accepte que les données enregistrées à l’occasion de cette recherche puissent faire l’objet d’un traitement informatisé anonyme. J’ai bien noté que le droit d’accès prévu par la loi du 6 août 2004 relative à l’informatique, aux fichiers et aux libertés s’exerce à tout moment auprès du médecin qui me suit dans le cadre de la recherche et qui connaît mon identité. Je pourrai exercer mon droit de rectification et d’opposition auprès de ce même médecin, qui contactera le promoteur de la recherche
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Après avoir discuté librement et obtenu réponse à toutes mes questions, j’accepte librement et volontairement de participer à cette recherche biomédicale dans les conditions précisées dans le formulaire d’information et de consentement. Nom et prénom du patient : …………………………………………………… Date :……./……./……. Signature Précédée de la mention « Lu et compris » :
Nom de l’investigateur : …………………………………………………… Date :……./……./……. Signature :
Ce document est à réaliser en 2 exemplaires originaux, dont le premier doit être gardé 15 ans par l’investigateur,
un autre remis à la personne donnant son consentement.
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Spirit
Administrative information
Title
1
Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym
Trial registration=> Page 3
2a
Trial identifier and registry name. If not yet registered, name of intended registry
=> Page 3
2b
All items from the World Health Organization Trial Registration Data Set
Protocol version
=> Page 3
3
Date and version identifier
Funding
=> Page 3
4
Sources and types of financial, material, and other support
Roles and responsibilities
=> Page 3-4
5a
Names, affiliations, and roles of protocol contributors
=> Page 4
5b
Name and contact information for the trial sponsor
=> Page 3-4
5c
Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation
of data; writing of the report; and the decision to submit the report for publication, including whether they will
have ultimate authority over any of these activities
=> Page 3
5d
Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication
committee, data management team, and other individuals or groups overseeing the trial, if applicable (see
Item 21a for data monitoring committee)
=> Page 3
Introduction
Background and rationale
6a
Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
=> Page 7
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Explanation for choice of comparators
=> Page 8
Objectives
7
Specific objectives or hypotheses
Trial design
=> Page 8
8
Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation
ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
=> Page 8
Methods: Participants, interventions, and outcomes
Study setting
9
Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be
collected. Reference to where list of study sites can be obtained Eligibility criteria
=> Page 8
10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists) Interventions
=> Page 9
11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
=> Page 10
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
=> Page 11-12
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
=> Page 11-12
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial Outcomes
=> Page 11-12
12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy
and harm outcomes is strongly recommended Participant timeline
=> Page 11-12
13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure) Sample size
=> Page 13-14
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14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations Recruitment
=> Page 13-14
15 Strategies for achieving adequate participant enrolment to reach target sample size
=> Page 14
Methods: Assignment of interventions (for controlled trials) Allocation: Sequence generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg,
blocking) should be provided in a separate document that is unavailable to those who enrol participants or
assign interventions
=> Page 14
Allocation concealment mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
Implementation
=> Page 14
16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions Blinding (masking)
=> Page 14
17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
=> Page 14
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial Methods: Data collection, management, and analysis Data collection
methods
=> NA
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
=> Page 14
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols Data management
=> Page 14
19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol Statistical methods
=> Page 14
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20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
=> Page 14
20b Methods for any additional analyses (eg, subgroup and adjusted analyses)
=> Page 14
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
=> Page 14
Methods:
Monitoring Data monitoring
21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement
of whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed
=> Page 16
21b Description of any interim analyses and stopping guidelines, including who will have access to these
interim results and make the final decision to terminate the trial Harms
=> Page 13
22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct Auditing
=> Page 13
23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
=> Page 13
Ethics and dissemination
Research ethics approval
24
Plans for seeking research ethics committee/institutional review board (REC/IRB) approval
Protocol amendments
=> Page 14-15
25
Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)
=> Page 14-15
Consent or assent
26a
Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how
(see Item 32)
=> Page 15
26b
Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
Confidentiality
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27
How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
Declaration of interests
28
Financial and other competing interests for principal investigators for the overall trial and each study site
Access to data
29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators Ancillary and post-trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
Dissemination policy
=> Page 16
31a
Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the
public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing
arrangements), including any publication restrictions
=> Page 16
31b
Authorship eligibility guidelines and any intended use of professional writers
=> Page 16
31c
Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code
=> Page 16
Appendices
Informed consent materials
32
Model consent form and other related documentation given to participants and authorised surrogates
Biological specimens
=> Appendice 1, legends page 20
33
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis
in the current trial and for future use in ancillary studies, if applicable
=>NA
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Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a multicentric,
randomised control trial - PREHAB study
Journal: BMJ Open
Manuscript ID bmjopen-2016-012876.R2
Article Type: Protocol
Date Submitted by the Author: 03-Nov-2016
Complete List of Authors: Le Roy, Bertrand; CHU Estaing, Digestive surgery Pereira, Bruno; University Hospital CHU Clermont-Ferrand, Biostatistic unit Bouteloup, Corinne; CHU Estaing, Digestive and Liver Disease
Costes, Frederic; CHU Gabriel Montpied, Department of physiology and medical sport Richard, Ruddy; CHU Gabriel Montpied, Department of physiology and medical sport Selvy, Marie; CHU Estaing, Digestive surgery and oncological department Petorin, Caroline; Oncology Gagniere, Johan; University Hospital of Clermont-Ferrand, Digestive and Hepatobiliary Surgery Futier, Emmanuel; CHU Estaing, Department of Anesthesia Slim, Karem; CHU Estaing, Digestive surgery and oncological department Meunier, Bernard; Centre Hospitalier Universitaire de Rennes Mabrut, Jean-Yves; Hopital de la Croix-Rousse
Mariette, C.; CHU Claude Huriez, Digestive and oncological surgery Pezet, Denis; Digestive surgery
<b>Primary Subject Heading</b>:
Surgery
Secondary Subject Heading: Rehabilitation medicine, Oncology
Keywords: Prehabilitation, Gastric cancer, Oesophageal disease < GASTROENTEROLOGY, Fitness, Gastrointestinal tumours < ONCOLOGY
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1
Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Bertrand Le Roy, MD1, Bruno Pereira, PhD
2, Corinne Bouteloup, MD
6,9,10, Frédéric Costes,
MD, PhD5,10
, Ruddy Richard, MD, PhD5,10
, Marie Selvy, MD1, Caroline Pétorin, MD
1, Johan
Gagnière, MD1, Emmanuel Futier, MD, PhD
3, Karem Slim, MD
1, Bernard Meunier, MD,
PhD7, Jean-Yves Mabrut, MD, PhD
8, Christophe Mariette, MD, PhD
4, Denis Pezet, MD,
PhD1.
