Clinical Trial Protocol
Trial title
BariSurg trial: Sleeve gastrectomy versus Roux-en-Y gastric bypass in obese patients with BMI 35-60 kg/m² – a multicenter randomized trial
trial registration numberDRKS00004766The information in this trial protocol is strictly confidential. It is for the use of the sponsor, investigator, trial personnel, ethics committee, the authorities, and trial subjects only. This trial protocol may not be passed on to third parties without the agreement of University of Heidelberg, Department of General, Visceral and Transplantation Surgery, Prof. Dr.Büchler as Principle Investigator
Roles and Responsibilities
Principal Investigator
Markus W. Büchler, MD
Professor and Chairman
Department of General, Visceral and Transplantation Surgery
Im Neuenheimer Feld 110, 69120 Heidelberg
Phone: + 49-6221-56-6201 (Secretariat Ms Irmgard Alffermann)
Fax: +49-6221-56-5450
Email:
Coordinating Investigator
Lars Fischer, MD
Professor and Vice Chairman
Beat Müller, MD
Vice Chairman
Department of General, Visceral and Transplantation Surgery
Im Neuenheimer Feld 110, 69120 Heidelberg
Phone +49-6221-56-39493
Fax +49-6221-56-7470
E-mail:
Biometrician
Reinhard Rychlik, MD, PhD
Professor
R&P, Research and Public Relations
Am Ziegelfeld 28, 51399 Burscheid/Germany
Phone+49-2174-71520
Fax+49-2174-715299
Project Management
Inga Rossion
Executive Manager
SDGC, StudyCenter of the German Surgical Society
Im Neuenheimer Feld 110, 69120 Heidelberg
Phone+49-6221-566984
Fax+49-6221-566988
Data Management
R&P, Research and Public Relations
Am Ziegelfeld 28, 51399 Burscheid/Germany
Phone +49-2174-71520
Fax +49-2174-715299
Quality Assurance
Clinical Monitoring
R&P, Research and Public Relations
Am Ziegelfeld 28, 51399 Burscheid/Germany
Phone +49-2174-71520
Fax +49-2174-715299
SAE-Management
R&P, Research and Public Relations
Am Ziegelfeld 28, 51399 Burscheid/Germany
Phone +49-2174-71520
Fax +49-2174-715299
Sponsor
University of Heidelberg
Department of General, Visceral and Transplantation Surgery
Trial Committees
Data Safety Monitoring Board
Prof. Dr. Peter Nawroth, Dept. of Medicine I and ClinicalChemistryUniversityof Heidelberg
E-mail:
Dr.Johannes Sander, Adipositas Zentrum Schön Klinik HamburgEilbek
E-mail:
Christian Stock, Institute of Medical Biometry and Informatics, University of Heidelberg
E-mail:
Steering committee
Prof. Dr. med. Lars FischerE-mail:
PD Dr. med. Beat MüllerE-mail:
Prof. Dr. Dr. med. Reinhard RychlikE-mail:
Writing committee
Anna-Laura Wekerle
Inga Wegener
Table of Contents
SYNOPSIS
FLOW CHART
Abbreviations
Abbreviations
1.0INTRODUCTION
1.1Scientific background
1.2Trial rationale
1.3Objectives
1.4Trial design
1.5Trial duration and schedule
2.0 Trial Conduct
2.1Eligibility criteria
2.1.1Number of patients and trial centers
2.1.2Inclusion criteria for patients
2.1.3Exclusion criteria for patients
2.1.4Criteria for withdrawal of patients
2.1.5Premature closure of the trial
2.2Intervention(s)
2.2.1Description of trial interventions
2.2.2Benefits and risks of trial interventions
2.2.3Assignment of intervention andrandomization
2.2.4Blinding/unblinding
2.3.Outcomes/endpoints
2.3.1Primary outcome/endpoint and assessment of primary outcome
