EndoBarrierTM in Obese Subjects With Type 2 Diabetes: Impact on Pancreatic Function, Insulin Resistance, Gut Peptides and Gut Permeability - a Pilot Study
Phase: NA
Conditions: Type 2 Diabetes, Obesity
Sponsor: Medical University of Graz

 
Version 1.9                                                                                                                                             Page 1 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
EndoBarrierTM in obese subjects with type 2 diabetes: Impact on pancreatic function, insulin 
resistance, gut peptides and gut permeability – a pilot study 
 
 
Ethics number: 26-280 ex 13/14                                                             
Protocol code: HS-2014-01 
Date and Version number: 04/09/2017                                                                                 Version 1.9 
Principal Investigator:  
Harald Sourij, MD, Associate Professor  
Co-Investigators:  
Christoph Högenauer, MD, Professor 
Julia Mader, MD, Assistant Professor 
           Thomas Pieber, MD, Professor 
           Vanessa Stadlbauer, MD, Associate Professor         
           Norbert Tripolt, MSc, PhD 
Biometrician:  
Sophie Narath, MMSc. 
 
Trial site address and telephone number: 
Medical University of Graz, Department of Endocrinology and Metabolism, Cardiovascular Diabetology 
Research Group, Austria, 8036 Graz, Auenbruggerplatz 15; Telephone: +43 (0)316 385 13270 Fax: +43 
(0)316 385 14332 
  
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
sponsor, the investigator team, regulatory authorities and members of the Research Ethics Committee. 
Trials Sponsor: 
Medical University of Graz 
Auenbruggerplatz 2-4 
8036 Graz  

 
Version 1.9                                                                                                                                             Page 2 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ................................................................................................................................... 2 
2. 
AMENDMENT HISTORY ............................................................................................................................... 5 
3. 
SYNOPSIS .................................................................................................................................................... 5 
4. 
BACKGROUND AND RATIONALE ................................................................................................................. 6 
5. 
AIMS OF THE STUDY .................................................................................................................................... 7 
6. 
OBJECTIVES ................................................................................................................................................. 8 
7. 
OUTCOMES ................................................................................................................................................. 8 
7.1  PRIMARY OUTCOME MEASURES ............................................................................................................................... 8 
7.2  SECONDARY OUTCOME MEASURES............................................................................................................................ 8 
8. 
STUDY DESIGN ............................................................................................................................................ 9 
8.1  DURATION OF STUDY ............................................................................................................................................. 9 
8.2  SOURCE DATA ...................................................................................................................................................... 9 
9. 
SELECTION AND WITHDRAWAL OF STUDY SUBJECTS ................................................................................. 10 
9.1  SUBJECT SELECTION AND RECRUITMENT .................................................................................................................. 10 
9.2  INCLUSION CRITERIA ............................................................................................................................................ 10 
9.3  EXCLUSION CRITERIA ........................................................................................................................................... 10 
9.4  WITHDRAWAL/DROP OUT OF SUBJECTS ................................................................................................................... 11 
9.5  PAYMENT TO SUBJECTS ........................................................................................................................................ 12 
9.6  END OF STUDY .................................................................................................................................................... 12 
10  STUDY PROCEDURES .................................................................................................................................... 13 
10.1  SCHEDULE OF STUDY PROCEDURES ........................................................................................................................ 13 
10.2   VISIT SCHEDULE ............................................................................................................................................... 14 
10.3  LABORATORY RESULTS ........................................................................................................................................ 17 
11  METHODS ..................................................................................................................................................... 18 
11.1  MEAL TOLERANCE TEST (MTT) ........................................................................................................................... 18 
11.2  BOTNIA CLAMP (COMBINED IVGTT AND HYPERINSULINAEMIC-EUGLYCAEMIC CLAMP) .................................................... 18 
11.3  BLOOD SAMPLING ............................................................................................................................................. 18 
11.4  GLP-1 AND GIP ANALYSIS .................................................................................................................................. 19 
11.5  DUAL-ENERGY X-RAY ABSORPTIOMETRY (DEXA) .................................................................................................... 19 
11.6  GUT MICROBIOTA ANALYSIS ................................................................................................................................ 19 
11.7  GUT PERMEABILITY (LACTULOSE/MANNITOL TEST).................................................................................................. 19 

 
Version 1.9                                                                                                                                             Page 3 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
11.8  FOOD FREQUENCY QUESTIONNAIRE (FFQ) ............................................................................................................ 20 
11.9 13C-UREA BREATH TEST (13C-UBT) ...................................................................................................................... 20 
11.10  MARKERS OF INSULIN RESISTANCE ...................................................................................................................... 20 
12  INVESTIGATIONAL MEDICINAL PRODUCT ..................................................................................................... 21 
12.1 MECHANISM OF ACTION...................................................................................................................................... 21 
12.2 THERAPEUTICAL INDICATIONS ............................................................................................................................... 21 
12.3. PRE-PROCEDURAL PRECAUTIONS .......................................................................................................................... 21 
12.4. PROCEDURAL PRECAUTIONS ................................................................................................................................ 21 
12.5. POST PROCEDURAL PRECAUTIONS ........................................................................................................................ 22 
13  ASSESSMENT OF SAFETY ............................................................................................................................... 23 
13.1. DEFINITION ..................................................................................................................................................... 23 
13.2. POTENTIAL ADVERSE EVENTS .............................................................................................................................. 23 
Serious Adverse Event ...................................................................................................................................... 24 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .............................................................................. 25 
Causal relationship of adverse event ............................................................................................................... 25 
14  STATISTICAL CONSIDERATIONS .................................................................................................................... 26 
14.1  CALCULATIONS ................................................................................................................................................. 26 
14.2  STATISTICAL ANALYSIS ........................................................................................................................................ 27 
15  STUDY MONITORING .................................................................................................................................... 27 
16  ETHICS .......................................................................................................................................................... 28 
16.1  INFORMED CONSENT ......................................................................................................................................... 28 
16.2 ETHICAL AND REGULATORY APPROVALS ................................................................................................................. 29 
17. FINANCE ....................................................................................................................................................... 29 
18. INSURANCE ................................................................................................................................................ 29 
19. RESPONSIBILITIES....................................................................................................................................... 29 
20. REFERENCES ............................................................................................................................................... 30 
 
 
 
 
 

 
Version 1.9                                                                                                                                             Page 4 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
LIST OF ABBREVIATIONS 
13C-UBT 
13C-Urease breath test 
AIR 
Acute Insulin Response 
AUC 
Area under Curve 
BID 
Twice a day 
BMI 
Body Mass Index 
BS 
Bariatric Surgery 
CRF 
Case Report Form 
DEGS 
Deutsche Erwachsenen Gesundheits-Survey  
DEXA 
Dual energy x-ray absorptiometry 
DI 
Disposition Index 
DPP-4 
Dipeptidyl-Peptidase Inhibitor - 4 
EBWL 
Excess body weight loss 
ECG 
Electrocardiography 
EIR 
Early Insulin Response 
FFQ 
Food Frequency Questionnaire 
GCP 
Good Clinical Practice 
GIP 
Gastric inhibitory polypeptide 
GLP-1 
Glucagon-like peptide-1 
HEC 
Hyperinsulinemic-euglycaemic Clamp 
ICH 
International Conference on Harmonisation 
IDF 
International Diabetes Federation 
IGI 
Insulinogenic Index 
IVGTT 
Intravenous glucose tolerance test 
MODY 
Maturity Onset Diabetes of the Young 
MTT 
Meal Tolerance Test 
NEMONIT 
Nationales Ernährungsmonitoring 
NSAID 
Non-steroidal anti-inflammatory drug 
OGTT 
Oral Glucose Tolerance Test  
T2DM 
Type 2 Diabetes Mellitus 
UKPDS 
United Kingdom Prospective Diabetes Study 
WHO 
World Health Organisation 

 
Version 1.9                                                                                                                                             Page 5 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
2. 
AMENDMENT HISTORY 
Amendment 
No. 
Protocol 
Version No. 
Date 
issued 
Author(s) of changes 
Details of Changes made 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 
SYNOPSIS 
Study Title 
Duodenal-jejunal bypass liner (EndoBarrierTM) in obese subjects with 
type 2 diabetes: Impact on pancreatic function, insulin resistance, gut 
peptides and gut permeability 
Study Design 
Open, single-centre, single-arm pilot study 
Study Participants 
Obese, adult, type 2 diabetic subjects with suboptimal glycaemic 
control and a BMI between 30 and 49 kg/m2. 
Number of Participants 
12 
Follow-up duration 
15 months 
Planned Duration 
30 months 
Primary Objective 
The primary aim of the study is to explore short and long-term effects 
of the EndoBarrierTM implantation on insulin resistance and beta-cell 
function assessed by repeated Botnia clamps.  
Secondary Objectives 
In addition we will determine the changes in gut peptides and gut 
permeability after implantation of a removable duodeno-jejunal 
bypass device in obese subjects with sub-optimally controlled type 2 
diabetes. Further we aim to investigate the changes in body weight, 
body composition, gut microbiota and the change in global 
cardiovascular risk from baseline to 9 months, estimated using the 
UKPDS risk engine. 

 
Version 1.9                                                                                                                                             Page 6 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
4. 
BACKGROUND AND RATIONALE 
Obesity has reached epidemic proportions in the western world and has risen to the top of the public 
health policy agenda. The World Health Organisation (WHO) predicts that by 2015 approximately 2.3 
billion adults will be overweight (BMI 25-29.9 kg/m²), and more than 700 million will be obese (BMI 30 
kg/m² or more )(1).  
In 2007, more than 40% of Austrian adults were either overweight or obese (11%) and the proportion 
of overweight people is projected to rise even further over the next 10 years (2). 
The association between obesity and type 2 diabetes mellitus (T2DM) is well recognised. A higher body 
mass index (BMI) is a strong predictor of T2DM (3).  
Currently, 285 million people suffer from type 2 diabetes, and this number is predicted to increase to 
439 million by 2030 (4). T2DM raises the risk for cardiovascular events, heart failure, eye problems, and 
kidney diseases. The International Diabetes Federation (IDF) report 2012 predicts that diabetes will 
strike one in ten adults by 2030 (5). Previous research has demonstrated that the impact of diabetes on 
everyday life and the likelihood of costly and disabling complications can be minimized by more 
intensive management of glucose (6), blood pressure (7) and cholesterol (8).  
Bariatric surgery (BS) has been established as a treatment option for morbidly obese patients or obese 
subjects with comorbidities such as T2DM. Bariatric surgery, besides reducing body weight, has been 
reported to improve glycaemic control in patients with T2DM and importantly to reduce cardiovascular 
events and overall mortality in obese subjects (9-12). 
Interestingly, the degree of improvement in hyperglycaemia or reductions in rates of cardiovascular 
events or mortality do not appear to be directly associated with the amount of weight loss, suggesting 
a role for other mechanisms (11-13). 
A crucial observation is that glycaemic improvement occurs rapidly, within the first weeks after BS, and 
cannot be explained by the relatively small weight loss seen during this short time period. These 
beneficial glycaemic changes after bypass procedures have been attributed to changes in incretin 
levels and other gut hormones (14). The more rapid stimulation of the distal ileum following operative 
exclusion of the duodenum and the proximal jejunum has been suggested as an explanation for the 
hormone changes observed (15). However, the definitive mechanisms leading to the rapid 
improvement in glycaemia or even remission of diabetes after BS have yet to be clarified.  
Though, surgical interventions are irreversible and not free of complications. In some cases they 
require re-surgery or endoscopic procedures to correct problems such as fistulas etc. have to be 
performed (16). Additionally, operative therapies are not suitable for all obese patients or are not well 
accepted by all operative candidates. 

 
Version 1.9                                                                                                                                             Page 7 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
Recently a duodenal-jejunal bypass sleeve (EndoBarrierTM Gastrointestinal Liner; GI Dynamics, Inc., 
Lexington, MA, USA) has been introduced. The EndoBarrierTM is a 60 cm long impermeable 
fluoropolymer sleeve-like device that is placed endoscopically via the mouth and anchored in the 
duodenum to create a duodenal-jejunal bypass for up to 12 months. It allows transit of chyme from the 
stomach through to the jejunum without any contact with the duodenal wall. By not allowing mixing 
with bile and pancreatic exocrine secretions in the proximal jejunum, it mimics a duodenal-jejunal 
bypass and therefore induces weight loss.  
A number of small studies have demonstrated the feasibility of implanting this device with subsequent 
weight reduction (17-19). In obese T2DM subjects a significant improvement in glycaemic parameters 
after EndoBarrierTM implantation has been observed (20) and a small randomised one-year study in 18 
T2DM subjects with sham endoscopy as the comparator, demonstrated superiority of the liner in terms 
of glycaemic control compared to routine diabetes treatment (21). A recent small pilot study suggested 
that the implantation of the bypass device enhances secretion of incretin hormones such as glucagon-
like peptide 1 (GLP-1), which might explain the improvement in glycaemic parameters observed. (22)  
The potential advantages of the EndoBarrierTM are that it is minimally invasive, can be inserted and 
removed endoscopically as an out-patient procedure under conscious sedation, and the putative costs 
are lower than with BS. However, long-term efficacy and safety data on a large number of patients 
implanted with the EndoBarrierTM are lacking. 
In addition, the detailed mechanisms of improved metabolic control induced by the EndoBarrierTM 
device as well as the impact on gut peptides or gut microbiota are largely unknown. As changes in gut 
microbiota have been suggested to be associated with changes in gut permeability, subsequent low-
grade chronic inflammation and insulin resistance as well as glycaemia (23), the impact of this device 
on gut microbiome composition needs to be further elucidated, as it is very likely that it impacts gut 
microflora. Moreover, although an effect on glucose control and incretin levels was shown after the 
EndoBarrierTM implantation, data on sustainability of these effects after removal of the device are not 
yet available.  
5. 
AIMS OF THE STUDY 
The aim of the study is to explore short and longer-term effects of the EndoBarrierTM implantation on 
insulin resistance and beta-cell function assessed by repeated Botnia clamps. In addition we will 
determine the changes in gut peptides and gut permeability after implantation of a removable 
duodeno-jejunal bypass device in obese subjects with sub-optimally controlled type 2 diabetes. Further 
we aim to investigate the changes in body weight and body composition and the change in global 
cardiovascular risk from baseline to 9 months, estimated using the UKPDS risk engine. 

 
Version 1.9                                                                                                                                             Page 8 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
6. 
OBJECTIVES 
6.1 
Primary objective 
Comparison of the changes in insulin sensitivity and beta-cell function following EndoBarrierTM 
implantation in patients with type 2 diabetes and suboptimal glycaemic control and a BMI between 30 
and 49kg/m2. 
6.2 
Secondary objectives 
- 
To assess the beta cell insulin response to oral and intravenous glucose loads early (4 weeks) 
and 9 months after EndoBarrierTM implantation as well as 6 months after removal of the 
duodeno-jejunal bypass device. 
- 
To assess changes in body weight from baseline to 9 and 15 months, respectively. 
- 
To determine changes in gut permeability and gut microbiota from baseline to 9 and 15 
months, respectively. 
- 
To investigate changes in incretin hormone levels during the meal tolerance test (MTT) from 
baseline to 9 and 15 months, respectively. 
- 
To evaluate changes in area under curve (AUC) of glucose from baseline to 9 and 15 months, 
respectively. 
- 
To assess changes in body composition assessed by dual energy x-ray absorptiometry (DEXA) 
from baseline to 9 and 15 months, respectively. 
- 
To evaluate correlations between MTT and Botnia clamp results regarding insulin sensitivity 
and beta-cell function 
- 
To determine changes in cardiovascular risk as assessed by the UKPDS risk engine from 
baseline to 9 months and 15 months, respectively. 
 
7. OUTCOMES 
7.1  Primary outcome measures 
- Acute insulin response to glucose during IVGTT will be used as a primary variable characterizing 
the beta cell function. Insulinogenic index (IGI), the early insulin response (EIR) and the ratio of 
AUC for C-peptide divided by AUC for glucose (AUCCP/AUCGLU) will be calculated. 
7.2  Secondary outcome measures 
- Plasma concentrations of incretins (GLP-1 and GIP) and its time profiles during MTT 
- OGTT calculations and modelling describing beta cell response to oral glucose load; insulin and 
c-peptide areas under the curve during OGTT 

 
Version 1.9                                                                                                                                             Page 9 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
- Change in gut permeability (Lactulose/Mannitol Test) 
- Weight loss will be reported as percentage of excess body weight loss (%EBWL) 4 and 36 weeks 
after EndoBarrierTM implantation as well as 6 months after removal of the EndoBarrierTM 
- Changes in cardiovascular risks (non-fatal and fatal coronary heart disease, fatal coronary 
disease, non-fatal and fatal stroke as well as fatal stroke)  
- Changes in gut microbiota 
 
8. 
STUDY DESIGN 
This is an open, single-centre, prospective, single-arm pilot study evaluating the effect of EndoBarrierTM 
implantation on insulin sensitivity and beta-cell function in obese patients with type 2 diabetes. 12 
subjects will be included in this pilot trial. The investigations will be performed at Medical University of 
Graz, Department of Internal Medicine, Division of Endocrinology and Metabolism and Division of 
Gastroenterology and Hepatology.  
At baseline all subjects will undergo Dual-energy X-ray absorptiometry (DEXA) measurement, Botnia 
clamp, blood sampling as well as a meal tolerance test (MTT) and a Lactulose/Mannitol test to 
determine gut permeability. 4 Weeks, 36 weeks as well as 62 weeks after EndoBarrierTM implantation 
all subjects will undergo the above-named tests and investigations, again. Additionally at the baseline 
visit as well as after one year, tissue samples and intestinal content will be collected endoscopically. 
This pilot trial limited in size and scope will give us insight into the actions, efficacy and safety of the 
EndoBarrierTM.  The results of this pilot trial will help us in calculating the sample size for a further 
planned trial comparing the EndoBarrierTM against other established weight loss interventions. 
8.1  Duration of Study 
It is anticipated that the study will run for 30 months (from first patient first visit until last patient last 
visit). 
8.2  Source Data 
Source documents comprise the CRF and hospital records, laboratory records and correspondence. 
All documents will be stored safely in a confidential manner.  The subject will be referred to by a 
unique study subject number/code, their initials and date of birth on all study-specific documentations. 
The only exceptions will be the signed Consent Forms, Subject Identification log and subject clinical file, 
all of which will be stored securely by the clinical site.  
Source data will be made available for internal and external audits or inspections by regulatory 
authorities to authorised personnel only. 

 
Version 1.9                                                                                                                                             Page 10 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
9. SELECTION AND WITHDRAWAL OF STUDY SUBJECTS 
9.1  Subject Selection and Recruitment 
The study population will consist of 12 subjects with type 2 diabetes mellitus and a BMI between 30 
and 49kg/m2. Patients will be identified from the outpatient clinic at the Department of Endocrinology 
and Metabolism, via Primary Care and adverts. 
9.2  Inclusion Criteria 
 
Participant is willing and able to give informed consent for participation in the study. 
 
Male or female, aged 18 - 70 years. 
 
Type 2 diabetes  
 
BMI 30-49 kg/m² 
 
HbA1c ≥ 6.5% (48 mmol/mol) 
 
Appropriate life style intervention measures have been tried but have failed to achieve or 
maintain adequate, clinically beneficial weight loss for at least 6 months 
 
Person is generally fit for intervention  
 
Person commits to the need for long-term follow-up 
9.3  Exclusion Criteria 
 
Type 1 diabetes mellitus 
 
Maturity Onset Diabetes of the Young (MODY) 
 
Secondary diabetes due to a specific disease or glucocorticoid therapy 
 
Pregnancy or women of childbearing age without adequate contraception 
 
Women who are breast-feeding 
 
Hypothalamic cause of obesity, Cushing syndrome 
 
Major psychiatric disease including diagnosed eating disorders, history of drug or alcohol abuse 
 
History of bariatric surgery or complex abdominal surgery 
 
Inflammatory bowel disease 
 
Pancreatitis 
 
Cholelithiasis 
 
Uncontrolled gastroesophageal reflux 
 
Known upper GI bleeding conditions, e.g. gastric or esophageal varices 
 
Congenital or acquired abnormalities of the upper GI tract, e.g. stenosis 

 
Version 1.9                                                                                                                                             Page 11 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
Subjects with or a history of coagulopathy, upper gastro-intestinal bleeding conditions such as 
esophageal or gastric varices, congenital or acquired intestinal telangiectasia 
 
Chronic non-steroidal anti-inflammatory drug (NSAID)  or aspirin treatment (Subjects unable to 
discontinue NSAIDs (non-steroidal anti-inflammatory drugs) during the implant period) 
 
Previous GI surgery that could affect the ability to place the device or the function of the 
implant 
 
GLP-1 receptor agonist therapy  
 
Known ischaemic heart disease or heart failure 
 
History of stroke 
 
Active Helicobacter pylori (Note: Subjects may be enrolled if they had a prior history of 
Helicobacter Pylori and were successfully treated) 
 
Actual iron deficiency anemia 
 
Subjects or Family history of a known diagnosis or pre-existing symptoms of systemic lupus 
erythematosus, scleroderma or other autoimmune connective tissue disorder 
 
Known malignancy or any other multimorbid patient condition or circumstance, which, in the 
opinion of the investigator, would affect the patient’s ability to participate in the protocol or 
would put the participant at an unjustified risk 
9.4  Withdrawal/Drop out of subjects 
Each subject has the right to withdraw from the study at any time without prejudice or 
compromise to future care.  
The investigator may discontinue or withdraw the subjects under the following circumstances: 
 
Significant protocol deviation 
 
Significant non-compliance with treatment regime or study procedures 
 
An adverse event that requires discontinuation of the study medication or results in inability to 
continue to comply with study procedures. If a subject is withdrawn due to an adverse event, 
the investigator will arrange for follow-up visits or telephone calls until the adverse event has 
resolved or stabilised. 
 
Consent withdrawn 
 
Lost to follow up 
 
The study will be stopped prematurely if any information relating to the IMP or any other 
aspect of the study arises that may cause harm to the participant. 
 
Any other situation that may, in the opinion of the investigator, make it unsafe or 
inappropriate for the subject to continue in the trial 

 
Version 1.9                                                                                                                                             Page 12 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
9.5  Payment to subjects 
Reimbursement of reasonable travel expenses will be considered.   
9.6  End of study 
The study end is defined as the last visit of the last patient. In the case of new data suggesting a 
significant safety concern of the device under investigation, the trial will be prematurely stopped. 

 
Version 1.9                                                                                                                                             Page 13 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
10  STUDY PROCEDURES  
10.1  Schedule of study procedures 
 
Screening 
Baseline 
Follow-up 
 
V1 
(1-14day before V2) 
V2 
V3 
(up to 3 
days after 
V2) 
V4 
(up to 3 
days after 
V2) 
V5 
(4 weeks  ±  
2 week after 
V4) 
V6 
(up to 3 days 
after V5) 
V7 
(36 weeks ± 
3 weeks) 
V8 
(up to 1 week 
after V7) 
V9 
(62 weeks ± 
3 weeks) 
V10 
(up to 1 week 
after V9) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demography, medical 
history 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
 
 
X 
 
X 
 
X 
 
Vital signs 
X 
X 
 
 
X 
 
X 
 
X 
 
Physical examination 
X 
X 
 
 
X 
 
X 
 
X 
 
Pregnancy test (females 
with childbearing potential) 
X 
X 
 
 
X 
 
X 
 
X 
 
Botnia clamp 
 
X 
 
 
X 
 
X 
 
X 
 
Blood sampling  
X 
 
X 
 
 
X 
 
X 
 
X 
Dual-energy X-ray 
absorptiometry (DEXA) 
 
X 
 
 
X 
 
X 
 
X 
 
Electrocardiography (ECG) 
X 
 
 
 
 
 
 
 
 
 
Meal tolerance test (MTT) 
 
 
X 
 
 
X 
 
X 
 
X 
13C-Urea breath test 
X 
 
 
 
 
 
 
 
 
 
Bypass liner insertion 
 
 
 
X 
 
 
 
 
 
 
Bypass liner removal 
 
 
 
 
 
 
X 
 
 
 
Food frequency 
questionnaire (FFQ) 
 
X 
 
 
X 
 
X 
 
X 
 
Biopsies 
 
 
 
X 
 
 
X 
 
 
 
Adverse Events 
 
 
X 
X 
X 
 
X 
 
X 
 
Stool sampling 
 
 
X 
 
 
X 
 
X 
 
X 
Lactulose/Mannitol Test  
 
 
X 
 
 
X 
 
X 
 
X 
Gastroscopy 
Abdomen Sonography 
Liver Elastography 
 
x 
 
 
 
 
 
 
 
 
 
 

 
Version 1.9                                                                                                                                             Page 14 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
10.2   Visit Schedule 
Visit 1 Screening (14 to 1 day(s) prior to potential enrolment) 
Severely obese patients with T2DM are eligible to participate in our study. Those who accomplish the 
inclusion criteria and none of the exclusion criteria will be enrolled in the trial and submitted to the 
following investigation procedures in the screening visit, after signing the informed consent: 
 
Check inclusion and exclusion criteria 
 
Check for demographic data, medical and surgical history and concomitant medication  
 
Date of birth, gender, race, smoking status, alcohol consumption,  
 
Body weight and body height 
 
Vital signs: resting pulse and blood pressure   
 
Blood sample for HbA1c 
 
Baseline safety blood tests (fasting): Full blood cell count, renal function tests, liver function 
tests 
 
Physical examination 
 
Pregnancy test in female woman of childbearing age. 
 
13C-urea breath test 
 
 
Visit 2 Baseline  
In the morning of the second study visit (V2) the subjects will arrive at the Division of Endocrinology 
and Metabolism between 07:00 and 08:00 AM of the pre-scheduled day, after at least 8 hours fasting.  
During V2, the Botnia-Clamp (testing procedure combining intravenous glucose tolerance test [IVGTT] 
and hyperinsulinemic-euglycaemic clamp [HEC]) will be performed.  
If blood recent blood values (within 6 weeks) are available to confirm the eligibility of a subject at the 
screening visit, visit 2 may also be performed together with the screening procedures. 
As part of this visit the following procedures will be performed: 
 
Review inclusion and exclusion criteria 
 
Vital signs: resting pulse and blood pressure   
 
Body weight 
 
Physical examination 
 
Concomitant medication review 
 
Botnia clamp 
 
DEXA 
 
Urinary pregnancy test in female woman of childbearing age 
 
Gastroscopy 
 
Abdomen Sonography and Liver elastography 
 
Diet instructions. 
Visit 3 Baseline (up to 3 days after V2) 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
Study visit 3 will take place not later than 3 days after V2.  
The subjects will arrive at the Division of Endocrinology and Metabolism after an overnight fast (at 
least 8 hours). Meal tolerance test (MTT) will be performed at V3.  
Additionally, at Visit 3 subjects will be instructed by a qualified person to consume a liquid diet the first 
week after EndoBarrierTM placement, puree diet during the second week, and normal diet (1200 – 1500 
kcal/day) combined with exercise and behaviour modification for the remainder of the implant 
duration. Participants will also be instructed to take a proton pump inhibitor (40mg BID omeprazole) 
starting 3 days before the implant through 2 weeks after explant. Daily multivitamin and iron 
supplements will be provided and recommended for use during the 52 weeks of the implant duration.  
 
Meal tolerance test 
 
Blood sampling 
 
Stool sampling 
 
Lactulose/Mannitol Test 
 
Visit 4 (Implantation of EndoBarrierTM) 
Patient preparation 
1. Patients must be fasting for 8 hours prior to the procedure. 
2. Patients must be started on a Proton Pump Inhibitor (40mg twice a day) three days before the 
procedure and continue regimen until two weeks after the device is removed. 
3. Spasmolytics may be used. 
Sedation 
4. The procedure will be performed under conscious sedation. 
Procedural Step 
5.    Insertion will be performed according to manufacturer instructions 
 
Visit 5 (week 4 ± 2 week) 
Study visit 5 will take place not later than six weeks after the implantation of the EndoBarrierTM.  
 
Physical examination 
 
Vital signs: resting pulse and blood pressure   
 
Body weight 
 
Concomitant medication review 
 
Botnia clamp 
 
DEXA 
 
Adverse events assessment 

 
Version 1.9                                                                                                                                             Page 16 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
Pregnancy Test 
 
Visit 6 (up to 3 days after V5)  
Study visit 6 will take place not later than 3 days after V5.  
 
Meal tolerance test 
 
Stool sampling 
 
Blood sampling 
 
Lactulose/Mannitol Test 
 
Visit 7 (36 weeks ± 3 weeks)  
Study visit 5 will take place not later than 39 weeks after the implantation of the EndoBarrierTM. At this 
visit the sleeve will be removed. 
 
Vital signs: resting pulse and blood pressure   
 
Body weight 
 
Concomitant medication review 
 
DEXA 
 
Adverse events assessment 
 
Biospies 
 
Botnia clamp 
 
Visit 8 (up to 1 week after V7) 
Study visit 8 will take place not later than 1 week after V7.  
 
Vital signs: resting pulse and blood pressure   
 
Body weight 
 
Concomitant medication review 
 
Adverse events assessment 
 
Meal tolerance test 
 
Stool sampling 
 
Blood sampling 
 
Lactulose/Mannitol Test 
 
Visit 9 (62 weeks ± 3 weeks) 
Study visit 9 will take place not later than 29 weeks after the removal of the EndoBarrierTM.  
 
Physical examination 

 
Version 1.9                                                                                                                                             Page 17 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
Vital signs: resting pulse and blood pressure   
 
Body weight 
 
Concomitant medication review 
 
Botnia clamp 
 
DEXA 
 
Adverse events assessment 
 
Pregnancy Test 
 
Visit 10 (up to 1 week after V9) 
Study visit 8 will take place not later than 1 week after V9.  
 
Meal tolerance test 
 
Stool sampling 
 
Blood sampling 
 
Lactulose/Mannitol Test 
 
Study end 
 
Safety visits (after 12, 24 and 48 weeks) 
12, 24 and 48 weeks after implantation safety visits will be carried out. As part of these visits blood 
samples (8ml) will be taken for safety measurements (including blood cell count, iron status, liver 
function). Additionally, the body weight will be recorded. 
 
10.3  Laboratory results 
All laboratory results will be reviewed and the reports signed by the study physician who will record 
whether it is normal, abnormal but not clinically significant, or abnormal and clinically significant. In the 
latter case, the eligibility of the subject will be reviewed. 
 
 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
11  METHODS 
11.1  Meal Tolerance Test (MTT)  
The MTT will be performed after an overnight fast (apart from water). A standard gauge cannula will be 
placed into a subcutaneous vein for blood sampling. In order to prevent blood clotting in the cannula 
and to keep the cannula working it will be occasionally flushed with sterile normal saline. A pre-meal 
blood sample will be taken (- 5mins) and then all subjects will be asked to drink Fortimel compact (10 
kcal/kg) over a period of 2-4 mins (time 0 mins). During the meal test further blood samples will be 
taken at 15, 30, 60, and 120 minutes.  All samples will be used for determination of glucose and insulin.  
The blood at each time point will be placed into a fluoride oxalate tube (1ml) for plasma glucose and 
into a serum tube for insulin. 
11.2  Botnia clamp (combined IVGTT and hyperinsulinaemic-euglycaemic clamp) 
The Botnia clamp is a validated design for assessment of beta cell function and insulin sensitivity (24). 
After an overnight fast of at least 8 hours and after baseline samples have been obtained, 0.3 g/kg 
bodyweight of 20% glucose solution will be given at time 0 min. Blood samples for the measurement of 
plasma glucose, insulin and C-peptide will be obtained at -10, 0, 2, 4, 6, 8, 10, 20, 30, 40, 50 and 60min. 
At 60 min after the glucose bolus, hyperinsulinaemic-euglycaemic clamp will be started to evaluate 
insulin sensitivity. A priming dose insulin (3IU/m2) followed by an infusion (40mU/m2/min) of short-
acting human insulin will be applied for 120 min. Blood glucose will be clamped at the concentration of 
5.0 ± 0.5 mmol/l by a variable infusion of 20% glucose. Blood samples for measurement of plasma 
glucose concentrations will be obtained at 5 min interval, for measurement of insulin concentrations in 
30 min intervals throughout the clamp. The mean amount of glucose infused during the last 60 min of 
euglycaemic clamp will be used to calculate the rate of whole-body glucose uptake. 
11.3  Blood sampling  
Glucose concentration in arterialized blood samples will be measured in duplicate, by using two Hitado 
Super GL (Hitado, Möhnesee, Germany). Insulin and C-peptide will be measured by using routinely 
available chemiluminescence on an ADVIA Centaur system (Siemens Healthcare Diagnostics, Eschborn, 
Germany). Routine parameters will be determined using a cobas analyzer (Roche Diagnostics, 
Mannheim, Germany). Plasma aliquots are prepared immediately after blood collection and stored at -
80°C until batch analysis. 20 ml of serum and plasma respectively will be taken and stored at visits 3, 6, 
8 and 10 for future biomarker analyses. 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
11.4  GLP-1 and GIP analysis 
Blood samples will be collected into pre-chilled tubes containing EDTA plus aprotoinin. After 
centrifugation plasma samples will be frozen at -80°C until analysis. For the determination of human 
active GIP a commercially available solid-phase sandwich ELISA Kit is used (GIP (active) ELISA; IBL 
International GmbH, Hamburg, Germany). The test is performed according the instructions provided by 
the distributor. Briefly, the coated plates are incubated with standards and samples. After that, 
incubation with labelled antibody is done followed by incubation with substrate solution. Reaction is 
stopped by addition of stop solution. After that, measurement is performed at 450nm in a Spectramax 
Plus 384 Microplate Spectrophotometer in combination with Spectramax Pro 4.6 software (Molecular 
devices, Ismaning, Germany). 
11.5  Dual-energy X-ray absorptiometry (DEXA) 
DEXA measurement will be performed with a GE Lunar iDEXA (GE Healthcare, Waukesha, WI, US) full 
size for the purpose of estimating percentage body fat according to the departmental Standard 
Operating Procedure. Body regions are defined using standard anatomical partitions. Scan areas are 
analysed to determine lean mass, fat mass, bone mineral content, and total body fluid percentage. 
11.6  Gut microbiota analysis 
Based on our previous studies the intestinal microbiota of the small intestine is not represented by the 
composition of the microbiota of stool samples. To study effects on the small intestine it is therefore 
mandatory to study samples obtained from the GI-tract.   
Tissue samples and intestinal content will be collected endoscopically from the upper small intestine 
(duodenum) in addition to stool samples before and after implantation (at the time of removal) of the 
endoscopic duodenal-jejunal bypass liner. Samples will be analyzed for the small intestinal and the 
fecal microbiota using 16S rDNA based microbial community profiling by next-generation sequencing 
(NGS). Dependent on these results in a second step whole genome shot-gun sequencing for intestinal 
metagenome analysis would be possible. Furthermore the small intestinal mucosal immune system 
and enteroendocrine cells will be assessed by immuno-phenotyping of biopsies by means of 
immunohistochemistry (IHC) and FACS analyses. 
11.7  Gut permeability (Lactulose/Mannitol Test) 
The patient drinks a solution of 200 ml water containing 5 g lactulose and 1 g mannitol. Urine is 
collected over 5 hours while fasting is continued for 3 hours after study start. The urine volume 
collected at 5 hours is measured and 1-ml aliquots are frozen immediately at -80C without 
preservative for subsequent analysis by high performance liquid chromatography. The mobile phase is 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
degassed acetonitrile in distilled deionized water (70/30 by vol) at a flow rate of 1 ml/min. Detection is 
performed by a refractive index detector (LC 1240 R.I. Detector; GBC Scientific Equipment, Dandenong, 
Australia).  
11.8  Food Frequency Questionnaire (FFQ)  
A self-administered, semi-quantitative FFQ was developed to assess usual food consumption within the 
German Health Examination Survey for Adults 2008-2011 (DEGS) (25). The relative validity of this 
questionnaire was studied among participants of another nationwide survey, the German National 
Nutrition Monitoring (NEMONIT) (26). The FFQ includes questions about the frequency and the 
amount of 53 food items, consumed during the past four weeks. Frequency of consumption of food 
items was asked according to specified categories. In addition, the respondents had to indicate the 
portion size of the food items consumed in predefined answering categories. Pictures were used to aid 
the estimation of portion size for 33 food items. In total, 29 food groups will be presented by the food 
frequency questionnaire.  
 
11.9 13C-urea breath test (13C-UBT) 
The diagnosis of helicobacter pylori infection is currently established by histological, rapid urease, and 
culture tests using endoscopic biopsy specimens or by a 13C-UBT. The latter is a non-invasive approach 
based on the potent urease activity of helicobacter pylori and many reports evaluating its clinical utility 
have been published (27). The 13C-UBT is an excellent and non-invasive method for diagnosis of 
helicobacter pylori infection in the intact stomach and it is especially useful for judging the results of 
eradication therapy  (28, 29).  
 
11.10  Markers of insulin resistance 
Serum-Aliquots will be used for untargeted analyses of signal peptides via Hot-MELT-MALDI technique 
(in co-operation with Prof. Makoto Sawada; University of Nagoya; Japan) to identify markers of insulin 
resistance. 
 
 
 
 
 
 
 

 
Version 1.9                                                                                                                                             Page 21 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
12  INVESTIGATIONAL MEDICINAL PRODUCT  
12.1 Mechanism of action 
The EndoBarrierTM works by creating a physical barrier between food and the intestinal wall. It is 
believed that this barrier alters the activation of hormonal signals that originate in the intestine. Food 
bypasses the duodenum and proximal jejunum as it does in a Roux-en-Y gastric bypass. 
 
12.2 Therapeutical indications 
The EndoBarrierTM System is indicated for the treatment of type 2 diabetes mellitus and/or obesity. 
Further, the EndoBarrierTM gastrointestinal liner is indicated for a maximum of 12 months. 
 
12.3. Pre-procedural precautions 
Patients must receive a Proton Pump Inhibitor (40 mg twice a day) 3 days prior to the procedure and 
should continue the medication until 2 weeks after the device is removed. To reduce the potential for 
infection, a single 2 gram dose of ceftriaxone should be administered intravenously 1-2 hours prior to 
device placement. Those individuals with known allergies or hypersensitivity to ceftriaxone, 
cephalosporins or penicillins should seek an equivalent, long acting, broad spectrum antibiotic. 
 
12.4. Procedural precautions 
A thorough gastroscopic examination of the stomach, pylorus and duodenum should be performed 
prior to device placement to ensure that the patient’s alimentary canal is free of abnormalities which 
could interfere with the delivery, function and removal of the gastrointestinal liner. This should include 
observation of the papilla and other accessory ducts. This examination should be made to ensure that 
they are not located in the bulbous duodenum. 
Placement and removal of the EndoBarrierTM requires the use of fluoroscopic guidance. Only water 
soluble contrast should be used. Gastrografin or equivalent is recommended. Do not use Barium. 
Caution should be used to protect the patient’s reproductive organs from the effects of radiation. 
An incorrectly positioned EndoBarrierTM may interfere with the bile duct or pylorus. Physicians should 
remove the incorrectly positioned device in these patients. Do not attempt to drag or push the device 
into position. Additionally, the EndoBarrierTM liner should be removed in any patient with clinical 
and/or chemical evidence of a biliary tract obstruction. Do not leave a device in place with a crossed 
tip. Crossed tips should be uncrossed by lifting them with endoscopic forceps. 
 

 
Version 1.9                                                                                                                                             Page 22 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
12.5. Post Procedural precautions 
It is unknown if certain foods (such as grains and nuts) could interfere with the proper functioning of 
the gastrointestinal liner. Therefore, patients receiving the device will be placed on a diet regimen 
similar to that of a Roux-en-Y gastric bypass patient. 
 
 
 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
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Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
13  ASSESSMENT OF SAFETY  
Safety endpoints: All adverse events reported by the patients will be assessed and reported as outlaid 
below. 
13.1. Definition 
An Adverse Event (AE) is defined as any untoward medical occurrence, including an exacerbation of a 
pre-existing condition, in a patient or clinical investigation subject administered a pharmaceutical 
product.  
13.2. Potential Adverse Events 
Potential complications during the placement procedure may include; 
- 
GI tract laceration 
- 
Oropharyngeal perforation 
- 
Esophageal perforation 
- 
Gastric perforation 
- 
Bowel perforation 
- 
Bleeding 
- 
Aspiration 
- 
Infection 
Potential complications during the treatment period may include: 
- 
Small bowel obstruction 
- 
Implant migration 
- 
Bezoar 
- 
Erosion 
- 
Bleeding 
- 
Vitamin and mineral deficiency 
- 
Dehydration 
- 
Constipation 
- 
Bloating 
- 
Diarrhea 
- 
Infection 
- 
Hypoglycemia 
- 
Hyperglycemia 
- 
Flatulence 

 
Version 1.9                                                                                                                                             Page 24 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
- 
GERD 
- 
Esophagitis 
- 
Pseudopolyps 
- 
Nausea/vomiting 
- 
GI pain/cramping 
- 
Peptic ulcer disease 
- 
Duodenitis 
- 
Gastric or bowel perforation 
- 
Local inflammatory tissue reaction 
- 
Flank/Back Pain 
- 
Alopecia 
Potential complications during and after device removal may include 
- 
GI tract laceration 
- 
Oropharyngeal perforation 
- 
Esophageal perforation 
- 
Gastric perforation 
- 
Bowel perforation 
- 
Bleeding 
- 
Aspiration 
- 
Adynamic ileus 
- 
Infection 
- 
Alopecia 
 
Serious Adverse Event  
A serious adverse event (SAE) is defined as any AE which: 
 
Results in death 
 
Is life-threatening 
 
Requires in-patient hospitalisation or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is considered as serious, when base upon appropriate medical judgement that may jeopardise 
the patient/subject, and may require medical or surgical intervention to prevent one of the 
other seriousness criteria from occuring. 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
Patients may be hospitalised for administrative or social reasons during the study (e.g. days on 
which infusion takes place, long distance from home to site). These and other hospitalisations 
planned at the beginning of the study do not need to be reported as a SAE in case they have been 
reported at screening visit in the source data and have been performed as planned 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information as documented above. 
According to ICH E2A all SUSARs should be reported in an expedited manner to Competent Authorities, 
Ethics Committees and investigators concerned on an individual basis within timelines. 
Regulatory timelines which have to be met are as follows: 
- 
Fatal and life-threatening AEs: 7 calendar days after receipt 
- 
Remaining serious AEs: 15 calendar days after receipt 
The Intensity/Severity of the AE should be judged based on the following: 
Mild: 
 
Awareness of sign(s) or symptom(s) which is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe:  
Incapacitating or causing inability to work or to perform usual activities 
 
Causal relationship of adverse event 
Medical judgement should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, dechallenge or rechallenge, confounding factors 
such as  concomitant medication, concomitant diseases and relevant history. Assessment of causal 
relationship should be recorded in case report forms.  
13.2 Reporting Procedure for all Adverse Events 
All Adverse events, serious and non-serious, will be collected, documented and reported on the 
appropriate CRFs/SAE reporting forms once informed consent has been signed and will end 28 days 
after completing the trial. 
The following information will be recorded:  
 
participant details 
 
adverse event description 
 
start date of event 

 
Version 1.9                                                                                                                                             Page 26 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
 
end date of event 
 
outcome of event 
 
severity of event 
 
treatment required 
 
relationship to study device (i.e. causality/relatedness) 
 
assessment of relatedness to other suspect drug or device 
 
action taken with study device 
 
whether subject withdrawn due to adverse event 
 
whether the event is serious 
 
Follow up information will be recorded as necessary 
AEs considered to be related to study medication as judged by a medically qualified investigator will be 
followed until resolution or the event is considered stable. All related AEs that result in a subject’s 
withdrawal from the study or are present at the end of the study will be followed up until a satisfactory 
resolution occurs. 
 
14  STATISTICAL CONSIDERATIONS 
14.1  Calculations  
The combination of MTT and IVGTT will allow a comprehensive assessment of different aspects of beta 
cell function along with reliable measures of insulin sensitivity assessed during the euglycaemic clamp 
procedure (30).  
From MTT data, the following empirical indices of beta cell function will be derived: a) insulinogenic 
index (IGI) calculated as (30 min insulin – basal insulin)/(30min glucose – basal glucose); b) the early 
insulin response (EIR) calculated using formula (30 min insulin – basal insulin)/(30 min glucose)(31) or 
c) ratio of AUC for C-peptide divided by AUC for glucose (AUCCP/AUCGLU). AUCs are determined by 
trapezoidal method. Additionally, we intend to implement the established mathematical modeling to 
describe distinct features of beta cell function (30, 32-34). The model describes the relationship 
between insulin secretion and glucose concentration coupled with a model of C-peptide kinetics. It 
provides not only basal insulin secretion rate and total insulin secretion during OGTT, but also three 
important indices of dynamic properties of beta cell function: beta cell sensitivity to glucose (glucose 
sensitivity), beta cell sensitivity to the rate of change of glucose (rate sensitivity) and a potentiation 
factor (representing relative potentiation of insulin secretion throughout the OGTT).     

 
Version 1.9                                                                                                                                             Page 27 of 32 
Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
Based on IVGTT measurements, the incremental trapezoidal area of insulin and C-peptide during the 
first 10 min after glucose administration represents the first-phase insulin response or acute insulin 
response (AIR). AIR will be also measured as the sum of insulin and C-peptide concentrations during 
the first 10 min after the glucose challenge. The incremental insulin/C-peptide secretion during the last 
50 min of IVGTT represents the second-phase insulin secretion. The C-peptide deconvolution will be 
applied to reconstruct insulin secretory rates independently of insulin clearance. 
It has been proved that rate sensitivity derived from OGTT is correlated to AIR calculated from IVGTT 
and it is therefore a valuable marker of first phase insulin secretion (34). AIR and rate sensitivity as well 
as insulin secretion rates are intended to be used for evaluation of beta cell insulin response to oral vs. 
intravenous glucose load. 
Insulin sensitivity will be assessed as the mean glucose uptake, calculated from the glucose infusion 
rates during the last 60 min of euglycaemic clamp (M-value) and as the ratio of glucose infusion rates 
during the last 60 min of clamp and the mean steady state insulin levels during the same interval (M/I  
= SI Index). 
14.2  Statistical analysis 
All data will be checked for distribution normality. Changes in beta cell function and other variables 
after EndoBarrierTM implantation will be assessed by analysis of variance (ANOVA) with repeated 
measures.  
Additionally, the results of this pilot will be compared to already available results from a trial with 
comparable patients after bariatric surgery. 
 
14.3  Sample size  
This study is planned as a pilot trial to gain first data about the parameter outlined in the primary and 
secondary parameter section. Currently there is not sufficient data available which would allow to 
calculate the sample size needed. However, previous pilot trials investigating measurements of glucose 
metabolism with EndoBarrier have used 10-16 subjects to demonstrate improvements.21,22 These data 
will then serve as a basis to perform adequately powered more definitive trials with this device in the 
future. 
 
15  STUDY MONITORING 
A risk-based approach will be taken to determine the frequency of study monitoring for the study 
which will be agreed with the Principal Investigator. Monitoring will be undertaken according to ICH 

 
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Division of Endocrinology and Metabolism
Cardiovascular Diabetology Research Group
Medical University of Graz
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Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
GCP and the study monitoring plan. The study monitor will be suitably trained, qualified and 
experienced to perform this task. Data will be evaluated for compliance with the protocol and accuracy 
in relation to source documents.  
 
16  ETHICS 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki, GCP-ICH and according to the protocol and the requirements of the concerned 
regulatory authorities.   
The EndoBarrierTM is indicated for the treatment of type 2 diabetes and/or obesity. The EndoBarrierTM 
gastrointestinal liner is indicated for a maximum of 12 months.  
The product is a thin tubular liner that isolates food from the digestive juices of the upper intestine. 
Although it avoids a surgical incision as required in conventional gastric by-pass surgery, an endoscopic 
procedure under sedation in hospital is still necessary to pass the liner, and later on to remove it. 
Although mostly well tolerated, patients may experience nausea, vomiting and upper abdominal pain. 
Other risks include infection and bleeding. It is contra-indicated in pregnancy. It is not a permanent 
treatment, and has to be removed after some months (mostly after 1 year). In that time it is 
anticipated that lifestyle changes will extend the duration of the improvement. 
 
16.1  Informed Consent 
1. Informed consent will be obtained for all participants in the study by the study physician. 
2. Written versions of the subject information and Informed consent will be presented to the 
subjects detailing:  
 
The exact nature of the study 
 
The implications and constraints of the protocol 
 
The known side effects and any risks involved in taking part.   
3. It will be clearly stated that the subject is free to discontinue their participation in the 
study at any time for any reason without prejudice to future care, and with no obligation 
to give the reason for withdrawal. 
4. The subject will be allowed as much time as wished to consider the information, and the 
opportunity to question the Investigator, their usual care provider or other independent 
parties to decide whether they will participate in the study.  Written Informed Consent 
will then be obtained by means of subject dated signature and dated signature of the 
person who presented and obtained the informed consent.  

 
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Division of Endocrinology and Metabolism
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Fax: ++43 (0) 316 385 14332
5. A copy of the signed Informed Consent will be given to the subjects. The original signed 
form will be retained at the study site. 
16.2 Ethical and Regulatory Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to the Ethics Committee of the Medical University of Graz, Austria.   
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents.  
 
17. FINANCE 
A research grant application has been submitted to the Austrian Nationalbank. 
 
18. INSURANCE 
Participant insurance according to legal requirements will be contracted. 
 
19. RESPONSIBILITIES 
The Principal Investigator is accountable for the conduct of the study. If any responsibilities are 
delegated, the Principal Investigator should maintain a list of appropriately qualified persons to whom 
he/she delegated specified significant study-related duties. 

 
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Division of Endocrinology and Metabolism
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Medical University of Graz
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20. 
REFERENCES 
1. 
(WHO) WHO. Obesity and overweight Geneva: World Health Organisation; 2006 [updated 
22.08.2013]. Available from: http://www.who.int/mediacentre/factsheets/fs311/en/index.html. 
2. 
(OECD) OfEC-oaD. Fit not fat - Austria key facts 2010 [updated 22.08.2013]. Available from: 
http://www.oecd.org/austria/obesityandtheeconomicsofpreventionfitnotfat-austriakeyfacts.htm. 
3. 
Stern MP, Haffner SM. Body fat distribution and hyperinsulinemia as risk factors for diabetes 
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Cardiovascular Diabetology Research Group
Medical University of Graz
Auenbruggerplatz 15
Tel: ++43 (0) 316 385 13270
Fax: ++43 (0) 316 385 14332
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