(1) Digestive surgery and oncological department, Hospital Estaing, 1, place Lucie-Aubrac,
63003 Clermont-Ferrand, France
(2) Biostatistics unit (DRCI), Clermont-Ferrand University Hospital, 63003 Clermont-
Ferrand, France
(3) Department of Anesthesia, Hospital Estaing, Clermont-Ferrand University Hospital, 1
Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
(4) Digestive and oncological surgery, Hospital Claude Huriez, place de Verdun, 59037 Lille,
France
(5) Department of Sports Medicine and Functional Explorations, Hospital, Gabriel Montpied,
Clermont-Ferrand, France
(6) University Hospital of Clermont-Ferrand, Digestive and Liver Disease Unit F-63003
Clermont-Ferrand, France
(7) Digestive surgery department, Hospital Pontchaillou, 2 rue Henri Le Guilloux, 35033
Rennes, France
(8) Digestive surgery department, Hospital Croix Rousse, 103 Grande rue de la Croix
Rousse, 69004 Lyon, France
(9) Clermont Auvergne University, University of Auvergne, Human Nutrition Unit, ECREIN,
BP 10448, F-63000 Clermont-Ferrand, France
(10) INRA, UMR 1019, UNH, CRNH Auvergne, F-63009 Clermont-Ferrand, France
Corresponding author
Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
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63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Word count: 3030
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Administrative information
Title: Effect of prehabilitation in gastroesophageal adenocarcinoma: study protocol of a
multicentric, randomised control trial - PREHAB study
Trial registration: NCT02780921
Protocol version: Version 5, 20 oct 2016
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY), a national public funding of research.
In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015.
A clinical research assistant will be commissioned by the sponsor (University Hospital of
Clermont-Ferrand) in order to monitor the progress of the study in accordance with the
Standard Operating Procedures implemented at the University Hospital of Clermont-Ferrand,
in accordance with the Good Clinical Practice and current French laws.
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov. The study sponsor and funders had not any role and
will have not any authority over: study design; collection, management, analysis, and
interpretation of data; writing of the report; and the decision to submit the report for
publication.
Any substantial change in the protocol or in the informed consent form will be presented to
the competent French authority (“Agence Nationale de Sécurité du Médicament et des
produits de santé”, Saint Denis, France) and a safety monitoring committee as well as first
inclusion, the interim analyses and end of study.
Protocol contributor
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Bertrand Le Roy
Service de chirurgie et oncologie digestive
1 place Lucie Aubrac
63000 Clermont-Ferrand
Tel: + 33 4 73 75 04 96
Email: [email protected]
Study sponsor:
C.H.U. de Clermont-Ferrand
58 Rue de Montalembert
63003 Clermont-Ferrand Cedex 1
Protocol contributors
Pr Christophe Mariette, principal investigator from Lille
Service de Chirurgie Digestive et Générale
Hôpital HURIEZ, CHRU Lille
Place de Verdun, 59037 Lille
Pr Meunier Bernard, principal investigator from Rennes
Service de Chirurgie Digestive et Générale
Hôpital Pontchaillou, CHRU Rennes
Rue Henri Le Guilloux, 35000 Rennes
Pr Jean Yves Mabrut, principal investigator from Lyon
Service de Chirurgie Digestive et Générale
Hôpital de la Croix Rousse, Hospice civils de Lyon
Grande rue de la croix rousse, 69317 Lyon
Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript.
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ABSTRACT
Introduction: Perioperative chemotherapy is the gold standard treatment of the resectable
gastroesophageal adenocarcinoma. However, 70% of patients can’t receive the complete
sequence because of a postoperative complication or a decrease of functional and nutritional
reserves. Recently, a new concept appeared in digestive surgery: the prehabilitation. This
interventional process consists of a patient preparation, between the surgical consultation and
the surgery, and is based on 3 components: 1) physical management 2) nutritional care and 3)
psychological care. Prehabilitation should decrease postoperative complications and improve
nutritional and physical status during the pre- and postoperative period. Therefore, it is
becoming essential to evaluate the effect of prehabilitation, compared to conventional care, on
the percentage of patients reaching the complete oncological treatment.
Methods and analysis: The PREHAB trial aimed to evaluate the efficacy of prehabilitation
compared to conventional care, in patients with gastroesophageal cancer with perioperative
chemotherapy. This trial is a prospective, randomised, controlled, open-blind, and
interventional study, in 4 centers. Patients (n=60 per group) will be randomly assigned for
management with either prehabilitation or conventional care. The primary outcome is the
percentage of patients reaching the complete oncological treatment decided in a
multidisciplinary tumour board. The secondary outcomes are the postoperative morbidity,
disease free survival, overall survival, feasibility of the protocol, length of stay, variation of
the functional reserve after the preoperative chemotherapy (defined by VO2peak, ventilatory
threshold and 6 min walk test), pre- and postoperative nutritional status, preoperative anxiety,
quality of life, 30- and 90 days mortality and cumulative dose of cytotoxic treatment received.
Ethics and dissemination: The study was approved by an independent medical ethics
committee (IRB00008526, CPP Sud-Est VI, Clermont-Ferrand, France) and by the competent
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French authority (ANSM, Saint Denis, France) and registered on Clinicaltrial.gov. The results
will be disseminated in a peer-reviewed journal.
Trial registration number: NCT02780921; pre-results.
Strengths and limitations of this study:
• A multicentric, prospective and randomized study
• Large number of participants (n=120)
• Prehabilitation includes nutritional care and psychological treatment
• Intra- and postoperative protocols are not standardized
• This study includes both oesophageal and stomach cancer
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INTRODUCTION
Perioperative chemotherapy is the gold standard treatment of the resectable and advanced
gastroesophageal adenocarcinoma. The efficacy of this strategy has been demonstrated in two
randomized studies.1 2
It reduces tumour size before surgery, treats micrometastases and
evaluates chemosensitivity. Disease free and overall survival rates were significantly
improved with perioperative chemotherapy compared to surgery alone. However, the
limitation of these studies is that among all patients requiring chemotherapy, almost 70% of
patients did not receive the complete sequence. This sequence is defined by the administration
of two to four cycles before and two to four cycles after the surgery, according to the
protocol. The major cause of absence or impossibility of realization of postoperative
chemotherapy was the presence of postoperative complication, postoperative serious asthenia
and impaired nutritional and physical status. 1 2
Poor physical condition assessed by
cardiopulmonary exercise testing, reflecting a reduced physiological reserve, is predictive of
postoperative complications. 3 4
Physical training, even during a short period and on a various
population, is beneficial in improving physical condition, cardiopulmonary function and
muscular mass of the patient.5-8
Prehabilitation over a six week period between pre-surgical
clinic appointment and surgery decreases postoperative morbidity and the hospital stay in
cardiovascular surgery, but no study has ever been performed in patients presented with
gastric or oesophageal cancer. 7 9-11
Prehabilitation revolves around three axes: 1) physical training based on initial
cardiopulmonary exercise testing (VO2peak, ventilatory threshold (VT) and 6-min walk test
(6MWT)), 3 times by week, supervised by a physical therapist 2) nutritional care to ensure the
compliance of the nutrition program and adapt the nutritional management based on protein
and energy needs and on the level of spontaneous oral intake and 2) psychological treatment
by a psychologist to reduce preoperative anxiety. To our knowledge, no study ever focused on
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the gastroesophageal cancer. The benefit of prehabilitation in this cancer may be particularly
important because 1) this surgery is associated with a high 90-day morbidity (40%, especially
respiratory) and 90-day mortality (5%) 2) the physical and nutritional status of these patients
is often precarious (cancer cachexia, gastroesophageal obstruction), and 3) the need to
preoperative chemotherapy declines physical reserves and is associated with a lengthening of
the time between pre-surgery clinic appointment and surgery of more than 3 months.12
Also,
we hypothesize, in this parallel, of noninferiority study that with physical training, a
personalized nutritional support and a psychologist global management may decrease
postoperative complications, increase postoperative nutritional status and so, would results in
an increase in the numbers of patients receiving their full cancer treatment. The aim of this
study was to compare the percentage of patients reaching the complete oncological treatment
previously decided in a multidisciplinary tumour board in the group with prehabilitation to the
group with conventional care, in patients with gastroesophageal adenocarcinoma.