2.3.2Secondary outcomes/endpoints and assessment of secondary outcomes
2.4.Patient schedule and documentation
2.4.1.Description of trial visits
3.Data Management
4.Statistical Procedures
4.1Sample size calculation
4.2Analysis variables and statistical methods
5.Quality Assurance
5.1Clinical data monitoring
5.2Assessment of Safety
5.2.1Data safety and monitoring board (DSMB)
5.2.2Definition, documentation and classification of Serious Adverse Events
5.3Direct access to source data/documents
6.Ethical and Legal Aspects
6.1Ethical Considerations
6.2Good Clinical Practice and Declaration of Helsinki
6.3Patient information and informed consent
6.4Confidentiality
6.5Responsibilities of investigator
6.6Approval of trial protocol and amendments
6.7Ongoing information for independent Ethics Committee (IEC)
6.8Steering Committee
7.Agreements
7.1Financing of the trial
7.2Reports
7.3Participating trial centers
8.References
9.Declaration of Investigator
Appendices
Appendix I Patient information sheet and informed consent form
Appendix IIDeclaration ofHelsinki 2013
SYNOPSIS
Coordinating Investigator / Prof. Dr. Lars FischerAcronym / BariSurg trial
Title / Sleeve gastrectomy versus Roux-en-Y gastric bypass in obese patients with BMI 35-60 kg/m² – a multicenter randomized trial
Trial registration number / DRKS00004766
Indication / obese patients with BMI 35-60 kg/m²
Objectives / To investigate the possible differences between sleeve gastrectomy versus Roux-en-Y gastric bypass on excess weight loss in patients in need of bariatric surgery
Trial design / Prospective, randomized, controlled, double blind (patient and observer) surgical trial
Interventions / Experimental intervention:
Sleeve gastrectomy
Control intervention:
Roux-en-Y gastric bypass
Eligibility criteria / Key inclusion criteria:
Age 18-70 years
BMI 40-60kg/m²
BMI 35-40 kg/m² with at least one obesity-related co-morbidity
Psychosomatical evaluation
Endocrinological evaluation
Written informed consent
Key exclusion criteria:
Pregnancy
Malignant disease in the past 5 years
Expected lack of compliance or inability to informed consent
≥ ASA IV
Previous bariatric surgery
History of major abdominal operation
Primary endpoint / Percent of excess weight loss after 24 months
Secondary endpoint(s) / Remission of obesity-related co-morbidity (Type 2 DiabetesMellitus type 2, arterial hypertension, sleep apnea, joint pain)
Quality of life (preoperatively, 12, 24, and 60 months)
Occurrence and course of gastrooesphageal reflux disease
Vitamin status
Morbidity
Mortality
Percent of excess weight loss after 60 months
Sample size / To be assessed for eligibility: n = 500
To be allocated to trial: n = 248
To be analyzed: n = 198
Trial sites (planned) / n = 6
Statistical analysis / Efficacy:
The primary efficacy endpoint is excess weight loss after 24 months.
Description of the primary efficacy analysis and population:
Confirmatory analysis will be based on the per-protocol analysis for patients without major protocol violations. The primary endpoint is analyzed with one-sided t-test (non-inferiority). The level of significance is set at 0.025.
Safety:
Exploratory analyses of frequencies of complications and serious adverse events.