METHODS AND ANALYSIS
Study setting
The present study is a prospective, randomised, controlled, open and multicentric, phase III
trial that compares prehabilitation (Prehab group) versus conventional care (control group) in
patients presenting with gastric and low oesophageal adenocarcinoma, treated by
perioperative chemotherapy. Inclusions will be performed in four French tertiary centers
(Figure 1).
Study objectives
In the experimental group (Prehab group), the main objective is to demonstrate an
improvement of the percentage of patients reaching the complete oncological treatment fixed
in a multidisciplinary tumour board. The secondary objectives is to evaluate the effect of the
prehabilitation on the postoperative morbidity according to Dindo-Clavien classification and
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Comprehensive Complication Index (CCI), severe morbidity (Clavien >2), disease free
survival (DFS), overall survival (OS), feasibility of the protocol (number of physical sessions
realized on the eighteen proposed), length of stay, variation of the functional reserve after the
chemotherapy (defined by VO2peak, VT and 6MWT), pre- and postoperative nutritional status,
preoperative anxiety, quality of life (EQ-5D survey) at the end of the treatment, 30- and 90
day mortality and cumulative dose of cytotoxic treatment received.13
Inclusion and exclusion criteria
To be included in the study, the participant is scheduled for surgical intervention of gastric or
oesophageal adenocarcinoma and received perioperative chemotherapy, subscribe to the
French national health insurance system and give their written consent. Patients cannot be
included in the study for one of the following criteria: <18 years of age, need for a
radiochemotherapy, treated for another cancer within 5 years, except basal cell skin
carcinoma or carcinoma in situ of the cervix, presenting with cognitive disorders or major
disability making impossible to understand the study and sign the informed consent, or being
breastfeeding or pregnant. Finally, patients already included in another clinical trial, or
estimated by the investigator to not be able to be compliant with the criteria of the study, or
with legal incapacity (person deprived of liberty or subject under guardianship) will not be
enrolled in this study. Guidelines regarding stopping participation are: withdrawal of patient
consent, non-compliance of the patient, adverse event and by decision of the investigator. In
case of withdrawal from the study, the patient will be followed and managed normally in the
digestive surgery department. The exclusion period during which the patient cannot
participate in another clinical trial is 15 days before inclusion and 0 days after the end of the
study.
Interventions
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After the first visit with his surgeon, the patient will be presented at the
multidisciplinary tumour board to validate the inclusion criteria and to schedule the
number of cycles of pre- and postoperative chemotherapy. After this step, a second
consultation with the surgeon will take place to verify all inclusion and exclusion
criteria and perform the randomization. For the two groups, an initial (before
chemotherapy) and final (one week before the surgery) evaluation will be performed.
The evaluation includes an exercise capacity evaluation by 1) an incremental
symptom-limited cardiopulmonary exercise test on a cycloergometer according to
international recommendations in order to determine VO2peak, and the ventilator
threshold (VT) and, 2) 6 minute walk distance (6MWT) performed according to the
ATS recommendations.14, 15
Moreover, the patients will be assessed for a nutritional
evaluation (albumin), bioelectric impedance analysis, evaluation of physical activity
and ingesta, evaluation of the level of depressive symptoms and anxiety with the
HADS survey and the quality of life (5Q-FD survey).
Study group (Figure 2)
“Prehab” group
Exercise intervention: The total-body exercise will consist of up to one hour of supervised
exercise for at least three days per week, for a total of 18 sessions, alternating between aerobic
and resistance training. Exercise intensity will be prescribed based on the target heart rate
obtained at VT during the initial CPET. The participant will exercise in the presence of the
physical therapist who will provide corrective feedback, if necessary.
Nutrition intervention: Initially, a nutritionist will perform a medical examination run
appropriate biological tests to evaluate the nutritional status and to provide individualized care
to each patient. Individual protein requirements will be calculated as 1.2g of protein per
kilogram of body weight (adjusted body weight was used for obese patients), as per European
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Society for Clinical Nutrition and Metabolism (ESPEN) guidelines regarding surgical
patients.16
Patients will be asked to consume the protein supplement within one hour of their
exercise regimen to capitalize on postexercise muscle protein synthesis.17
Then, a dietician
will assess the compliance of the nutritional support at each cycle of chemotherapy and will
adjust it, if necessary. After the preoperative chemotherapy, a second evaluation by a
nutritionist will be performed.
Psychologist intervention: Patients will receive up to a one hour visit with a trained
psychologist who will provide techniques aiming to reducing anxiety, such as relaxation
exercises based on imagery and visualization, together with breathing exercises. Each patient
will practice these exercises with the psychologist initially and at each cycle of chemotherapy
and at home two to three times per week. Once performed, the exercices at home will be
marked on diaries. The psychologist also provides suggestions on how to enhance and
reinforce patients’ motivation to comply with the exercise and nutritional aspects of the
intervention.
Control group:
The control group will be treated according to conventional care; will not receive any specific
intervention before surgery except nutritional support and physiotherapy at the surgeon’s
discretion.
Study outcomes
The primary outcome is, in patients presenting with gastric or oesophageal adenocarcinoma,
the percentage of patients in each group, receiving the full perioperative oncological
treatment, previously defined by a multidisciplinary tumour board. If a patient does not
complete a chemotherapy course (=event), he will be considered as a subject who did not
receive the full protocol (chemotherapy-surgery-chemotherapy). However, a decrease in dose
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of chemotherapy or a stop of a component of chemotherapy will not be considered as an
event.
The secondary outcomes are: postoperative morbidity at 3 months according to Dindo-
Clavien classification and Comprehensive Complication Index (CCI); severe morbidity at 3
months (Clavien >2); disease free survival (DFS), survival defined by the time, in months,
before recurrence at 3- and 5-years after the end of the postoperative chemotherapy; overall
survival (OS), defined by the time, in months, of the overall survival at 3- and 5; feasibility of
the protocol defined by the percentage of physical sessions realized on the eighteen proposed
in the preoperative period; length (in days) of postoperative stay; difference between the
initial (before preoperative chemotherapy) and final (after preoperative chemotherapy) VO2 at
the VT (ml.min-1
.kg-1
); difference between the initial and final value of VO2peak (ml.min-1
.kg-
1.); difference between the initial and final 6MWT (meters); difference between the initial and
final weight (Kg); difference between the initial and final albuminemia (g/l); difference
between the initial and final evaluation on the score of HADS survey (Hospital anxiety and
depression scale) to assess the anxiety and depression from a survey with 14 questions;
difference of the score between the initial evaluation and at 3-months after the surgery of the
quality of life defined by the EQ-5D survey; 30- and 90 days mortality.
Methodology and study design
The trial will be performed in four centres. Patients will be recruited, treated and followed-up
at the digestive surgery department of the University Hospital of Clermont-Ferrand (France),
Lille (France), Lyon (France) and Rennes (France). After the multidisciplinary tumour board
will check all the inclusion and exclusion criteria, the PREHAB trial will be proposed by
surgeons to patients with gastric or oesophageal adenocarcinoma and concomitant
perioperative chemotherapy. Patients will be informed of the trial protocol and, on
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acceptance, will be randomised in the “Prehab” group or the control group by the surgeon or
the oncologist. Randomisation will be carried out using a dedicated centralised telephone
system and accessible round the clock. The randomisation sequence will be generated by a
biostatistician using random blocks and stratification as a function of the centers and type of
cancer (œsophagus or stomach). The trial will be open blinded because of the procedures
employed and with an objective primary endpoint. The patient will be informed of the
randomisation arm throughout the trial. The only criteria, which will be recorded, for
discontinuing or modifying allocated interventions for a given trial participant is the
participant request.
Statistical considerations
Estimation sample size
According to previous works, we estimated the percentage of patients in each group, realizing
the full perioperative oncological treatment around 30%.1,2
A sample size of n=56 patients by
randomized group would provide 90% statistical power to detect an absolute difference of
30% (30% vs. 60%) for a two-sided α level of 0.05. Finally, a total of 60 patients by group
will be considered. An interim analysis is planned after enrolment of the first 60 patients
using the Lan and DeMets, O’Brien-Fleming method (East software, Cytel Inc, Cambridge,
Massachusetts, USA). The type I error is fixed at 0.003 for this interim analysis. The time
schedule of enrolment has been estimated at 18 months.
Statistical analysis
Statistical analysis will be conducted on intention to treat (ITT) using Stata software, V.13
(StataCorp, College Station, Texas, USA). A two-sided p value of less than 0.05 will be
considered to indicate statistical significance (except interim analysis). Baseline
characteristics will be presented for each randomized group as the mean ± SD or the median
[interquartile range] according to the statistical distribution for continuous data, and as the
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number of patients and associated percentages for categorical parameters.
Comparisons between independent groups will be analysed using the χ2 or Fisher's exact test
for categorical variables (notably unplanned readmission and primary outcome: percentage of
patients realizing the full perioperative oncological treatment) and Student t-test or Mann-
Whitney's test for quantitative parameters (notably weight loss, BMI body mass index,
albumin, body impedance, length of stay, VO2peak, VT, 6MWT, depressive and anxious
symptoms evaluated using HADS, quality of Life according EQ-5D). The normality will be
studied by the Shapiro-Wilk test and the homoscedasticity using the Fisher-Snedecor test. The
analysis of the primary outcome will be complemented by multivariate analysis using
generalized linear mixed model (logistic for dichotomous dependent variable) to take into
account (1) fixed effects covariates retained according to univariate analysis results and
clinical relevance, and (2) random-effects (between and within centre and surgeon
variabilities). Censored data such as overall survival or event-free survival will be estimated
using Kaplan-Meier method and compared (i) by log-rank test in univariate situation and (ii)
using Cox proportional hazard model in the multivariate context. Regarding the analysis of
repeated measures, random-effect models (linear or generalised linear) will be considered to
study the fixed effects group, time-points evaluation and interaction ‘group x time’, taking
into account between and within subject variability.
In prehab group, a dose-response study will be proposed to assess (i) the impact of the
number of prehabilitation sessions really realized and (ii) the compliance prehabilitation care
(dietary and nutritional management). A particular focus will be done on lost to follow-up. A
study with the abandonment considered as a censored data will be proposed using Kaplan-
Meier estimation. If the frequency of missing data is greater than 5%, we will perform
additional analyses using imputation methods.
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ETHICS AND DISSEMINATION
Approval
In accordance with the Declaration of Helsinki and French regulations on clinical trials, the
study was presented to an independent ethics committee, the “Comité de Protection des
Personnes Sud Est 6” (reference: AU1228, IRB00008526, Clermont-Ferrand, France). The
approval of the committee was obtained on March 7th
, 2016. The protocol was declared to the
competent French authority (“Agence Nationale de Sécurité du Médicament et des produits de
santé”, Saint Denis, France) and registered under number 2015 A01733-46. Authorisation was
obtained on December, 21st 2015. Any substantial change in the protocol or in the informed
consent form will be presented to both authorities as well as first inclusion, interim analyses
and end of study. Data monitoring will be performed per French regulations requirements. As
required by the IRB, a Safety Monitoring Committee (DSMC) has been set up. Data will be
collected at each trial visit (every two months) and at the interim analyses, regarding any
adverse events (AE) and serious AE. All serious AE causally related to treatment procedures
will be reported to the relevant ethics committees, the lead site and the independent Data and
DSMC for their review and recommendations. The DSMC comprises independent clinicians
with an interest in prehabilitation and a statistician. Overview is carried out through the
review of AE and serious AE, all of which are reported at the regular committee meetings.
Each meeting determines the Board's recommendation to the Steering Committee as to
whether the study is safe to continue. The study is currently registered on the clinical trials
website under the following number: NCT02780921. The current protocol version is the firth,
since April 20th
, 2016.
Patient informed consent
According to international regulations on clinical trials, written informed consent will be
obtained from patients prior to their participation in the study (Appendices 1 and 2). Patients
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will voluntarily confirm their understanding and willingness to participate in the study after
having been informed (in writing and verbally) by oncologists on all the aspects of the study.
They also will be informed about requirements regarding data protection and direct access to
their individual data. The patients will be informed that they are free to withdraw from the
study at any time at their own discretion, without necessarily giving reasons.
Data collection and quality management
Experienced and trained study coordinators will be dedicated to data acquisition, coding,
security and storage, under the responsibility of investigators. Each study data will be
anonymised. Data will be recorded in paper case report forms at the time of each patient
contact. These will be faxed to the study lead site for checking followed by entry into the
secure study database. Data will be collected and managed using REDCap electronic data
capture tools hosted at the University Hospital of Clermont-Ferrand.18
Research Electronic
Data Capture (REDCap) is a secure, web-based application designed to support data capture
for research studies, providing: 1) an intuitive interface for validated data entry; 2) audit trails
for tracking data handling and export procedures; 3) automated export procedures for
seamless data downloads to common statistical packages; and 4) procedures for importing
data from external sources. A clinical research assistant will be commissioned by the sponsor
(University Hospital of Clermont-Ferrand) in order to monitor the progress of the study in
accordance with the Standard Operating Procedures implemented at the University Hospital
of Clermont-Ferrand, in accordance with the Good Clinical Practice and current French laws.