Secondary endpoints:
Exploratory analysis
Trial duration / First patient in to last patient out (month):78
Duration of the entire trial (months): 90
Recruitment period (months):18
Financing of the trial / none
FLOW CHART
Abbreviations
AE / Adverse EventBMI / Body mass index
CI / Confidence Interval
CRF / Case Report Form
CV / Curriculum vitae
DM / Data management
DSMB / Data Safety Monitoring Board
EC / Ethics Committee
EGD / Esophagogastroduodenoscopy
EWL / Excess weight loss
FPI / First Patient In
FU / Follow-up
GCP / Good Clinical Practice
GERD / Gastrooesophageal reflux disease
GIQLI / Gastrointestinal quality of life index
GSRS / Gastrointestinal symptom related score
ICH / International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use
IEC / Independent Ethics Committee
ITT / Intention-To-Treat
ISF / Investigator Site File
LPI / Last Patient In
LPO / Last Patient Out
POD / Post Operation Day
QLQ / Quality of Life Questionnaire
QoL / Quality of Life
RCT / Randomized Controlled Trial
R&P / Research and Public Relations (Statistics, Data management, Monitoring, Safety)
RR / Relative Risk
RYGB / Roux-en-Y-gastric bypass
SG / Sleeve gastrectomy
SAE / Serious Adverse Event
SDGC / StudyCenter of German Surgical Society
SDV / Source Data Verification
SF-36 / Short-Form-36 Health Survey
SOP / Standard Operating Procedure
TMF / Trial Master File
T2DM / Type 2 Diabetes mellitus
V / Visit
1.0INTRODUCTION
1.1Scientific background
The effect of bariatric surgery on obesity and correlated co-morbidities such as type 2 diabetes mellitus (T2DM) or arterial hypertension is no longer doubted [1–3]. Reliable data showing improved overall patient survival and a reduced cancer incidence, especially in females, following bariatric surgery are available [4]. Additionally, bariatric surgery can now be performed safely and with acceptable morbidity and mortality [5,6]. The procedures performed in the field of bariatric surgery are still evolving and include rather simple procedures such as gastric banding and more advanced techniques, such as biliopancreatic diversion or ileal transposition. Looking from a more general point of view, Roux-en-Y-bypass (RYGB) and the sleeve gastrectomy (SG) seem to be the most commonly performed procedures, a finding that is likely due to their positive risk/benefit correlation [6].
1.2Trial rationale
RYGB is still considered superior to SG [7,8]. This belief, however, is mostly based on historical considerations, as RYGB was one of the first bariatric procedures ever performed [9]. Because of recent evidence including systematic reviews and randomized controlled trials, SG has become more and more accepted as a stand-alone bariatric surgery procedure [10–16]. The systematic review data revealed, among other things, that excess weight loss (EWL) after SG was not significantly different from EWL following RYGB, 24 months after surgery [14]. This finding is consistent with that of Peterli et al., who also observed no significant differences in 12 month post-op EWL between SG and RYGB [9]. Another randomized controlled trial (RCT) from Finland, comparing SG and RYGB, revealed a significantly reduced operative time and complication rates in favor of the SG group [12]. As a result, the German statistic on obesity surgery for 2011 revealed for the first time, that more SG resections than RYBGs were performed [14,17,18]. Nevertheless, SG is still regarded with scepticism due to the lack of long-term results and randomized controlled studies. Major criticism includes not only the effect of SG on EWL, but also on the course of obesity related co-morbidities, on gastrooesophageal reflux disease (GERD), and on quality of life (QoL) [19]. Furthermore, it seems that SG is correlated with rather specific complications such as fistulas and/or stenosis. The incidence of these complications are reported with the range 0% to 17.5% [18]. Conversely, SG has a rather fast learning curve and can be performed within a short operative time. In addition, SG is considered less technically challenging than RYGB, due to the lack of anastomosis. Based on these unresolved controversies, randomized controlled studies comparing SG and RYGB are urgently needed.
1.3Objectives
The primary endpoint of the BariSurg RCT, to compare EWL rates 24 months after SG and RYGB, was chosen based upon findings of a systematic review [14]. BariSurg will be a multicenter, randomized controlled, patient and observer blinded trial. Major secondary endpoints will be morbidity, mortality, re-operation rate, remission of obesity-related co-morbidities, the occurrence and course of GERD, QoL, and the eventually EWL at 60 months after surgery.
1.4Trial design
The BariSurg trial is a multicenter, randomized controlled, patient and observer blinded trial with two parallel study groups
1.5Trial duration and schedule
The duration of the trial for each patient is expected to be 60 months. The duration of the overall trial is expected to be 90months, including prearrangement and analysis.
The trial duration is from fourth quarter 2013 to fourth quarter 2020, including 18 month of recruitment followed by fiveyears of follow-up. Recruitment of patients will start in November 2013. The actual overall duration or recruitment time may differ.