Access to data and dissemination of results
The data set will be the property of the sponsor (CHU Clermont-Ferrand). However, the
principal investigator and the project manager will have full access to the final data set. The
results will be communicated in a peer-reviewed journal, presented at international congresses
and summarized on ClinicalTrials.gov.
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DISCUSSION
The perioperative chemotherapy became the gold standard treatment in advanced gastric and
low œsophageal adenocarcinoma, with an improvement of DFS and OS.1 2
However, the
limitation of these studies is that, among all patients requiring chemotherapy, 70% of patients
will not receive the complete treatment sequence. In these studies, only patients in good
nutritional and physical status without postoperative complications can receive postoperative
treatment. 1 2
A meta-analysis reported that prehabilitation improved postoperative morbidity,
length of stay, nutritional and physical status.7 The PREHAB study presented here should
demonstrate if the prehabilitation increases the percentage of patients reaching the complete
oncological treatment defined in a multidisciplinary tumour board, to increase DFS and OS.
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BIBLIOGRAPHY
1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJH, Nicolson
M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal
cancer. N Engl J Med. 2006;355(1):11–20.
2. Ychou M, Boige V, Pignon J-P, Conroy T, Bouché O, Lebreton G, et al. Perioperative
chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma:
an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol Off J Am Soc Clin Oncol.
2011;29(13):1715–21.
3. Hennis PJ, Meale PM, Grocott MPW. Cardiopulmonary exercise testing for the
evaluation of perioperative risk in non-cardiopulmonary surgery. Postgrad Med J.
2011;87(1030):550–7.
4. Carlisle J, Swart M. Mid-term survival after abdominal aortic aneurysm surgery
predicted by cardiopulmonary exercise testing. Br J Surg. 2007;94(8):966–9.
5. Fong DYT, Ho JWC, Hui BPH, Lee AM, Macfarlane DJ, Leung SSK, et al. Physical
activity for cancer survivors: meta-analysis of randomised controlled trials. BMJ.
2012;344:e70.
6. Kemi OJ, Wisloff U. High-intensity aerobic exercise training improves the heart in
health and disease. J Cardiopulm Rehabil Prev. 2010;30(1):2–11.
7. Valkenet K, van de Port IGL, Dronkers JJ, de Vries WR, Lindeman E, Backx FJG.
The effects of preoperative exercise therapy on postoperative outcome: a systematic review.
Clin Rehabil. 2011;25(2):99–111.
8. Jaggers JR, Simpson CD, Frost KL, Quesada PM, Topp RV, Swank AM, et al.
Prehabilitation before knee arthroplasty increases postsurgical function: a case study. J
Strength Cond Res Natl Strength Cond Assoc. 2007 May;21(2):632–4.
9. Van Adrichem EJ, Meulenbroek RL, Plukker JTM, Groen H, van Weert E.
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Comparison of two preoperative inspiratory muscle training programs to prevent pulmonary
complications in patients undergoing esophagectomy: a randomized controlled pilot study.
Ann Surg Oncol. 2014;21(7):2353–60.
10. Bruns ER, van den Heuvel B, Buskens CJ, van Duijvendijk P, Festen S, Wassenaar
EB, et al. The effects of physical prehabilitation in elderly patients undergoing colorectal
surgery: a systematic review. Colorectal Dis. 2016;18(8):267-277.
11. Moran J, Guinan E, McCormick P, Larkin J, Mockler D, Hussey J, et al. The ability of
prehabilitation to influence postoperative outcome after intra-abdominal operation: A
systematic review and meta-analysis. Surgery. 2016 Jul 7; pii: S0039-6060(16)30152-0.
12. West J, Wood H, Logan RFA, Quinn M, Aithal GP. Trends in the incidence of
primary liver and biliary tract cancers in England and Wales 1971-2001. Br J Cancer.
2006;94(11):1751–8.
13. Dindo D, Demartines N, Clavien P-A. Classification of surgical complications: a new
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg.
2004;240(2):205–13.
14. American Thoracic Society; American College of Chest Physicians. ATS/ACCP
Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med.
2003;167(2):211-77.
15. ATS Committee on Proficiency Standards for Clinical Pulmonary Function
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir
Crit Care Med. 2002;166(1):111-7.
16. Weimann A, Braga M, Harsanyi L, Laviano A, Ljungqvist O, Soeters P, et al. ESPEN
Guidelines on Enteral Nutrition: Surgery including organ transplantation. Clin Nutr Edinb
Scotl. 2006;25(2):224–44.
17. Campbell WW, Leidy HJ. Dietary protein and resistance training effects on muscle
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and body composition in older persons. J Am Coll Nutr. 2007;26(6):696S–703S.
18. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic
data capture (REDCap)--a metadata-driven methodology and workflow process for providing
translational research informatics support. J Biomed Inform. 2009;42(2):377–81.
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Contributors: BL, CB, FC, RR, BM, JYM, MS, CP, JG, EF, KS, CM and DP led the
conceptualisation, design and implementation of this research protocol with the collaboration
of the FRENCH (Fédération de recherche en chirurgie digestive). BP led the development of
the statistical analysis plan. BL participated in the design of the protocol for interventions and
assessments. All the authors have read and approved the final manuscript. BL, CB, FC, BP,
CM and DP will have access to the final trial dataset, ancillary study, post-trial care and
disclosure of contractual agreements
Funding: This study has received a grant from PHRC (Protocole Hospitalier en Recherche
Clinique) 2015 (PHRC IR 2015 LE ROY). There is no financial and other competing interests
for principal investigators for the overall trial and each study site.
Ethics approval IRB00008526 and ANSM (2015-A01733-46).
Provenance and peer review Not commissioned; externally peer reviewed.
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Figures:
1. Consort diagram: Flow chart
2. Study diagram
Appendices:
1. Informed form
2. Consent form
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Consort diagram
Figure 1
254x190mm (300 x 300 DPI)
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Study diagram
Figure 2
254x190mm (300 x 300 DPI)
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Appendice 1
FORMULAIRE D’INFORMATION Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation dans le cancer de l’estomac et de
l’œsophage Promoteur de l’essai :
CHU de Clermont Ferrand, 58 rue Montalembert, 63003 Clermont Ferrand Cedex 1, France Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy Service de chirurgie digestive et hépato-biliaire 1 Place Lucie Aubrac 63003 Clermont-Ferrand
Madame, Monsieur, il vous est proposé de participer à un protocole de recherche clinique, dont le but
est de montrer qu’on peut améliorer votre récupération post opératoire et optimiser la poursuite de votre traitement de chimiothérapie en vous préparant physiquement, psychologiquement et le plan nutritionnel avant l’intervention. Cette prise en charge est appelée « préhabilitation » et va vous être expliquée ci-après plus en détails.
Cependant avant de décider de prendre part à cette étude biomédicale, il est important que vous preniez
le temps de lire et de comprendre les informations suivantes concernant le déroulement de ce protocole. Cette note d’information décrit l’objectif, les procédures, les bénéfices et les risques de l’étude. Elle explique entre autre votre droit à vous retirer de l’étude à tout moment sans avoir à vous justifier. S’il y a quoi que ce soit dans ce document que vous ne comprenez pas, veuillez demander à votre médecin ("investigateur") ou au personnel de l’étude de vous l’expliquer. Prenez votre temps pour décider si vous souhaitez ou non participer à cette étude ; parlez-en avec vos amis ou vos proches. Si vous choisissez de participer, il vous sera demandé de signer un document intitulé « Formulaire de consentement » et ce en 2 exemplaires, dont un vous sera remis. Si vous refusez de prendre part à l’étude, ceci n’aura aucune conséquence sur votre prise en charge médicale.
Pour pouvoir participer à cette étude vous devez être couvert par un régime de Sécurité Sociale. Rationnel de l’étude
Vous allez être opéré de votre cancer œsogastrique dans le service de chirurgie de votre CHU. Comme toute intervention chirurgicale, elle comporte des risques propres à chaque type d’intervention. Ces risques peuvent induire une augmentation de votre durée d’hospitalisation, une diminution plus ou moins longue de votre qualité de vie voire une impossibilité à poursuivre votre traitement de chimiothérapie. Récemment des chirurgiens ont montré qu’une préparation durant 6 semaines avant l’opération, pouvait améliorer les résultats post-opératoires sur la morbidité globale, le statut nutritionnel, le retour plus rapide aux activités quotidiennes permettant, en autre, de réaliser tout le protocole de chimiothérapie prévu initialement. Cette prise en charge est appelée « préhabilitation ». Elle repose sur 3 volets.
- une prise en charge physique qui consiste à réaliser des exercices cardiovasculaires 3 fois par semaine sous surveillance médicale dans le service de médecine du sport et de réadaptation de votre l’hôpital Paraphe du patient
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- une prise en charge nutritionnelle qui consiste à établir avec un médecin nutritionniste et un diététicien, un programme alimentaire pouvant conduite à une supplémentation nutritionnelle si nécessaire
- une prise en charge psychologique avec le soutien d’un psychologue qui vous recommandera, en
autre, des tests de relaxation à réaliser à la maison. Ce protocole a déjà montré son intérêt dans le domaine de la chirurgie cardio vasculaire ou du cancer colorectal. Aussi, nous souhaiterions en faire de même pour la chirurgie du cancer œsogastrique d’où l’étude à laquelle nous vous proposons de participer.
Déroulement de l’étude : Après information par votre chirurgien et après lecture de cette note, si vous acceptez de rentrer dans l’étude, un bilan pré-opératoire standard pour votre pathologie pourra être réalisé si nécessaire. De même vous pourrez être amené à voir ou revoir un anesthésiste à la demande du chirurgien. Nous vous demanderons également de bien vouloir compléter, répondre à quelques questionnaires évaluant votre qualité de vie, vos habitudes alimentaires, vos activités quotidiennes... Après ces évaluations et si vous répondez toujours aux critères du protocole, un tirage au sort sera réalisé afin de déterminer dans quel groupe vous allez entrer durant vos séances de chimiothérapie pré opératoire 1) groupe contrôle : préparation standard selon les référentiels actuels, 2) groupe préhabilitation. Paraphe du patient
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Paraphe du patient
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La préparation standard consistera : a) à bénéficier de séance de kinésithérapie respiratoire si nécessaire, b) à prendre des compléments alimentaires si nécessaire soit par voie orale, soit à l’aide de sonde naso-
gastrique (sonde qui passe par les narines pour aller directement dans le tube digestif) soit par injection. c) à évaluer votre anxiété à l’aide de questionnaires
La "préhabilitation" consistera :
a) à réaliser des exercices physiques à raison de 1h, 3 fois par semaine durant 6 semaines dans le service de médecine du sport de votre Hôpital et ce, sous la surveillance médicale d’un kinésithérapeute. Ces activités seront adaptées à vos propres capacités et selon vos résultats aux examens cardio respiratoires réalisés au préalable avant tout traitement. Ils débuteront 2 mois avant votre chirurgie.
Les exercices réalisés seront de 2 types : * des exercices d’endurance dont le but sont d’améliorer votre résistance cardio vasculaire en
réalisant du vélo et/ou de la marche, * des exercices de renforcement musculaires (bras, épaules, poitrine, abdomen, dos hanches et
jambe) à l’aide de matériel type haltères, élastiques …...
Tous ces exercices seront actualisés au cours du temps en fonction de vos progrès, performances. b) à suivre un programme nutritionnel élaboré avec un nutritionniste 2 mois avant votre chirurgie. Ce
dernier sera établi en fonction de vos besoins, de vos habitudes alimentaires et pourra être adapté, modifié en cours du programme avec l’aide du diététicien qui vous rencontrera régulièrement lors de vos
venues à l’hôpital pour vos séances de chimiothérapie. Vous reverrez également le nutritionniste à la fin de vos 6 semaines de préhabilitation.
c) à vous rendre à des consultations de psychologies pour apprendre à gérer, contrôler votre anxiété, à
mieux appréhender votre traitement de chimiothérapie et les effets secondaires associés. Pour cela il vous sera demandé d’assister à 3 consultations d’1h avec un psychologue qui vous apprendra des exercices de relaxations à réaliser ensuite à votre domicile. Ces consultations auront lieu au cours des 2 mois précédents votre chirurgie
A la fin de vos séances de chimiothérapie, vous bénéficierez à nouveaux de bilans (et ce, peu importe dans quel groupe vous êtes inclus) afin de faire le point sur :
1) votre résistance cardiorespiratoire 2) votre état nutritionnel, 3) votre niveau d’anxiété
De même il vous sera demandé de répondre à des questionnaires Ensuite, un suivi médical 1 mois puis à la fin de votre traitement de chimiothérapie adjuvante sera
réalisé par le biais d’une consultation afin d’évaluer les suites opératoires, votre qualité de vie, votre autonomie. Le déroulement de chaque consultation comprendra un examen médical clinique, des questionnaires spécifiques à l’étude à compléter.
Paraphe du patient
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Bénéfices et risques de l’étude
Les bénéfices potentiels pour vous de participer à cette étude pourraient être une meilleure récupération post opératoire, une durée d’hospitalisation plus courte et surtout un retour plus rapide à vos activités du quotidien, et peut être une meilleur tolérance de la chimiothérapie.
Ce projet ne devrait pas engendrer de risque supplémentaire pour vous si ce n’est peut être un surplus de
fatigue liée aux exercices, examens et consultations supplémentaires requis par l’essai, voire des contraintes supplémentaires comme disponibilités, déplacements, suivi alimentaire .
Modalité de recrutement
Ce protocole sera proposé à 120 patients répondant aux critères d’inclusion et d’exclusion. Ces 120 patients seront inclus après signature du consentement éclairé. Traitements administrés dans le cadre de cette étude
Aucun traitement supplémentaire autre que ceux utilisés en routine pour votre prise en charge thérapeutique ne sera nécessaire à la conduite de cette étude. Evaluations réalisées
Nous essayerons au mieux de concilier les examens, consultations spécifiques au protocole avec vos venues au CHU dans le cadre de votre traitement de chimiothérapie. Si des visites supplémentaires s’avéraient nécessaires pour des questions de disponibilités, d’organisation de services sachez que cela n’induire aucun frais supplémentaire pour vous.
De même lors de votre prise en charge, suivi, il vous sera remis des questionnaires permettant d’évaluer
votre qualité de vie, votre niveau d’anxiété ou encore votre statut physique et nutritionnel. Ces questionnaires devront être remplis sur place et prendront au maximum une vingtaine de minutes.
Durée totale de votre participation à ce protocole
La durée totale de votre participation à cette étude sera de 6 mois. Indemnisation
Il n’y aura aucune indemnisation dans le cadre de cette étude.
Période d’exclusion La période d’exclusion définie dans le cadre de cette étude est de 15 jours avant votre inclusion jusqu’à
votre sortie d’étude, période pendant laquelle vous ne pourrez pas participer à un autre protocole de recherche clinique. Paraphe du patient
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Conservation de matériel biologique Cette étude ne fera l’objet d’aucune conservation de matériel biologique
Protection des patients et confidentialité Cette recherche a reçu l’avis favorable du Comité de Protection des Personnes sud est VI le
…………………………… ainsi que l’autorisation préalable de l’autorité compétente de santé datée du ………………………... Il est possible que cette recherche soit interrompue, si les circonstances le nécessitent, par le promoteur ou à la demande de l’autorité de santé.
Votre participation à cette recherche biomédicale n'engendrera pour vous aucun frais supplémentaire par rapport à ceux que vous auriez dans le cadre de la prise en charge standard de votre maladie.
Toutefois, pour pouvoir participer à cette recherche vous devez être affilié(e) ou bénéficier d’un régime de sécurité sociale.
Le CHU de Clermont-Ferrand, qui organise cette recherche biomédicale en qualité de promoteur, a contracté une assurance conformément aux dispositions législatives, garantissant sa responsabilité civile et celle de tout intervenant auprès de la Société Hospitalière d’Assurances Mutuelles (SHAM, contrat n° 147161). Dans le cas où votre état de santé serait altéré du fait de votre participation à l’étude, conformément à la loi de Santé Publique n°2004-806 du 9 août 2004, vous seriez en droit de recevoir des dédommagements dans le cadre de ce contrat d’assurance spécifique.
Dans le cadre de la recherche biomédicale à laquelle le CHU de Clermont-Ferrand (établissement
promoteur) vous propose de participer, un traitement informatique de vos données personnelles va être mis en œuvre pour permettre d’analyser les résultats de la recherche au regard de l’objectif de cette dernière qui vous a été présenté. A cette fin, les données médicales vous concernant et les données relatives à vos habitudes de vie, seront transmises au Promoteur de la recherche ou aux personnes ou sociétés agissant pour son compte, en France ou à l’étranger. Ces données seront identifiées par un numéro de code et par vos initiales. Ces données pourront également, dans des conditions assurant leur confidentialité, être transmises aux autorités de santé françaises, à d’autres entités du CHU de Clermont Ferrand (établissement promoteur).
Conformément aux dispositions de loi relative à l’informatique aux fichiers et aux libertés, vous disposez
d’un droit d’accès et de rectification. Vous disposez également d’un droit d’opposition à la transmission des données couvertes par le secret professionnel susceptibles d’être utilisées dans le cadre de cette recherche et d’être traitées.
Vous pouvez également accéder directement ou par l’intermédiaire d’un médecin de votre choix à l’ensemble de vos données médicales en application des dispositions de l’article L. 1111-7 du code de la santé publique. Ces droits s’exercent auprès du médecin qui vous suit dans le cadre de la recherche et qui connaît votre identité.
Par ailleurs, vous pourrez être tenu informé des résultats globaux de cette recherche à la fin de l’étude. Vous êtes libre d'accepter ou de refuser de participer à cette recherche. De plus vous pouvez exercer à tout
moment votre droit de retrait de cette recherche sans avoir à vous justifier. Le fait de ne plus participer à cette recherche ne modifiera pas la qualité des soins qui vous sont prodigués. Vous pouvez demander à tout moment des explications complémentaires sur l’étude à l’équipe soignante.
Lorsque vous aurez lu cette note d’information et obtenu les réponses aux questions que vous vous posez en interrogeant le médecin investigateur, il vous sera proposé, si vous en êtes d’accord,
Paraphe du patient
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de donner votre consentement écrit en signant le document préparé à cet effet en accord avec le code de la santé publique visant à protéger les personnes se soumettant à une étude biomédicale. Votre consentement écrit n’enlève en aucun cas la responsabilité des médecins qui vous soignent A qui devez-vous vous adresser en cas de questions ou de problèmes ?
En cas de problèmes, d’événements indésirables en cours d’essai ou de questions, vous pouvez vous adresser aux personnes suivantes :
Vos contacts dans l’étude
Bertrand Le Roy (Coordonnateur) Service de Chirurgie Digestive Hôpital Estaing CHU de Clermont-Ferrand 1 place Lucie et Raymond Aubrac 63003 Clermont-Ferrand cedex 1 Tel: 04 73 75 04 94 Fax : 04 73 75 19 22 [email protected]
Brigitte Gillet (Ingénieur Hospitalier, Attaché de recherche clinique) Service de Chirurgie Digestive Unité d'Oncologie Digestive Hôpital Estaing CHU de Clermont-Ferrand 1 place Lucie et Raymond Aubrac 63003 Clermont-Ferrand cedex 1Tel: 04 73 75 52 26 Fax : 04 73 75 19 22 [email protected]
Paraphe du patient sur toutes les pages
Date : ……/……/…… Signature du patient Paraphe de l’investigateur (Précédée de la mention « Lu et compris »)
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Appendice 2
FORMULAIRE DE CONSENTEMENT DE PARTICIPATION A UNE RECHERCHE BIOMEDICALE
Etude pilote, randomisée, multicentrique sur l’effet de la préhabilitation dans le cancer de l’œsophage et de l’estomac
Promoteur de l’essai :
CHU de Clermont Ferrand, 58 rue Montalembert, 63003 Clermont Ferrand Cedex 1, France Code promoteur : PHRC IR 2015 LE ROY
Investigateur coordonnateur :
Docteur Bertrand Le Roy Service de chirurgie digestive et hépato-biliaire 1 Place Lucie Aubrac 63003 Clermont-Ferrand
Je soussigné(e) Mme, Mlle, M. (rayer les mentions inutiles) (nom, prénom)…………………………………………… Né(e) le ………………….…………………... Déclare : - que le Docteur (nom, prénom, téléphone) ……………………………………………..…………….. m’a proposé
de participer à l’étude sus nommée, - qu’il m’a expliqué en détail le protocole, - qu’il m’a notamment fait connaître :
• l’objectif, la méthode et la durée de l’étude • les contraintes et les risques potentiels encourus • mon droit de refuser de participer et en cas de désaccord de retirer mon consentement à tout moment • mon obligation d’inscription à un régime de sécurité sociale • que, si je le souhaite, à son terme, je serais informé(e) par le médecin investigateur de ses résultats globaux • que je ne serais pas autorisé(e) à participer à d’autres études cliniques durant toute ma participation à ce
protocole estimée à 6 mois maximum. • que le Comité de Protection des Personnes Sud Est VI a émis un avis favorable en date du
xx/xx/xxxx(Préciser le nom de CPP sollicité et la date d’obtention de l’avis favorable) • que l’ANSM (Agence Nationale de Sécurité du Médicament et des produits de santé) a délivré une
autorisation pour cette étude • que dans le cadre de cette étude le promoteur, le CHU de Clermont-Ferrand, a souscrit à une assurance
couvrant cette recherche (contrat SHAM 147161). - que j’ai répondu en toute bonne foi aux questions concernant mon état de santé et ma participation à d’autres
études. Les informations relatives à l’étude recueillies par l’investigateur sont traitées confidentiellement. J’accepte que les données enregistrées à l’occasion de cette recherche puissent faire l’objet d’un traitement informatisé anonyme. J’ai bien noté que le droit d’accès prévu par la loi du 6 août 2004 relative à l’informatique, aux fichiers et aux libertés s’exerce à tout moment auprès du médecin qui me suit dans le cadre de la recherche et qui connaît mon identité. Je pourrai exercer mon droit de rectification et d’opposition auprès de ce même médecin, qui contactera le promoteur de la recherche
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Après avoir discuté librement et obtenu réponse à toutes mes questions, j’accepte librement et volontairement de participer à cette recherche biomédicale dans les conditions précisées dans le formulaire d’information et de consentement. Nom et prénom du patient : …………………………………………………… Date :……./……./……. Signature Précédée de la mention « Lu et compris » :
Nom de l’investigateur : …………………………………………………… Date :……./……./……. Signature :
Ce document est à réaliser en 2 exemplaires originaux, dont le premier doit être gardé 15 ans par l’investigateur,
un autre remis à la personne donnant son consentement.
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Spirit
Administrative information
Title
1
Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym
Trial registration=> Page 3
2a
Trial identifier and registry name. If not yet registered, name of intended registry
=> Page 3
2b
All items from the World Health Organization Trial Registration Data Set
Protocol version
=> Page 3
3
Date and version identifier
Funding
=> Page 3
4
Sources and types of financial, material, and other support
Roles and responsibilities
=> Page 3-4
5a
Names, affiliations, and roles of protocol contributors
=> Page 4
5b
Name and contact information for the trial sponsor
=> Page 3-4
5c
Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation
of data; writing of the report; and the decision to submit the report for publication, including whether they will
have ultimate authority over any of these activities
=> Page 3
5d
Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication
committee, data management team, and other individuals or groups overseeing the trial, if applicable (see
Item 21a for data monitoring committee)
=> Page 3
Introduction
Background and rationale
6a
Description of research question and justification for undertaking the trial, including summary of relevant
studies (published and unpublished) examining benefits and harms for each intervention
=> Page 7
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6b
Explanation for choice of comparators
=> Page 8
Objectives
7
Specific objectives or hypotheses
Trial design
=> Page 8
8
Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation
ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)
=> Page 8
Methods: Participants, interventions, and outcomes
Study setting
9
Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be
collected. Reference to where list of study sites can be obtained Eligibility criteria
=> Page 8
10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and
individuals who will perform the interventions (eg, surgeons, psychotherapists) Interventions
=> Page 9
11a Interventions for each group with sufficient detail to allow replication, including how and when they will be
administered
=> Page 10
11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose
change in response to harms, participant request, or improving/worsening disease)
=> Page 11-12
11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence
(eg, drug tablet return, laboratory tests)
=> Page 11-12
11d Relevant concomitant care and interventions that are permitted or prohibited during the trial Outcomes
=> Page 11-12
12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood
pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,
median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy
and harm outcomes is strongly recommended Participant timeline
=> Page 11-12
13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for
participants. A schematic diagram is highly recommended (see Figure) Sample size
=> Page 13-14
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14 Estimated number of participants needed to achieve study objectives and how it was determined, including
clinical and statistical assumptions supporting any sample size calculations Recruitment
=> Page 13-14
15 Strategies for achieving adequate participant enrolment to reach target sample size
=> Page 14
Methods: Assignment of interventions (for controlled trials) Allocation: Sequence generation
16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any
factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg,
blocking) should be provided in a separate document that is unavailable to those who enrol participants or
assign interventions
=> Page 14
Allocation concealment mechanism
16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,
opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned
Implementation
=> Page 14
16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to
interventions Blinding (masking)
=> Page 14
17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome
assessors, data analysts), and how
=> Page 14
17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s
allocated intervention during the trial Methods: Data collection, management, and analysis Data collection
methods
=> NA
18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related
processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of
study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.
Reference to where data collection forms can be found, if not in the protocol
=> Page 14
18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be
collected for participants who discontinue or deviate from intervention protocols Data management
=> Page 14
19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality
(eg, double data entry; range checks for data values). Reference to where details of data management
procedures can be found, if not in the protocol Statistical methods
=> Page 14
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20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the
statistical analysis plan can be found, if not in the protocol
=> Page 14
20b Methods for any additional analyses (eg, subgroup and adjusted analyses)
=> Page 14
20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any
statistical methods to handle missing data (eg, multiple imputation)
=> Page 14
Methods:
Monitoring Data monitoring
21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement
of whether it is independent from the sponsor and competing interests; and reference to where further details
about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed
=> Page 16
21b Description of any interim analyses and stopping guidelines, including who will have access to these
interim results and make the final decision to terminate the trial Harms
=> Page 13
22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse
events and other unintended effects of trial interventions or trial conduct Auditing
=> Page 13
23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent
from investigators and the sponsor
=> Page 13
Ethics and dissemination
Research ethics approval
24
Plans for seeking research ethics committee/institutional review board (REC/IRB) approval
Protocol amendments
=> Page 14-15
25
Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,
analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)
=> Page 14-15
Consent or assent
26a
Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how
(see Item 32)
=> Page 15
26b
Additional consent provisions for collection and use of participant data and biological specimens in ancillary
studies, if applicable
Confidentiality
Page 38 of 39
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
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on July 12, 2020 by guest. Protected by copyright.
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J Open: first published as 10.1136/bm
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nloaded from
For peer review only
=> Page 15
27
How personal information about potential and enrolled participants will be collected, shared, and maintained
in order to protect confidentiality before, during, and after the trial
Declaration of interests
28
Financial and other competing interests for principal investigators for the overall trial and each study site
Access to data
29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that
limit such access for investigators Ancillary and post-trial care
30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial
participation
Dissemination policy
=> Page 16
31a
Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the
public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing
arrangements), including any publication restrictions
=> Page 16
31b
Authorship eligibility guidelines and any intended use of professional writers
=> Page 16
31c
Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code
=> Page 16
Appendices
Informed consent materials
32
Model consent form and other related documentation given to participants and authorised surrogates
Biological specimens
=> Appendice 1, legends page 20
33
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis
in the current trial and for future use in ancillary studies, if applicable
=>NA
Page 39 of 39
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on July 12, 2020 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2016-012876 on 7 Decem
ber 2016. Dow
nloaded from