Table 1: Trial time plan
Inclusion of first patient (FPI) / IV quarter /2013Inclusion of last patient (LPI) / I quarter /2015
End of trial last patient (LPO) / I quarter / 2020
Database Closure / II quarter 2020
Statistical Analysis / III quarter 2020
Report / IV quarter 2020
2.0 Trial Conduct
2.1Eligibility criteria
Patients between 18 and 70 years old, a BMI between 35 and 60 kg/m² and an indication for bariatric surgery according to the most recent German S3 guidelines will be eligible. Patients with a BMI of 35-40 kg/m² need to have at least one obesity related co-morbidity such as T2DM or arterial hypertension.
2.1.1Number of patients and trial centers
A total of 248 patients will be randomized, with 124 patients assigned to each treatment arm. The BariSurg RCT will be conducted at six bariatric centers: the University of Heidelberg, Krankenhaus Sachsenhausen (Frankfurt am Main), Schwarzwald-Baar-Klinikum (Villingen-Schwennigen), Städtisches Klinikum Karlsruhe (Karlsruhe), Evangelisches Krankenhaus Zweibrücken (Zweibrücken) and Krankenhaus Bad Cannstatt (Stuttgart).
2.1.2Inclusion criteria for patients
- Age 18-70 years
- BMI 40-60kg/m²
- BMI 35-40 kg/m² with at least one obesity-related co-morbidity
- Psychosomatical evaluation
- Endocrinological evaluation
- Signed informed consent
2.1.3Exclusion criteria for patients
- Pregnancy
- Malignant disease in the past 5 years
- Expected lack of compliance or inability to informed consent
- ≥ASA IV
- Previous bariatric surgery
- History of major abdominal operation
2.1.4Criteria for withdrawal of patients
Patients are free to leave the trial at any time and without giving reasons for their decision. Subjects may be withdrawn from the trial for the following reasons: (a) At their own request or (b) if, in the investigator’s opinion, continuation of the trial would be detrimental to the subject’s well-being. In case of (b), the reason for withdrawal must be recorded in the CRF and in the patient’s medical records.
All ongoing Serious Adverse Events (SAEs) of withdrawn subjects have to be followed up until no more signs and symptoms are verifiable or the patient is in stable condition.
2.1.5Premature closure of the trial
The trial may be prematurely closed by the principal investigator in consultation with the steering committee and the responsible biometrician.
If the termination of the trial becomes necessary, the steering committee of the trial will discuss this issue with the independent Data Safety Monitoring Board (DSMB). Reasons that may necessitate a termination of the trial include the following:
The incidence or severity of serious adverse events/morbidity in this trial indicates a potential health hazard caused by the study treatment.
It appears that patients’ enrolment is unsatisfactory with respect to quality and/or quantity or data recording is severely inaccurate and/or incomplete.
External evidence demanding a termination of the trial.
The independent ethics committee (IEC) must then be informed.
2.2Intervention(s)
2.2.1Description of trial interventions
Patients will be asked to complete standard preoperative diagnostics including esophagogastroduodenoscopy (EGD), endocrine-, psychosomatic- and cardiac examinations, and will also fill out three questionnaires (Short-Form-36 Health Survey (SF-36) [20], Gastrointestinal Quality of Life Index (GIQLI) [21] and Gastrointestinal Symptom Rating Score (GSRS) [22]. Two weeks before surgery, patients will be asked to reduce their weight by following a low calorie liquid diet [23]. In order to standardize the surgical technique for SG and RYGB as much as possible, all participating centers will receive a movie showing key steps of both procedures. Preoperatively, a single-shot antibiotic prophylaxis will be given. For the surgical procedure, the patient will be placed in the supine position 45° (reverse Trendelenburg).
Roux-en-Y-gastric bypass
After the gastroesophageal junction is identified, the stomach is transsected with a stapler 6 cm below the junction. A pouch is created along a 42 French calibrating tube. A 70cm biliopancreatic limb is defined and a gastroenterostomy will be performed using either a 30mm linear or 25 mm circular stapling technique. The common channel (jejunojenostomy) will be stapled after another 150 cm antecolic limb. All patients will be discharged with the recommendation of oral intake of multivitamin tablets twice daily.
Sleeve gastrectomy
The gastroepiploic vessels are divided 6 cm prepyloric along the great curvature, until the angle of His and the left crus of the diaphragm are visible. Along with a 42 French bougie, the stomach is then resected using linear stapler devices. At the angle of His the stapler line is sutured. All patients will be discharged with the recommendation of oral intake of multivitamin tablets twice daily.
2.2.2Benefits and risks of trial interventions
The surgical procedures examined in this trial are well established and in current daily use, so no increased medical risks are expected for patients participating in the trial.SG is associated with a morbidity between 0-17.5% and a mortality between 0-1.2% [14]. The most frequently occurring postoperative complications are insufficiencies/fistulas at the staple line, leakage, stenosis of the sleeve and dilatation of the sleeve [5]. RYGB has a morbidity rate of 2-10% and a mortality of 0.5-0.8% [7]. Frequently observed complications include anastomotic insufficiency, especially with regard to the gastrojejunostomy, and dumping syndrome. For both bariatric procedures, nutritional supplementation might be necessary for the remainder of the patient’s life.
2.2.3Assignment of intervention andrandomization
After patients who were checked for inclusion and exclusion criteria and have given their informed consent, randomization will be performed through an internet-based randomization tool ( Randomization is performed by block randomization and will be stratified for each center until the enrolment goal of 248 patients has been reached.
2.2.4Blinding/unblinding
Patient and observer will be blinded in this trial. In case of emergencies, including possible reoperation, patients can be unblinded at any time. Every center will store the randomization information for every patient in an envelope. In cases of emergency, the attending surgeon may access the information in the envelopes at any time.
2.3.Outcomes/endpoints
The summary of the primary and the secondary endpoints depicts different points of view concerning the efficacy and safety of bariatric procedures. In doing so, medical issues as well as patient assessment can be analyzed.
2.3.1Primary outcome/endpoint and assessment of primary outcome
The primary endpoint is defined as EWL at 24 months after surgery (RYGB or LSG). Power calculation was based on the results of the systematic review of Fischer et al. [14].
2.3.2Secondary outcomes/endpoints and assessment of secondary outcomes
Long-term EWL at 60 months, morbidity, mortality, course of obesity related co-morbidities (T2DM, arterial hypertension, joint pain, sleep apnea, blood dyslipidemia), vitamin status, incidence and/or course of GERD and quality of life (as defined by the SF 36) will form the secondary endpoints. The course of obesity-related co-morbidities is assessed by laboratory examinations and current medication use. T2DM remission will be measured by HbA1c, fasting glucose and medications used. Arterial hypertension will be monitored by medication and blood pressure measurements. The course of joint pain and dyslipidemia are assessed by pain and respectively lipid metabolism medication and laboratory examination. The course of Sleep apnea is analyzed by patients’ application of C-PAP-mask. Nutritional substitution will be assessed using a questionnaire which was developed in the bariatric center of the university hospital of Heidelberg. GERD incidence and course of GERD will be assessed with EGD and by using GSRS and GIQLI as standardized questionnaires. To evaluate quality of life, the validated SF-36 questionnaire will be used. Secondary endpoints will be evaluated preoperatively, at discharge, 6-9, 12, 24, 36, 48 and 60 months postoperatively. Questionnaires and EGD will be performed at 12, 24 and 60 months after surgery.
2.4.Patient schedule and documentation
2.4.1.Description of trial visits
Patient’s scheduled for intervention SG or RYGB are screened at Visit 1. All patients fulfilling inclusion criteria are randomized intraoperatively(Visit 2). Patients are planned to follow-up at hospital discharge, months 3 till 6, months 12, 24, 36, 48 and 60 post operative (Visits 4 - 9). The following parameters should be documented:
Demographic and baseline clinical data:
Baseline data: If a patient has given informed consent and all inclusion criteria are fulfilled and exclusion criteria are adhered to, then the following baseline data are documented.
Demographic data: