A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Assessing the Effect of Gelesis100 on Body Weight in Overweight and Obese Subjects With and Without Type 2 Diabetes
Phase: NA
Conditions: Overweight, Obesity
Sponsor: Gelesis, Inc.

Protocol Number: G-04 (Version: 5.0; Version Date: August 24, 2016) 
Gelesis, Srl. 
Product: Gelesis100 
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CLINICAL INVESTIGATION PLAN 
(PROTOCOL) 
 
 
PRODUCT: Gelesis100 
 
 
TITLE: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study Assessing the Effect of Gelesis100 on Body Weight in Overweight 
and Obese Subjects with and without Type 2 Diabetes 
 
STUDY NAME: GLOW (Gelesis Loss Of Weight) 
 
 
 
 
 
 
PROTOCOL NUMBER: G-04 
 
VERSION: 5.0 (Post-Amendment 4) 
 
VERSION DATE: August 24, 2016 (Final) 
 
 
 
 
 
 
 
Not For Distribution – Do Not Copy 
This document is confidential and is to be distributed for review only to 
investigators, study staff, and applicable independent ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to 
others without written authorization from Gelesis, Srl., unless it is necessary to 
obtain informed consent from potential study participants. 
 
 

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Product: Gelesis100 
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SPONSOR/MANUFACTURER Name: Gelesis, Srl. 
 
Address: Via Verdi, 188 
73021 Calimera (LE) 
Italy 
 
Phone: +39 0832 872 749 
Fax: +39 0802 121 708 
Signature (Yishai Zohar):  
 
 
 
 
SPONSOR’S TRIAL 
MONITOR 
Name: Hassan M. Heshmati, M.D. 
 
Address: Gelesis, Srl. 
501 Boylston Street, Suite 6102 
Boston, MA 02116 
USA 
 
Phone: +1 215 275-1275 
Fax: +1 617 249-1570 
E-mail: hheshmati@gelesis.com 
Signature:  
                
 
 
 
EMERGENCY CONTACT 
Name: Hassan M. Heshmati, M.D. 
 
Address: Gelesis, Srl. 
501 Boylston Street, Suite 6102 
Boston, MA 02116 
USA 
 
Phone: +1 215 275-1275 
Fax: +1 617 249-1570 
E-mail: hheshmati@gelesis.com 
 
 
 

Protocol Number: G-04 (Version: 5.0; Version Date: August 24, 2016) 
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Product: Gelesis100 
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PRINCIPAL/COORDINATING 
INVESTIGATOR 
 
EMERGENCY CONTACT 
BACKUP 
Name: Frank L. Greenway, M.D. 
 
Address: Pennington Biomedical Research 
Center 
6400 Perkins Road 
Baton Rouge, LA 70808 
USA 
 
Phone: +1 225 763-2578 
Fax: +1 225 763-3022 
E-mail: frank.greenway@pbrc.edu 
Signature:  
 
 
 
 
 
 

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CHANGES 
 
Replacement: 
- 
Page 3 (Principal/Coordinator Investigator) 
 
Addition: 
- 
Section 1 (Body weight criteria, Interim analysis) 
- 
Section 2 (Serum amylase, Genomic tests, Procedures for extension study) 
- 
Section 4 (AMY1, BDNF, CAPN10, CP, FTO, KCNJ11, LEPR, MC4R, NEGR1, 
NPC1, PCSK1, PPARG, SH2B1, SLC16A13, TCF7L2) 
- 
Section 5.2 (Details on hydration of Gelesis100) 
- 
Section 7 (Description of extension study) 
- 
Section 8.1 (Serum lipids) 
- 
Section 8.3 (Body weight criteria) 
- 
Section 11.3 (Physical activity) 
- 
Section 11.3.2.1 (Serum amylase, Genomic tests) 
- 
Section 12.1 (Scheduling of Visit 2 and Visit 13) 
- 
Section 12.2.1 (Serum amylase, Genomic tests) 
- 
Section 12.2.12 (Informed consent related to extension study) 
- 
Section 12.2.13 (Randomization related to extension study, Visit status related to 
extension study) 
- 
Section 15.5.4 (Interim analysis, Management of SADE) 
- 
Section 15.5.4.1 (Unblinding for interim analysis) 
- 
Section 15.5.4.2 (Unblinding for management of SADE) 
- 
Section 15.6 (Interim analysis) 
- 
Section 15.7.5 (Serum amylase, Genomic tests) 
- 
Section 26 (References) 
 
Deletion: 
- 
Section 4 (Ltd., s.r.o.) 
- 
Section 8.2 (Competitive enrollment) 
- 
Section 9.2.1 (Medication for chronic disease) 
 
Clarification and Optimization: 
- 
Section 9.1 (11 mg) 
- 
Section 11.3.1.7 (Mild binge eater) 
- 
Section 13.1.3 (Health Canada) 
- 
Section 13.3.2 (Health Canada) 
- 
Section 14.2.1 (Stopping rules, Interim analysis) 
- 
Section 15.3 (Study endpoints) 
- 
Section 15.4 (Sample size determination) 
- 
Section 15.7 (Statistics) 
- 
Section 15.7.1.1 (ITT population) 
- 
Section 15.8 (Statistics) 
- 
Section 15.8.6.1 (Study endpoints) 

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- 
Section 15.8.6.3 (Statistics) 
- 
Section 17.2 (Informed Consent Form) 
- 
Section 18.7 (Financial arrangements) 
- 
Section 20 (Protocol deviations) 
- 
Section 25 (Audit by Sponsor) 
 
Correction: 
- 
Section 9.1.9 (Detailed) 
- 
Section 15.7.3 (Biased) 
 
 
 

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TABLE OF CONTENTS 
 
1. CLINICAL TRIAL SUMMARY .............................................................................. 11 
2. STUDY FLOW CHART ............................................................................................ 18 
3. CLINICAL INVESTIGATION PLAN APPROVAL .............................................. 19 
4. ABBREVIATIONS ..................................................................................................... 20 
5. INTRODUCTION AND RATIONALE .................................................................... 22 
5.1 Disease Background ..............................................................................................................................22 
5.2 Investigational Product .........................................................................................................................23 
5.2.1 Clinical Data ....................................................................................................................................24 
5.3 Rationale.................................................................................................................................................30 
6. OBJECTIVES ............................................................................................................. 30 
6.1 Primary...................................................................................................................................................31 
6.2 Secondary ...............................................................................................................................................31 
7. DESIGN ....................................................................................................................... 31 
8. POPULATION ............................................................................................................ 31 
8.1 Number of Subjects ...............................................................................................................................32 
8.2 Countries and Sites ................................................................................................................................32 
8.3 Inclusion Criteria...................................................................................................................................32 
8.4 Exclusion Criteria ..................................................................................................................................33 
9. TREATMENT ............................................................................................................. 34 
9.1 Investigational Product .........................................................................................................................34 
9.1.1 Selection of Gelesis100 Amount .....................................................................................................35 
9.1.2 Selection of Placebo ........................................................................................................................35 
9.1.3 Packaging and Labeling ...................................................................................................................35 
9.1.4 Responsibilities ................................................................................................................................35 
9.1.5 Storage Conditions ...........................................................................................................................36 

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9.1.6 Administration Method ....................................................................................................................36 
9.1.7 Treatment of Overdose ....................................................................................................................36 
9.1.8 Compliance Assessment ..................................................................................................................36 
9.1.9 Retrieval and/or Destruction ............................................................................................................36 
9.2 Concomitant Medication .......................................................................................................................37 
9.2.1 Prohibited Medication......................................................................................................................37 
9.2.2 Permitted Medication .......................................................................................................................37 
9.3. Diet and Life-Style Recommendations ................................................................................................38 
9.3.1 Diet ..................................................................................................................................................38 
9.3.2 Life-Style .........................................................................................................................................38 
10. STUDY DURATION ................................................................................................ 39 
10.1 Study Duration per Subject ................................................................................................................39 
10.1.1 Screening Period ............................................................................................................................39 
10.1.2 Baseline Period ..............................................................................................................................39 
10.1.3 Treatment Period ...........................................................................................................................39 
10.1.4 Post-Treatment Follow-up Period ..................................................................................................39 
10.2. Total Study Duration .........................................................................................................................39 
11. STUDY ENDPOINTS ............................................................................................... 39 
11.1 Effectiveness Endpoints ......................................................................................................................39 
11.1.1 Co-Primary Endpoints ...................................................................................................................39 
11.1.2 Secondary Endpoints .....................................................................................................................40 
11.1.3 Tertiary Endpoints .........................................................................................................................40 
11.2 Safety Endpoints ..................................................................................................................................40 
11.2.1 Adverse Events ..............................................................................................................................40 
11.2.2 Physical Examination ....................................................................................................................40 
11.2.3 Vital Signs .....................................................................................................................................41 
11.2.4 Laboratory Tests ............................................................................................................................41 
11.3 Assessment Methods ............................................................................................................................41 
11.3.1 Clinical ...........................................................................................................................................41 
11.3.2 Biological .......................................................................................................................................44 
12. VISITS ....................................................................................................................... 44 
12.1 Schedule ................................................................................................................................................44 
12.2 Assessments ..........................................................................................................................................45 
12.2.1 Visit 1 (Screening Visit; Day -21 to -1) .........................................................................................45 
12.2.2 Visit 2 (Baseline Visit; Day 0) .......................................................................................................45 
12.2.3 Visit 3 (First Double-Blind Visit; Day 8 ± 2) ................................................................................46 
12.2.4 Visit 4 (Second Double-Blind Visit; Day 15 ± 2) ..........................................................................46 
12.2.5 Visit 5 (Third Double-Blind Visit; Day 29 ± 2) .............................................................................47 
12.2.6 Visit 6 (Fourth Double-Blind Visit; Day 43 ± 2) ...........................................................................47 
12.2.7 Visit 7 (Fifth Double-Blind Visit; Day 57 ± 2) ..............................................................................47 

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12.2.8 Visit 8 (Sixth Double-Blind Visit; Day 71 ± 2) .............................................................................47 
12.2.9 Visit 9 (Seventh Double-Blind Visit; Day 85 ± 2) .........................................................................48 
12.2.10 Visit 10 (Eighth Double-Blind Visit; Day 113 ± 3) .....................................................................48 
12.2.11 Visit 11 (Ninth Double-Blind Visit; Day 141 ± 3) ......................................................................49 
12.2.12 Visit 12 (Tenth Double-Blind Visit; Day 169 ± 3) ......................................................................49 
12.2.13 Visit 13 (First Follow-up Visit; Day 171; 2 days after Visit 12) (Last visit if entering extension 
study) ........................................................................................................................................................49 
12.2.14 Visit 14 (Second Follow-up Visit; Day 197 ± 3) .........................................................................50 
12.3 Definition of Source Data ....................................................................................................................50 
13. SAFETY MONITORING AND REPORTING ..................................................... 50 
13.1 Adverse Event and Device Deficiency ................................................................................................50 
13.1.1 Investigational Product in this Clinical Study ................................................................................50 
13.1.2 Definitions .....................................................................................................................................50 
13.1.3 Adverse Event and Device Deficiency Recording, Assessment, and Reporting Procedure ..........51 
13.1.4 Anticipated Adverse Device Effects ..............................................................................................52 
13.1.5 Risk Analysis .................................................................................................................................53 
13.1.6 Precautions to Minimize Risk ........................................................................................................53 
13.2 Pregnancy .............................................................................................................................................53 
13.3 Responsibilities for Adverse Event and Pregnancy Reporting ........................................................53 
13.3.1 Responsibilities of the Investigator ................................................................................................53 
13.3.2 Responsibilities of the Sponsor ......................................................................................................54 
14. TREATMENT/STUDY DISCONTINUATION .................................................... 54 
14.1 Temporary Treatment Discontinuation.............................................................................................54 
14.2 Permanent Treatment/Study Discontinuation ..................................................................................54 
14.2.1 Reasons ..........................................................................................................................................54 
14.2.2 Procedures......................................................................................................................................55 
15. STATISTICAL CONSIDERATIONS .................................................................... 55 
15.1 Treatment Arms ..................................................................................................................................55 
15.2 Baseline and Visit Windows ................................................................................................................56 
15.3 Description of Study Endpoints ..........................................................................................................56 
15.4 Sample Size Determination and Rationale ........................................................................................56 
15.5 Randomization, Stratification, Blinding, and Unblinding ...............................................................57 
15.5.1 Randomization ...............................................................................................................................57 
15.5.2 Stratification ..................................................................................................................................57 
15.5.3 Blinding .........................................................................................................................................57 
15.5.4 Unblinding .....................................................................................................................................58 
15.6 Interim Analysis...................................................................................................................................59 

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15.6.1 Procedures for Interim Analysis ....................................................................................................60 
15.6.2 Conditional Power Calculation ......................................................................................................60 
15.6.3 Rule and Method for Increasing Sample Size ................................................................................61 
15.6.4 Data Provided to Data Monitoring Committee ..............................................................................61 
15.6.5 Stopping Rule ................................................................................................................................61 
15.6.6 Stopping Rule Provided to Sponsor by Data Monitoring Committee ............................................61 
15.6.7 Type I Error Rate Adjustment........................................................................................................62 
15.7 General Statistical Considerations .....................................................................................................62 
15.7.1 Analysis Populations......................................................................................................................62 
15.7.2 Covariates ......................................................................................................................................62 
15.7.3 Missing Data ..................................................................................................................................62 
15.7.4 Multiple Comparisons and Multiplicity .........................................................................................62 
15.7.5 Subgroup Analysis .........................................................................................................................63 
15.8 Statistical Methods ..............................................................................................................................63 
15.8.1 Subject Disposition ........................................................................................................................63 
15.8.2 Demographics and Baseline Characteristics Analysis ...................................................................64 
15.8.3 Extent of Exposure to Study Product .............................................................................................64 
15.8.4 Compliance with Diet, Life-Style, and Study Product ...................................................................64 
15.8.5 Concomitant Medications/Therapies .............................................................................................64 
15.8.6 Effectiveness Analysis ...................................................................................................................64 
15.8.7 Safety Assessments ........................................................................................................................65 
16. STUDY COMMITTEES .......................................................................................... 66 
16.1 Steering Committee .............................................................................................................................66 
16.2 Data Monitoring Committee ...............................................................................................................66 
17. ETHICAL CONSIDERATIONS ............................................................................. 66 
17.1 Principles ..............................................................................................................................................66 
17.2 Informed Consent ................................................................................................................................66 
17.3 Ethics Committee/Institutional Review Board ..................................................................................67 
17.4 Confidentiality .....................................................................................................................................67 
18. ADMINISTRATIVE AND REGULATORY PROCEDURES ............................. 67 
18.1 Laws ......................................................................................................................................................67 
18.2 Clinical Trials Registration .................................................................................................................68 
18.3 Curriculum Vitae .................................................................................................................................68 
18.4 Record Retention .................................................................................................................................68 
18.5 Data Protection ....................................................................................................................................68 

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18.6 Insurance ..............................................................................................................................................68 
18.7 Financial Arrangements ......................................................................................................................68 
19. CLINICAL INVESTIGATION PLAN AMENDMENTS ..................................... 69 
20. CLINICAL INVESTIGATION PLAN DEVIATIONS ......................................... 69 
21. STUDY MONITORING .......................................................................................... 69 
21.1 Responsibilities of the Sponsor ...........................................................................................................69 
21.2 Responsibilities of the Investigator ....................................................................................................70 
22. PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE 
CLOSE-OUT OF A SITE .............................................................................................. 70 
22.1 Decided by the Sponsor .......................................................................................................................70 
22.2 Decided by the Investigator ................................................................................................................70 
23. PROPERTY RIGHTS .............................................................................................. 71 
24. COMMUNICATION AND PUBLICATION OF RESULTS ............................... 71 
25. QUALITY ASSURANCE AUDITS AND REGULATORY INSPECTIONS ..... 71 
26. REFERENCES .......................................................................................................... 72 
27. APPENDICES ........................................................................................................... 74 
27.1 Appendix 1: Binge Eating Disorder ...................................................................................................75 
27.2 Appendix 2: Food Habits ....................................................................................................................79 
27.3 Appendix 3: Food Habits and Satisfaction ........................................................................................81 
27.4 Appendix 4: Impact of Weight on Quality of Life ............................................................................83 
27.5 Appendix 5: List of Source Data ........................................................................................................86 
 
 
 

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1. CLINICAL TRIAL SUMMARY 
 
TITLE 
A randomized, double-blind, placebo-
controlled, parallel-group study assessing the 
effect of Gelesis100 on body weight in 
overweight and obese subjects with and 
without type 2 diabetes 
 
OBJECTIVES 
Primary:  
- placebo-adjusted weight loss ≥ 3.0% 
- weight loss of at least 5% in ≥ 35% of 
subjects on Gelesis100 
 
Secondary:  
- decrease in serum insulin 
- decrease in insulin resistance (homeostasis 
model assessment-insulin resistance  
“HOMA-IR”) 
- decrease in plasma glucose 
- decrease in glycosylated hemoglobin 
(HbA1c) 
- safety and tolerability similar to placebo or 
clinically acceptable 
 
DESIGN 
Multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, fixed-
amount 
 
NUMBER OF SUBJECTS 
Approximately 460:  
- 230 subjects on Gelesis100 
- 230 subjects on placebo 
 
COUNTRIES AND SITES 
US, Canada, and several European countries, 
approximately 38 sites 
 
INCLUSION CRITERIA 
- male and female ambulatory subjects (it is 
recommended to have at least 45% of each 
gender) 
- age ≥ 22 years and  65 years 
- body mass index (BMI) ≥ 27 and  40 (it is 
recommended to have at least 70% of 
subjects with BMI < 35 and body weight  
< 120 kg in at least 92% of all subjects; 
subjects with BMI < 30 should have at least 
one comorbidity including untreated or 

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metformin-treated type 2 diabetes, untreated 
dyslipidemia with low-density lipoprotein 
(LDL) cholesterol ≥ 130 mg/dL (≥ 3.37 
mmol/L) and/or triglycerides ≥ 150 mg/dL  
(≥ 1.69 mmol/L) or drug-treated 
dyslipidemia, and untreated hypertension 
with supine systolic blood pressure (SBP)  
≥ 140 mm Hg and/or supine diastolic blood 
pressure (DBP) ≥ 90 mm Hg based on the 
mean of two consecutive readings or drug-
treated hypertension) 
- fasting plasma glucose ≥ 90 mg/dL and  
≤ 145 mg/dL (≥ 5.0 mmol/L and  
≤ 8.1 mmol/L); it is recommended to have 
approximately 45 to 55% non-diabetic 
normoglycemic subjects (fasting glucose ≥ 90 
mg/dL and < 100 mg/dL or ≥ 5.0 mmol/L and 
< 5.6 mmol/L) and the rest, non-diabetic 
impaired fasting glucose subjects (fasting 
glucose ≥ 100 mg/dL and < 126 mg/dL or  
≥ 5.6 mmol/L and < 7.0 mmol/L) or diabetic 
subjects either untreated (fasting glucose  
≥ 126 mg/dL and ≤ 145 mg/dL or ≥ 7.0 
mmol/L and ≤ 8.1 mmol/L) or metformin-
treated (metformin dose ≤ 1500 mg/day, 
fasting glucose ≤ 145 mg/dL or ≤ 8.1 
mmol/L) 
- ability to follow verbal and written 
instructions 
- informed consent form signed by the 
subjects 
 
EXCLUSION CRITERIA 
- pregnancy (or positive serum or urine 
pregnancy test(s) in females of childbearing 
potential) or lactation 
- absence of contraception in females of 
childbearing potential 
- history of allergic reaction to 
carboxymethylcellulose, citric acid, sodium 
stearyl fumarate, raw cane sugar, gelatin, and 
titanium dioxide 
- administration of investigational products 
within 1 month prior to Screening Visit 
- subjects who stopped smoking within 6 
months prior to Screening Visit or 
considering smoking cessation during the 

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study 
- subjects anticipating surgical intervention 
during the study 
- known type 1 diabetes 
- history of eating disorders including binge 
eating (except mild binge eater) 
- weight change > 3 kg within 3 months prior 
to and during the Screening period 
- supine SBP > 160 mm Hg and/or supine 
DBP > 95 mm Hg 
- angina, coronary bypass, or myocardial 
infarction within 6 months prior to Screening 
Visit 
- history of swallowing disorders 
- esophageal anatomic abnormalities (e.g., 
webs, diverticuli, rings) 
- history of gastroesophageal reflux disease 
- history of gastric or duodenal ulcer 
- history of gastroparesis (chronic nausea, 
vomiting, heartburn, …) 
- history of gastric bypass or any other gastric 
surgery 
- history of small bowel resection (except if 
related to appendectomy) 
- history of intestinal stricture (e.g., Crohn’s 
disease) 
- history of intestinal obstruction or subjects 
at high risk of intestinal obstruction including 
suspected small bowel adhesions 
- history of abdominal radiation treatment 
- history of pancreatitis 
- history of malabsorption 
- history of sucrose intolerance 
- laxative users 
- history of hepatitis B or C 
- history of human immunodeficiency virus 
- history of cancer within the past 5 years 
(except adequately-treated localized basal cell 
skin cancer or in situ uterine cervical cancer) 
- any other clinically significant disease 
interfering with the assessments of 
Gelesis100 (e.g., disease requiring corrective 
treatment, potentially leading to study 
discontinuation) 
- abnormal serum thyroid-stimulating 
hormone (TSH) 

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- HbA1c > 8.5% (> 69 mmol/mol) 
- serum LDL cholesterol ≥ 190 mg/dL  
(≥ 4.93 mmol/L) 
- serum triglycerides ≥ 500 mg/dL  
(≥ 5.65 mmol/L) 
- positive test for drugs in the urine 
- any relevant biochemical abnormality 
interfering with the assessments of 
Gelesis100 
- anti-obesity medications (including herbal 
preparations) within 1 month prior to 
Screening Visit 
- antidiabetic medications within 1 month 
prior to Screening Visit (except stable dose of 
metformin, ≤ 1500 mg/day, for at least 1 
month in subjects with type 2 diabetes) 
- systemic corticosteroids within 1 month 
prior to Screening Visit 
- thyroid hormones or preparations within 1 
month prior to Screening Visit (except stable 
dose of replacement therapy for at least 1 
month) 
- TSH suppression therapy for thyroid cancer 
- estrogen within 1 month prior to Screening 
Visit (except stable dose of replacement 
therapy for at least 1 month or non-oral 
contraceptive for at least 3 months) 
- any other medication or product known to 
cause weight loss or weight gain within 1 
month prior to Screening Visit 
- change in medications treating dyslipidemia 
within 1 month prior to Screening Visit 
(including change in dose) 
- change in medications treating hypertension 
within 1 month prior to Screening Visit 
(including change in dose) 
- medications requiring mandatory 
administration with meal at lunch or dinner 
- anticipated requirement for use of 
prohibited concomitant medications 
 
INVESTIGATIONAL PRODUCT 
Gelesis100 (medical device in capsule) and 
matching placebo 
 
TREATMENT ASSIGNMENT 
Gelesis100 (2.25 g) versus placebo, twice 
daily, before lunch and dinner (20-30 min 

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AND ADMINISTRATION 
before meal) 
 
Randomization ratio of 1:1 with 230 subjects 
per arm (2 arms) 
 
Stratification by country (or combination of 
countries), based on gender (male and 
female), BMI at Screening Visit (< 35 and  
≥ 35), and fasting glucose status at Screening 
Visit (normal and impaired/diabetic) 
 
Subjects to be treated in a parallel-group 
design, for 24 weeks 
 
DIET AND LIFE-STYLE 
- hypocaloric diet (-300 kcal/day), meals to 
be consumed with water as instructed 
- moderate-intensity exercise 
- no change in smoking habits 
 
STUDY DURATION PER 
SUBJECT 
Screening period: up to 3 weeks 
Baseline period: 1 day 
Treatment period: 24 weeks 
Post-treatment follow-up period: 4 weeks 
 
TOTAL STUDY DURATION 
Approximately 2 years (including 
approximately 1 and half years for 
enrollment) 
 
EFFECTIVENESS ENDPOINTS 
Co-primary:  
- body weight 
- body weight responders (≥ 5% weight loss) 
 
Secondary:  
- plasma glucose status 
- plasma glucose 
- HOMA-IR 
- HbA1c 
- BMI 
 
Tertiary:  
- body weight responders (≥ 10% weight loss) 
- estimated excess body weight 
- body weight status 
- waist circumference 
- serum insulin 

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- serum C-reactive protein (CRP) 
- serum lipids 
- blood pressure 
- food intake 
- food habits 
- satisfaction 
- impact of weight on quality of life 
(IWQOL) 
 
SAFETY ENDPOINTS 
- adverse events (AEs) 
- physical examination 
- vital signs 
- laboratory tests 
 
VISITS 
Fourteen visits including the Screening Visit 
 
STATISTICAL ANALYSIS 
- this sample size of 460 randomized subjects 
(230 per arm) with an anticipated dropout rate 
of 30% (322 subjects completing the study, 
161 per arm) will allow establishing both 
super-superiority and superiority with 
sufficient statistical power 
- the sample size will provide 85% statistical 
power for a 3.0% margin super-superiority 
(i.e., delta of at least 4.5%) with a common 
SD of 5.0% and a type I error rate of 0.05 
(one-sided test) 
- the sample size will also provide at least 
90% statistical power to establish the 
superiority (difference between the two arms 
greater than 0) with a common SD of 5.0% 
and a type I error rate of 0.05 (two-sided 
tests) 
- study endpoints will be analyzed as percent 
change or change from baseline to Days 169 
or 171 
- continuous parameters will be assessed by 
analysis of covariance model using the 
stratification factors and the respective 
baseline values for the endpoint in the model 
- categorical parameters will be assessed by 
Logit model using the stratification factors 
and the respective baseline values for the 
endpoint in the model 
- safety data will be summarized for each arm 

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- an interim analysis will be performed when 
approximately 50% of subjects have been 
randomized and completed Visit 13 (Week 
24) or early terminated, whichever comes 
first 
 
STUDY START DATE 
Second half of 2014 
 
STUDY END DATE 
First half of 2017 
 

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2. STUDY FLOW CHART 
 
Period 
(duration) 
Screening 
( 21 days) 
Baseline 
(1 day) 
Double-blind treatment 
(168 days) 
Follow-up 
(28 days) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13I 
14 
Day 
-21 to -1 
0 
8 
15 
29 
43 
57 
71 
85 
113 
141 
169 
171 
197 
Week 
-3 to 0 
0 
1 
2 
4 
6 
8 
10 
12 
16 
20 
24 
25 
28 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
XJ 
 
Demography, height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Menopausal status, smoking status, medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Weight, waist circumference, vital signs (blood pressure, heart rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietary interview 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Binge eating disorder 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Food habits before treatment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testA 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Urine pregnancy testA, serum amylaseB, genomic testsC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Electrocardiogram, urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSHD 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Plasma glucose 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
Serum insulin 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
IWQOLE 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum CRP, vitaminsF 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Serum albumin 
X 
X 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
Hematology, blood chemistry, HbA1c 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
Food intakeG 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
Food habits and satisfaction after treatment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Concomitant medication recording, AEs recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Gelesis100/placebo accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Gelesis100/placebo dispensedH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AFemales of childbearing potential only. BAt any of the Visits 2, 3, 4, 5, 9, or 13. CAt any of the Visits 2, 3, 4, 5, 9, or 13 (tests not mandatory). DThe assessment of Week 12 is for subjects on replacement therapy 
with thyroid hormones or preparations only. EAt selected sites. FAt selected sites (vitamins include vitamin A, vitamins B1, B2, B6, B9, and B12, vitamin D, and vitamin E). GFood diary on 2 consecutive weekdays 
and 1 weekend day before the visit. HAdministration begins on Day 1 and continues through Day 168, before lunch and dinner. ILast visit if entering extension study. JIf entering extension study. 

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3. CLINICAL INVESTIGATION PLAN APPROVAL 
 
A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Assessing the 
Effect of Gelesis100 on Body Weight in Overweight and Obese Subjects with and 
without Type 2 Diabetes. 
 
I agree to the terms of this Clinical Investigation Plan. I will conduct the study according 
to the procedures specified herein, and according to principles of Good Clinical Practices, 
ISO 14155:2011, and local regulations and requirements. 
 
 
Investigator: 
 
 
Name: _________________________________________________ 
 
 
Signature: ______________________________________________ 
 
 
Date: _________________________________________________ 
 

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4. ABBREVIATIONS 
 
ADE: adverse device effect 
AE: adverse event 
am: ante meridiem 
AMY1: salivary amylase 
ANCOVA: analysis of covariance 
BDNF: brain-derived neurotrophic factor 
BMI: body mass index 
C: Celsius 
CAPN10: calpain-10 
CEE: Central and Eastern Europe 
cm: centimeter 
CMC: carboxymethylcellulose 
CP: conditional power 
CRF: case report form 
CRO: Contract Research Organization 
CRP: C-reactive protein 
DBP: diastolic blood pressure 
dL: deciliter 
ECG: electrocardiogram 
EEA: European Economic Area 
e.g.: exempli gratia 
EN: European Norm 
F: Fahrenheit 
FDA: Food and Drug Administration 
fl: fluid 
FLOW: First Loss Of Weight 
FTO: fat mass and obesity associated 
g: gram 
GCP: Good Clinical Practices 
GED: general educational development 
GLOW: Gelesis Loss Of Weight 
h: hour 
HbA1c: glycosylated hemoglobin 
HDL: high-density lipoprotein 
HOMA-IR: homeostasis model assessment-insulin resistance 
ICH: International Conference on Harmonisation 
i.e.: id est 
in: inch 
ISO: International Organization for Standardization 
ITT: intention-to-treat 
IWQOL: impact of weight on quality of life 
kcal: kilocalorie 

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KCNJ11: potassium voltage-gated channel subfamily J member 11 
kg: kilogram 
L: liter 
lb: pound 
LDL: low-density lipoprotein 
LEPR: leptin receptor 
MA: Massachusetts 
MC4R: melanocortin-4 receptor 
M.D.: Medical Doctor 
mg: milligram 
M.I.: middle initial 
min: minute 
mL: milliliter 
mm Hg: millimeters of mercury 
mmol: millimole 
mol: mole 
μU: microunit 
n: number 
NEGR1: neuronal growth regulator 1 
NPC1: Niemann-Pick disease, type C1 
oz: ounce 
PCSK1: proprotein convertase subtilisin/kexin type 1 
pH: power of hydrogen 
pm: post meridiem 
PP: per protocol 
PPARG: peroxisome proliferator-activated receptor gamma 
QEWP-R: questionnaire on eating and weight patterns-revised 
SADE: serious adverse device effect 
SAE: serious adverse event 
SAP: Statistical Analysis Plan 
SAS: Statistical Analysis System 
SBP: systolic blood pressure 
SD: standard deviation 
SH2B1: SH2B adapter protein 1 
SLC16A13: solute carrier family 16 member 13 
Srl.: società a responsabilità limitata 
TCF7L2: transcription factor 7-like 2 
TEAE: treatment-emergent adverse event 
TSH: thyroid-stimulating hormone 
UADE: unanticipated adverse device effect 
USADE: unanticipated serious adverse device effect 
US: United States 
USA: United States of America 
WHO: World Health Organization 
 

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5. INTRODUCTION AND RATIONALE 
5.1 Disease Background 
Overweight (body mass index (BMI) ≥ 25 and < 30) and obesity (BMI ≥ 30) are 
becoming major health problems worldwide (1). The overweight/obesity epidemic was 
first noted in US and then spread to other industrialized nations; it is now being seen even 
in developing countries (2). The World Health Organization (WHO) estimated that the 
worldwide prevalence of obesity has nearly doubled between 1980 and 2008. In 2008, 
approximately 500 million adults around the globe were obese and in 2014, this number 
reached 600 million. 
 
Overweight and obesity are responsible for increased morbidity and mortality (3). The 
comorbid conditions associated with overweight/obesity include cancer, coronary heart 
disease, delayed puberty, depression, disability, dyslipidemia, gallbladder disease, gout, 
hypertension, liver disease, osteoarthritis, respiratory dysfunction, sleep apnea, sexual 
impairment, social discrimination, type 2 diabetes, and other practical limitations and 
challenges. Weight loss of at least 5 to 10% appears to lower the risk of many of these 
comorbidities (4). 
 
Overweight and obesity are chronic conditions and this characteristic should be 
considered when facing overweight and obese individuals. Management of overweight 
and obesity includes hypocaloric diet, exercise, behavior modification, device (e.g., 
intragastric balloon), drug, and surgery (bariatric surgery) (1, 5, 6, 7). The therapeutic 
benefit of all currently available anti-obesity tools is limited by their marginal efficacy, 
variable tolerability and safety profiles, and poor compliance. 
 
The intragastric balloon is an intervention designed to reduce stomach volume (7), but 
there are conflicting data on sustained weight loss and no clear data indicating a decrease 
in mortality. Side effects include balloon movement, nausea, vomiting, pain, and stomach 
ulceration. 
 
The results from bariatric surgery suggest that limiting the functional volume of the 
stomach is an effective modality for the treatment of obesity (6). However, because of the 
risk of peri-operative complications and the relatively high cost, bariatric surgery is 
usually reserved for the severely obese subjects. 
 
A need exists for a product that is easy to use, safe, and effective at inducing weight loss. 
Interventions which act mechanically by occupying stomach volume, increasing the 
elastic modulus and viscosity of the upper gastrointestinal content, and extending gastric 
emptying time, could potentially be very beneficial. 
 
A medical device which induces satiety and decreases hunger could result in decreased 
caloric intake and weight loss. The advantage of such a medical device is that it would 

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not require to drastically restrict food choices and would circumvent the challenge of 
unacceptable hunger levels which has derailed so many dietary interventions in the past. 
 
5.2 Investigational Product 
Gelesis100 is a novel, biocompatible hydrogel, composed of carboxymethylcellulose 
(CMC) sodium salt (E466) cross-linked with citric acid (E330). More than 99% of 
Gelesis100 consists of CMC and the rest is composed of citric acid. CMC and citric acid 
are safe food additives for use within the European Union (European Directive 95/2/EC 
on Food Additives other than Colors and Sweeteners) and are listed in the List of Dietary 
Supplement Ingredients in use before October 15, 1994 published by the National 
Nutritional Food Association. In the proposed study, Gelesis100 will be used as a 
medical device. It is considered as a Class III device in Europe, a Class IV device in 
Canada, and a non-significant risk device in US. 
 
Following ingestion of the Gelesis100 (capsule presentation), the capsule disintegrates in 
the stomach and releases a hydrogel which is capable of absorbing water solutions up to 
100 times its original weight in the gastrointestinal environment. The Gelesis100 device 
hydrates in the stomach and converts a volume of liquids into a volume of small, distinct 
gel particles. The hydrated gel particles mix homogenously with ingested foods, creating 
a larger volume with a higher elasticity and viscosity of the stomach and small intestine 
contents. For example, 2.25 g of Gelesis100 will create a volume of approximately 225 
mL. The created volume does not exceed the volume of liquid present, minimizing the 
risk of distension. The hydration rate of Gelesis100 in the different parts of the 
gastrointestinal tract has been demonstrated in vitro (Figure 1). Variations in its hydration 
capacity are mainly related to variations of the pH and ionic strength of the external 
solutions. The transit time reported in Figure 1 is only an example. Transit time is 
affected by the meal size and content. 
 
 
 

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Figure 1. Performance of Gelesis100 in simulated gastrointestinal conditions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
By occupying the gastric and intestinal cavities and by increasing the elasticity and the 
viscosity of the ingested foods, Gelesis100 induces satiety and reduces food intake, 
thereby contributing to weight reduction. Gelesis100 partially degrades in the large 
intestine and loses its three dimensional matrix structure and most of its absorption 
capacity. The water is absorbed from the hydrogel back in the colon and the device is 
expelled in the feces. 
 
All relevant information concerning Gelesis100 is available in the Investigator’s 
Brochure (8). This Clinical Investigation Plan will summarize the available clinical data. 
 
5.2.1 Clinical Data 
5.2.1.1 Effect on Satiety and Hunger 
This study was aimed to assess the effects of a single administration of Gelesis100 on 
satiety and hunger (9). The study was conducted at the Agostino Gemelli Hospital, Rome, 
Italy. Ninety-five subjects were studied (Table 1). Study subjects received 2 g of 
Gelesis100 versus placebo before breakfast, lunch, and dinner, in a double-blind, cross-
over fashion. There was a 2-day washout period between each administration of 
Gelesis100 for each subject. Meals consisted of habitual intake and were consumed at 
home. Satiety was assessed using a self-administered questionnaire immediately, and 30 
and 60 min after meal. The questionnaire included 5 options to score the feeling of 
satiety: not at all (score 0), a little (score 1), enough (score 2), very (score 3), and very 
much (score 4). Hunger was assessed using the same type of questionnaire before meal. 
 
Simulated gastrointestinal transit time (min) 
Hydration ratio (g/g) 

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Table 1. Clinical characteristics of the 95 study subjects. 
 
Gender (n) 
Age (years) 
BMI* 
Male 
Female 
Mean ± SD 
Range 
Mean ± SD 
Range 
22 
73 
41 ± 12 
19-67 
31.1 ± 7.5 
18.0-55.9 
*Twenty-one subjects had normal (or subnormal) BMI, 22 were overweight, and 52 were 
obese. 
 
Gelesis100 significantly increased the feeling of satiety at 30 min after breakfast and 
dinner (Table 2) and at 60 min after lunch and dinner (Table 3). 
 
Table 2. Satiety scores (mean ± SD) at 30 min post-meal. 
 
Meal 
Gelesis100 
Placebo 
P value 
Breakfast 
1.85 ± 0.93 
1.63 ± 0.95 
0.037 
Lunch 
1.84  1.14 
1.66  0.87 
0.071 
Dinner 
1.98  0.97 
1.70  1.01 
0.004 
 
 
Table 3. Satiety scores (mean ± SD) at 60 min post-meal. 
 
Meal 
Gelesis100 
Placebo 
P value 
Breakfast 
2.13 ± 1.00 
2.12 ± 0.83 
0.960 
Lunch 
2.35  1.06 
2.07  0.86 
0.007 
Dinner 
2.46  1.12 
2.15  0.99 
0.006 
 
The placebo-adjusted effect of Gelesis100 on satiety (first meal effect) is reported in 
Figure 2. 
 
 
 

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Figure 2. Placebo-adjusted change in post-meal satiety scores (%) after Gelesis100 
administration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The administration of Gelesis100 before lunch significantly decreased the feeling of 
hunger before the subsequent dinner (Table 4). 
 
Table 4. Hunger scores (mean ± SD) before lunch and dinner following 
Gelesis100/Placebo administration before breakfast and lunch, respectively. 
 
Time 
Gelesis100 
Placebo 
P value 
Before lunch 
1.71 ± 1.00 
1.67 ± 0.83 
0.702 
Before dinner 
1.47 ± 1.16 
1.77 ± 0.98 
0.011 
 
The placebo-adjusted effect of Gelesis100 on hunger (second meal effect) is reported in 
Figure 3. 
 
 
 
0
5
10
15
20
Breakfast
Lunch
Dinner
30 min
60 min
*P < 0.05 
**P < 0.01 
**
**
**
*
Percent 

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Figure 3. Placebo-adjusted change in pre-meal hunger scores (%) before lunch and 
dinner, after Gelesis100 administration before breakfast and lunch, respectively. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment with Gelesis100 was safe and well tolerated. Fifteen subjects (15.8%) reported 
at least 1 symptom during the study. No detailed information was recorded as to whether 
the symptoms occurred after the administration of Gelesis100 or placebo (or both). 
Gastrointestinal symptoms (solicited adverse events “AEs”) were reported in 13 subjects 
(13.7%) during the study (Table 5). 
 
Table 5. Gastrointestinal symptoms during Gelesis100/Placebo administration in 95 
subjects. 
 
Symptoms* 
Number of subjects 
Percentage of subjects 
Nausea 
7 
7.4 
Constipation 
4 
4.2 
Stomach ache 
4 
4.2 
Vomiting 
1 
1.1 
Diarrhea 
1 
1.1 
*No information was recorded as to whether the symptoms occurred after the 
administration of Gelesis100 or placebo. 
 
Three subjects (3.2%) reported more than 1 gastrointestinal symptom during the study: 2 
reported 2 symptoms (stomach ache and diarrhea, nausea and constipation) and 1 
reported 3 symptoms (nausea, vomiting, and stomach ache). Of the 7 subjects who 
-20
-15
-10
-5
0
5
Lunch
Dinner
Pre-meal
*P < 0.02 
*
Percent 

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reported nausea during the study, all had a medical history of at least 1 gastrointestinal 
disorder (esophagitis, epigastralgia, colitis, constipation, and proctitis). Non-
gastrointestinal symptoms (isolated headaches) were reported in 2 subjects (2.1%) during 
the study. No serious AE (SAE) was observed during the study. 
 
In conclusion, a single administration of Gelesis100 significantly increases the post-meal 
feeling of satiety in humans. The administration of Gelesis100 before lunch significantly 
decreases the feeling of hunger before the subsequent dinner. The treatment is safe and 
well tolerated. 
 
5.2.1.2 Effect on Body Weight 
This study (FLOW = First Loss Of Weight) was aimed to assess the effect of repeated 
administration of Gelesis100 on body weight (10). The study was conducted at 5 sites in 
3 European countries (Denmark, Czech Republic, and Italy). One hundred twenty-eight 
subjects were randomized into 3 arms: Gelesis100 2.25 g, Gelesis100 3.75 g, or placebo. 
Subjects received 5 capsules of Gelesis100 or placebo before lunch and dinner, in a 
double-blind and parallel-group fashion. A hypocaloric diet (-600 kcal/day) was 
prescribed to all subjects. The duration of the treatment was 12 weeks. One hundred 
twenty five subjects had at least one post-baseline assessment of body weight (intention-
to-treat “ITT” population). Forty-two of the ITT subjects were on Gelesis100 2.25 g, 41 
on Gelesis100 3.75 g, and 42 on placebo (Table 6). One hundred ten subjects completed 
the key visit of the study at Day 87 for the assessment of body weight. One hundred 
twenty-six subjects provided safety data. The primary efficacy endpoint was assessed by 
analysis of covariance (ANCOVA) model in the ITT population with baseline weight, 
gender, and BMI status as covariates. 
 
Table 6. General characteristics of the ITT population at baseline. 
 
Parameter 
Gelesis100 2.25 g  
(n = 42) 
Gelesis100 3.75 g  
(n = 41) 
Placebo  
(n = 42) 
Male (n) 
13 (31%) 
14 (34%) 
13 (31%) 
Female (n) 
29 (69%) 
27 (66%) 
29 (69%) 
Age (years)* 
42.4  12.3 
46.1  11.2 
44.0  11.7 
BMI* 
31.2  2.3 
31.8  2.5 
32.0  2.3 
Overweight (n) 
14 (33%) 
12 (29%) 
12 (29%) 
Obese (n) 
28 (67%) 
29 (71%) 
30 (71%) 
Glucose (mg/dL)* 
Glucose (mmol/L)* 
93  10 
5.18  0.54 
94  9 
5.20  0.50 
96  10 
5.31  0.58 
*Mean  SD. 
 
Body weight decreased significantly at Day 87 in subjects on Gelesis100 2.25 g with a 
placebo-adjusted weight loss of 2.0% and a total body weight loss of 6.1% (Table 7). 
 

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Table 7. Body weight (% change from baseline) at Day 87 in the ITT population. 
 
Arm 
Number of subjects 
Mean ± SD 
P value  
(versus placebo) 
Gelesis100 2.25 g 
42 
-6.1  5.1 
0.026 
Gelesis100 3.75 g 
41 
-4.5  4.5 
0.859 
Placebo 
42 
-4.1 ± 4.4 
- 
 
Subjects on Gelesis100 2.25 g had higher rate of weight loss ≥ 10% and lower rate of 
weight gain (Table 8). Lower tolerability and compliance may explain the observed 
efficacy result with Gelesis100 3.75 g. 
 
Table 8. Body weight response at Day 87 in the ITT population. 
 
Parameter 
Gelesis100 2.25 g  
(n = 42) 
Gelesis100 3.75 g  
(n = 41) 
Placebo  
(n = 42) 
Weight gain 
3 (7%) 
9 (22%) 
7 (17%) 
Weight loss < 5% 
21 (50%) 
13 (32%) 
18 (43%) 
Weight loss ≥ 5% 
18 (43%) 
19 (46%) 
17 (40%) 
Weight loss ≥ 10% 
11 (26%) 
5 (12%) 
5 (12%) 
 
The extent of weight loss at Day 87 was more pronounced in subjects on Gelesis100  
2.25 g with impaired fasting glucose at baseline. The placebo-adjusted weight loss was 
5.3% and the total body weight loss was 10.9% (Table 9). There was a significant 
negative correlation between fasting glucose at baseline and change in body weight at 
Day 87 in subjects on Gelesis100 2.25 g (r = -0.50; P < 0.001) contrasting with a lack of 
significant correlation in Gelesis100 3.75 g arm (r = -0.01; P = 0.968) and placebo arm  
(r = -0.06; P = 0.708). 
 
Table 9. Body weight (% change from baseline) at Day 87 in the ITT population in 
subjects with impaired fasting glucose at baseline. 
 
Arm 
Number of subjects 
Mean ± SD 
P value  
(versus placebo) 
Gelesis100 2.25 g 
9 
-10.9  4.3 
0.019 
Gelesis100 3.75 g 
9 
-4.2  5.7 
0.348 
Placebo 
11 
-5.6 ± 4.8 
- 
 
Treatment with Gelesis100 was safe and well tolerated. Thirty-one subjects (74%) on 
Gelesis100 2.25 g, 35 subjects (85%) on Gelesis100 3.75 g, and 36 subjects (84%) on 
placebo reported at least 1 AE during the study (mainly gastrointestinal AEs). Bloating, 
flatulence, abdominal pain, and diarrhea were the most common gastrointestinal AEs 
with lower prevalence in Gelesis100 2.25 g compared to placebo and Gelesis100 3.75 g 

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arms (Table 10). Common cold and headache were the most common non-
gastrointestinal AEs. SAEs were observed in 3 subjects on placebo (gallstone and 
abdominal pain). The AEs were usually of mild intensity, occurred at different times 
during the course of the study, and resolved within 1 week in most cases. 
 
Table 10. Gastrointestinal AEs* in the safety population. 
 
Parameter 
Gelesis100 2.25 g  
(n = 42) 
Gelesis100 3.75 g  
(n = 41) 
Placebo  
(n = 43) 
Any gastrointestinal AE 
25 (60%) 
31 (76%) 
32 (74%) 
Bloating** 
12 (29%) 
15 (37%) 
16 (37%) 
Flatulence** 
11 (26%) 
15 (37%) 
13 (30%) 
Abdominal pain** 
9 (21%) 
12 (29%) 
15 (35%) 
Diarrhea** 
8 (19%) 
10 (24%) 
16 (37%) 
*Gastrointestinal AEs were solicited and recorded through a questionnaire. **Similar 
AEs are grouped under one main term. 
 
Dropout after randomization occurred in 2 subjects (5%) on Gelesis100 2.25 g, 10 
subjects (24%) on Gelesis100 3.75 g, and 9 subjects (21%) on placebo. No AE was 
responsible for the dropout with Gelesis100 2.25 g. 
 
In conclusion, repeated administration of Gelesis100 (2.25 g twice daily) over 12 weeks 
significantly decreases the body weight in overweight and obese subjects, especially in 
subjects with impaired fasting glucose at baseline. The treatment is safe and well 
tolerated. 
 
5.3 Rationale 
Gelesis100 increases the volume and elasticity of the stomach and small intestine 
contents, and thus, inducing satiety and reducing food intake. Through its mechanical and 
non-pharmacological approach, Gelesis100, as a medical device, is a product that is well-
positioned to overcome the limitations of the current weight-loss tools and fulfill the 
overwhelming unmet medical need for a safe and effective weight-loss product in 
overweight and obese subjects, especially in those with impaired fasting glucose. 
 
6. OBJECTIVES 
This study has the following objectives: 
 

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6.1 Primary 
 To assess the decrease in body weight after repeated administration of Gelesis100 
over a period of 168 days in overweight and obese subjects with and without type 
2 diabetes (“placebo-adjusted” or “difference with placebo” weight loss ≥ 3.0%) 
 To assess the body weight loss of at least 5% after repeated administration of 
Gelesis100 over a period of 168 days in overweight and obese subjects with and 
without type 2 diabetes (≥ 35% of subjects on Gelesis100) 
 
6.2 Secondary 
 To assess the decrease in serum insulin after repeated administration of 
Gelesis100 over a period of 168 days in overweight and obese subjects with and 
without type 2 diabetes 
 To assess the decrease in insulin resistance (homeostasis model assessment-
insulin resistance “HOMA-IR”) after repeated administration of Gelesis100 over 
a period of 168 days in overweight and obese subjects with and without type 2 
diabetes 
 To assess the decrease in plasma glucose after repeated administration of 
Gelesis100 over a period of 168 days in overweight and obese subjects with and 
without type 2 diabetes 
 To assess the decrease in glycosylated hemoglobin (HbA1c) after repeated 
administration of Gelesis100 over a period of 168 days in overweight and obese 
subjects with and without type 2 diabetes 
 To demonstrate safety and tolerability similar to placebo or clinically acceptable 
of repeated administration of Gelesis100 over a period of 168 days in overweight 
and obese subjects with and without type 2 diabetes 
 
7. DESIGN 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
fixed-amount study using 1 amount of Gelesis100. 
 
At the end of this study, an extension study will be proposed to all subjects who have 
completed 24 weeks of treatment and lost at least 3% of their body weight from baseline 
in order to assess the effectiveness and safety of Gelesis100 after an additional exposure 
of 24 weeks on an open-label basis. 
 
8. POPULATION 
The population will include overweight and obese subjects with and without type 2 
diabetes. 
 

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8.1 Number of Subjects 
Approximately 460 subjects will be randomized in this study (approximately 230 on 
active product and 230 on placebo). The selection and enrollment of subjects through 
advertisement is highly recommended. Subjects who once failed to meet the 
inclusion/exclusion criteria will not be re-screened (except for fasting plasma glucose and 
serum lipids, upon approval from the Sponsor). 
 
8.2 Countries and Sites 
The study will be conducted in US, Canada, and several European countries in 
approximately 38 sites.  
 
The lists of Advisors, Investigators, investigation sites, laboratories, and other parties are 
reported in separate documents. The Sponsor will update and maintain these lists and 
communicate them with the Clinical Study Report. 
 
8.3 Inclusion Criteria 
1. Male and female ambulatory subjects (it is recommended to have at least 45% of 
each gender) 
2. Age ≥ 22 years and  65 years 
3. BMI ≥ 27 and  40 (it is recommended to have at least 70% of subjects with BMI 
< 35 and body weight < 120 kg in at least 92% of all subjects; subjects with BMI 
< 30 should have at least one comorbidity including untreated or metformin-
treated type 2 diabetes, untreated dyslipidemia with low-density lipoprotein 
(LDL) cholesterol ≥ 130 mg/dL (≥ 3.37 mmol/L) and/or triglycerides ≥ 150 
mg/dL (≥ 1.69 mmol/L) or drug-treated dyslipidemia, and untreated hypertension 
with supine systolic blood pressure (SBP) ≥ 140 mm Hg and/or supine diastolic 
blood pressure (DBP) ≥ 90 mm Hg based on the mean of two consecutive 
readings or drug-treated hypertension) 
4. Fasting plasma glucose ≥ 90 mg/dL and ≤ 145 mg/dL (≥ 5.0 mmol/L and  
≤ 8.1 mmol/L); it is recommended to have approximately 45 to 55% non-diabetic 
normoglycemic subjects (fasting glucose ≥ 90 mg/dL and < 100 mg/dL or ≥ 5.0 
mmol/L and < 5.6 mmol/L) and the rest, non-diabetic impaired fasting glucose 
subjects (fasting glucose ≥ 100 mg/dL and < 126 mg/dL or ≥ 5.6 mmol/L and < 
7.0 mmol/L) or diabetic subjects either: 
- untreated (fasting glucose ≥ 126 mg/dL and ≤ 145 mg/dL or ≥ 7.0 mmol/L and  
≤ 8.1 mmol/L) 
- or metformin-treated (metformin dose ≤ 1500 mg/day, fasting glucose ≤ 145 
mg/dL or ≤ 8.1 mmol/L) 
5. Ability to follow verbal and written instructions 
6. Informed Consent Form signed by the subjects 
 

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8.4 Exclusion Criteria 
1. Pregnancy (or positive serum or urine pregnancy test(s) in females of childbearing 
potential) or lactation 
2. Absence of medically approved contraceptive methods in females of childbearing 
potential (e.g., hysterectomy, non-oral contraceptive medications or intrauterine 
device combined with a barrier method, two combined barrier methods such as 
diaphragm and condom or spermicide, or condom and spermicide; bilateral tubal 
ligation and vasectomy are not acceptable contraceptive methods) 
3. History of allergic reaction to CMC, citric acid, sodium stearyl fumarate, raw 
cane sugar, gelatin, and titanium dioxide 
4. Administration of investigational products within 1 month prior to Screening Visit 
5. Subjects who stopped smoking within 6 months prior to Screening Visit or 
considering smoking cessation during the study 
6. Subjects anticipating surgical intervention during the study 
7. Known type 1 diabetes 
8. History of eating disorders including binge eating (except mild binge eater) 
9. Weight change > 3 kg within 3 months prior to and during the Screening period 
10. Supine SBP > 160 mm Hg and/or supine DBP > 95 mm Hg (mean of two 
consecutive readings) 
11. Angina, coronary bypass, or myocardial infarction within 6 months prior to 
Screening Visit 
12. History of swallowing disorders 
13. Esophageal anatomic abnormalities (e.g., webs, diverticuli, rings) 
14. History of gastroesophageal reflux disease 
15. History of gastric or duodenal ulcer 
16. History of gastroparesis (chronic nausea, vomiting, heartburn, …) 
17. History of gastric bypass or any other gastric surgery 
18. History of small bowel resection (except if related to appendectomy) 
19. History of intestinal stricture (e.g., Crohn’s disease) 
20. History of intestinal obstruction or subjects at high risk of intestinal obstruction 
including suspected small bowel adhesions 
21. History of abdominal radiation treatment 
22. History of pancreatitis 
23. History of malabsorption 
24. History of sucrose intolerance 
25. Laxative users 
26. History of hepatitis B or C 
27. History of human immunodeficiency virus 
28. History of cancer within the past 5 years (except adequately-treated localized 
basal cell skin cancer or in situ uterine cervical cancer) 
29. Any other clinically significant disease interfering with the assessments of 
Gelesis100, according to the Investigator (e.g., disease requiring corrective 
treatment, potentially leading to study discontinuation) 
30. Abnormal serum thyroid-stimulating hormone (TSH) 
31. HbA1c > 8.5% (> 69 mmol/mol) 

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32. Serum low-density lipoprotein cholesterol ≥ 190 mg/dL (≥ 4.93 mmol/L) 
33. Serum triglycerides ≥ 500 mg/dL (≥ 5.65 mmol/L) 
34. Positive test for drugs in the urine 
35. Any relevant biochemical abnormality interfering with the assessments of 
Gelesis100, according to the Investigator 
36. Anti-obesity medications (including herbal preparations) within 1 month prior to 
Screening Visit 
37. Antidiabetic medications within 1 month prior to Screening Visit (except stable 
dose of metformin, ≤ 1500 mg/day, for at least 1 month in subjects with type 2 
diabetes) 
38. Systemic corticosteroids within 1 month prior to Screening Visit 
39. Thyroid hormones or preparations within 1 month prior to Screening Visit (except 
stable dose of replacement therapy for at least 1 month) 
40. TSH suppression therapy for thyroid cancer 
41. Estrogen within 1 month prior to Screening Visit (except stable dose of 
replacement therapy for at least 1 month or non-oral contraceptive for at least 3 
months) 
42. Any other medication or product known to cause weight loss or weight gain 
within 1 month prior to Screening Visit 
43. Change in medications treating dyslipidemia within 1 month prior to Screening 
Visit (including change in dose) 
44. Change in medications treating hypertension within 1 month prior to Screening 
Visit (including change in dose) 
45. Medications requiring mandatory administration with meal at lunch or dinner 
46. Anticipated requirement for use of prohibited concomitant medications (see 
Section 9.2.1) 
 
9. TREATMENT 
9.1 Investigational Product 
Gelesis100 (medical device in capsule) and matching placebo will be used. Each capsule 
of Gelesis100 contains approximately 750 mg of CMC sodium salt cross-linked with 
citric acid, and 11 mg of sodium stearyl fumarate. Each capsule of placebo contains 
approximately 900 mg of raw cane sugar (sucrose). 
 
The envelopes of Gelesis100 and placebo capsules are provided by Capsugel. They each 
contain 126 mg of gelatin and 4 mg of titanium dioxide. The gelatin component is an 
animal-derived product. According to Capsugel, the gelatin undergoes stringent 
preliminary physical, chemical, and microbiological tests before it is released into 
production by the Capsugel quality control department. 
 

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9.1.1 Selection of Gelesis100 Amount 
Since Gelesis100 hydrates approximately 100 times its weight in the gastrointestinal 
tract, the proposed amount of 2.25 g of Gelesis100 (3 capsules before lunch and dinner) 
will expose the subjects to a volume of approximately 225 mL. This is well below the 
estimated volume of the human stomach which is about 900 mL (11) but is similar to the 
amount used in the FLOW study showing significant decrease in body weight and a good 
safety profile. 
 
9.1.2 Selection of Placebo 
To minimize the risk of unblinding in case the capsules are opened accidentally or 
intentionally, raw cane sugar was selected as placebo since it has the same color and 
shape as Gelesis100. Raw cane sugar contains sucrose (simple carbohydrate). The daily 
amount of sucrose (< 6 g/day) administered through placebo capsules is clinically 
acceptable (12) and has no significant health impact (including in diabetic subjects), 
especially if the subjects are following the dietary recommendations of the study. Indeed, 
substantial evidence from clinical studies demonstrates that dietary sucrose does not 
increase glycemia more than isocaloric amounts of starch (13). 
 
9.1.3 Packaging and Labeling 
The study product will be packaged in polypropylene bottles (3 capsules per bottle) and 
the bottles will be packaged in weekly boxes. Each weekly box will contain allowance 
for 1 additional day of dosing (i.e., 2 x 3 additional capsules) in the event the subsequent 
visit is delayed or the study product is damaged or lost. Each bottle will be appropriately 
labeled in accordance with the regulatory specifications and requirements. Each product 
(Gelesis100 or placebo) will have a unique serial number as part of the label. The labels 
will have 6 languages: English, French, Danish, Czech, Italian, and Spanish, in 
accordance with language requirements in US, Canada, and the European Economic Area 
(EEA) [status: 1/2007]. 
 
9.1.4 Responsibilities 
The Investigator (or designee) will maintain an accurate record of receipt of the 
investigational product as shipped by the Sponsor, including the date received, the batch 
number, and the serial number. One signed copy of this receipt will be returned to the 
Sponsor when the contents of the shipment have been verified. 
 
The personnel in charge of the storage and dispensation of the investigational product 
will insure that the product is securely maintained as specified by the Sponsor and in 
accordance with the regulatory requirements. 
 
The investigational product will be used for the purpose of this study only, and will be 
dispensed in accordance with the Investigator’s prescription. It is the responsibility of the 
Investigator to ensure that an accurate record of investigational product dispensed and 

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returned is maintained. The product disposition record will specify the amount dispensed 
to each subject and the date of dispensation. The inventory record will be available for 
inspection at any time. At the completion of the study, the Investigator (or designee) will 
make available copies of this inventory record to the Sponsor (or designee) upon request. 
 
Any quality issue noticed with the receipt or use of the investigational product by the 
Investigator (or designee) should be promptly notified to the Sponsor (or designee). 
 
9.1.5 Storage Conditions 
The investigational product will be sent by the Sponsor to the Investigator according to 
local regulatory requirements. It will be stored at the site, in a secure and safe place, 
between 5C (41F) and 30C (86F), under the responsibility of the Investigator or other 
authorized individual. 
 
9.1.6 Administration Method 
At each dosing of study product, a subject will consume 3 capsules. Damaged capsules 
should not be used. Capsules will be self-administered orally by the subjects 20 to 30 min 
before meals at lunch and dinner, with approximately 100 mL of water. After the 
capsules are taken, subjects will wait 5 to 10 min and then proceed to slowly drink  
500 mL of water over a period of up to 10 min. After this water intake, subjects will wait 
an additional 10 min before beginning to consume their meal in a slow manner. Drinking 
additional water during and after the meal is highly recommended. 
 
9.1.7 Treatment of Overdose 
Overdose with Gelesis100 may cause nausea, vomiting, flatulence, bloating, abdominal 
pain, constipation, diarrhea, or other unexpected side effects. The Investigator is 
responsible for any decision regarding the treatment of the overdose. 
 
9.1.8 Compliance Assessment 
Compliance will be assessed by counting of capsules remaining in each bottle, at each 
visit. 
 
Product accountability will be under Investigator’s direct supervision. The appropriate 
electronic case report form (CRF) will be completed regarding the dosing and the 
treatment assignment. 
 
9.1.9 Retrieval and/or Destruction 
At the completion of the study, investigational product, including all empty, partially 
used, and unused bottles, will be returned to the Sponsor (or designee). Detailed 

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treatment and accountability logs will be established and countersigned by the 
Investigator and the Monitoring Team Representative (or designee). 
 
The Investigator will not destroy the unused investigational product unless requested 
officially in writing by the Sponsor. 
 
9.2 Concomitant Medication 
9.2.1 Prohibited Medication 
 Oral contraceptives 
 Anti-obesity medications or other medications (including herbal preparations 
especially those containing amphetamine-like compounds) for weight reduction 
 Antidiabetic medications (except stable dose of metformin, ≤ 1500 mg/day, in 
subjects with type 2 diabetes already on treatment) 
 Systemic corticosteroids (oral, rectal, injectable) 
 Thyroid hormones or preparations (except stable dose of replacement therapy in 
subjects already on thyroid hormones or preparations) 
 Diuretics 
 Estrogen (except stable dose of replacement therapy or non-oral contraceptive in 
subjects already on treatment) 
 Any other medication or product known to cause weight loss or weight gain 
 Change in medications treating dyslipidemia (including change in dose) 
 Change in medications treating hypertension (including change in dose) 
 Any medication affecting gastrointestinal motility 
 Addictive medications including amphetamines, barbiturates, cannabinoids, 
cocaine, opiates, and phencyclidine 
 
The intake of prohibited medication for more than 7 days in case of oral formulation and 
at least once in case of injectable formulation is a major protocol deviation and will result 
in subject discontinuation from the study. The oral intake of prohibited medication for 7 
days or less is a minor protocol deviation and will not result in subject discontinuation 
from the study. 
 
9.2.2 Permitted Medication 
 Non-oral medications used for contraception 
 All other drugs than those listed in Section 9.2.1, if considered necessary for the 
subject, with a stable dose (when possible), at the discretion of the Investigator (if 
they are not taken within 2 h before and after the study product administration in 
case of oral drugs) 
 
Subjects should avoid the intake of any oral drugs and/or vitamin supplements within 2 h 
before and after the study product administration to prevent a potential reduction in the 

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efficacy of these drugs/vitamin supplements (secondary to a decrease in their intestinal 
absorption). 
 
At selected sites where vitamins are measured, subjects taking vitamin supplements 
should continue their intake without any change of the dose or the timing of 
administration during the study. 
 
9.3. Diet and Life-Style Recommendations 
9.3.1 Diet 
During the entire study (from the Baseline Visit to the last Follow-up Visit), a 
hypocaloric diet will be prescribed to all subjects. The energy requirement will be 
calculated by the dietitian based on the estimated basal metabolism rate and the physical 
activity of each subject at the Screening Visit using the Harris-Benedict equation (14). 
From this amount of energy, 300 kcal/day will be subtracted to obtain the recommended 
hypocaloric diet. The energy content will not be less than 1,200 kcal/day. 
 
The daily dietary intake will include approximately 45% to 50% of calories from 
carbohydrate, up to 30% of calories from fat (< 10% saturated fat, < 200 mg cholesterol), 
and 20% to 25% of calories from protein. Meals should be consumed slowly with water 
as instructed. The meal time should remain relatively unchanged during the study. The 
interval between lunch and dinner should be at least 5 h. The average daily alcohol 
consumption should be ≤ 20 g/day (or ≤ 140 g/week). The daily sodium intake of each 
subject should remain unchanged. 
 
The compliance of the subjects with the proposed diet will be assessed by a dietitian at 
each dietary interview during the study. The instructions on water intake should be 
reinforced if there is an increase in serum albumin from baseline of more than 1 g/L at 
Visit 4 (Day 15), Visit 5 (Day 29), and Visit 9 (Day 85). 
 
9.3.2 Life-Style 
Subjects will be instructed to have moderate-intensity physical activity (e.g., 30 min 
walking every day) during the study. 
 
Subjects will be instructed to continue, without change, their smoking habits during the 
study. 
 
The compliance of the subjects with the proposed life-style will be assessed by the 
Investigator’s Team at each visit during the study. 
 

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10. STUDY DURATION 
10.1 Study Duration per Subject 
10.1.1 Screening Period 
The maximum duration of the screening period is 21 days. 
 
10.1.2 Baseline Period 
The duration of the baseline period is 1 day. 
10.1.3 Treatment Period 
The duration of the double-blind treatment period (active product versus placebo) is  
168 days with a visit window of 2 or 3 days (see Section 12.1). 
 
10.1.4 Post-Treatment Follow-up Period 
The duration of the follow-up period is 28 days with a visit window of 3 days for Visit 14 
but no visit window for Visit 13 (see Section 12.1). 
 
10.2. Total Study Duration 
The total study duration will be approximately 2 years (including approximately 1 and 
half years for enrollment). The start date is expected to be during the second half of 2014 
and the end date during the first half of 2017. 
 
11. STUDY ENDPOINTS 
When hydrated, Gelesis100 has some weight by itself. At any time following the first day 
of Gelesis100 administration, subjects may accumulate up to 1 kg of hydrated Gelesis100 
in their gastrointestinal tract. Therefore, it is likely to observe an initial weight gain 
during the first days or weeks of treatment until the extra weight is counter-balanced by 
the weight loss caused by Gelesis100. An interval of 2 days is required for any remaining 
Gelesis100 to be eliminated from the gastrointestinal tract. For these reasons, to ensure 
that the weight of Gelesis100 does not mask the true amount of weight loss, the end of 
treatment assessment of body weight and weight-related parameters will be performed on 
Day 171, approximately 60 h after the last administration of Gelesis100. 
 
11.1 Effectiveness Endpoints 
11.1.1 Co-Primary Endpoints 
 Body weight (percent change from baseline to Day 171) 
 Body weight responders (≥ 5% weight loss from baseline to Day 171) 

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11.1.2 Secondary Endpoints 
 Plasma glucose status (normal, impaired, diabetic) (change from baseline to  
Day 171) 
 Plasma glucose (percent change from baseline to Day 171) 
 HOMA-IR (percent change from baseline to Day 171) 
 HbA1c (change from baseline to Day 171) 
 BMI (change from baseline to Day 171) 
 
11.1.3 Tertiary Endpoints 
 Body weight responders (≥ 10% weight loss from baseline to Day 171) 
 Estimated excess body weight (percent change from baseline to Day 171) 
 Body weight status (normal, overweight, obese) (change from baseline to  
Day 171) 
 Waist circumference (change from baseline to Day 171) 
 Serum insulin (percent change from baseline to Day 171) 
 Serum C-reactive protein (CRP) (change from baseline to Day 171) 
 Serum total cholesterol (percent change from baseline to Day 171) 
 Serum LDL cholesterol (percent change from baseline to Day 171) 
 Serum high-density lipoprotein (HDL) cholesterol (percent change from baseline 
to Day 171) 
 Serum total cholesterol/HDL cholesterol ratio (change from baseline to Day 171) 
 Serum triglycerides (percent change from baseline to Day 171) 
 Supine and standing SBP and DBP (change from baseline to Day 171) 
 Food intake (change from baseline to Day 169) 
 Food habits (change from baseline to Day 169) 
 Satisfaction (overall impression on Day 169) 
 Impact of weight on quality of life (IWQOL) (change from baseline to Day 171) 
(at selected sites) 
 
The secondary and tertiary effectiveness endpoints are for supportive purposes only. 
 
11.2 Safety Endpoints 
11.2.1 Adverse Events 
 All AEs and SAEs (including ADEs and SADEs) 
 
11.2.2 Physical Examination 
 Full physical examination (excluding pelvic and rectal examination) 
 

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11.2.3 Vital Signs 
 Supine and standing SBP and DBP 
 Supine and standing heart rate 
 
11.2.4 Laboratory Tests 
 Hematology including hemoglobin, hematocrit, red blood cell count, reticulocyte 
count, white blood cell count with differential, and platelet count 
 Blood chemistry including plasma glucose and serum sodium, potassium, 
chloride, calcium, phosphorous, magnesium, blood urea nitrogen, creatinine, uric 
acid, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, total 
protein, albumin, total bilirubin, alkaline phosphatase, lactate dehydrogenase, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, 
and 
gamma 
glutamyltransferase 
 Vitamins including vitamin A, vitamins B1, B2, B6, B9, and B12, vitamin D, and 
vitamin E (vitamins will be measured in approximately 60 subjects from the sites 
of Czech Republic and the site of Rome, Italy) 
 
11.3 Assessment Methods 
All the assessments, unless otherwise specified, will be performed in the morning 
(between approximately 7 am and 10 am), before product intake, on fasting subjects (10 
to 12-h fast) with no moderate or intense physical activity within the past 12 h. Physical 
examination, dietary interview, and electrocardiogram (ECG) can be performed at any 
time during the day regardless of food or investigational product intake. 
 
11.3.1 Clinical 
11.3.1.1 Physical Examination 
A full physical examination (excluding pelvic and rectal examination) will be performed 
by the Investigator. The physical examination will cover the following areas: 
- general appearance 
- eyes 
- ears, nose, throat 
- neck 
- respiratory 
- cardiovascular 
- endocrine 
- hepatic 
- gastrointestinal 
- genitourinary 
- peripheral vascular 
- neurological 
- musculoskeletal 
- extremities 

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- lymphatic 
- dermatological 
- allergies 
- psychiatric 
 
11.3.1.2 Body Weight 
Body weight should be obtained with the subject wearing undergarments or very light 
clothing and no shoes, and with an empty bladder. The same scale should be used 
throughout the study. The use of a balance-beam scale is recommended. If a digital scale 
is used, testing with standard weights is of particular importance. The scale needs to be 
calibrated within 12 months prior to the first Screening Visit and its precision should be 
verified every 4 months after the first Screening Visit. The floor surface on which the 
scale rests must be hard and should not be carpeted or covered with another soft material 
and the scale must not be moved during the entire duration of the study. The scale should 
be balanced with both weights at zero and the balance bar aligned. The subject should 
stand in the center of the platform as standing off-center may affect the measurement. 
The weights are moved until the beam balances (the arrows are aligned). The weight is 
read and recorded. Self-reported weights are not acceptable. Subjects must not read the 
scale themselves. 
 
11.3.1.3 Waist Circumference 
Waist circumference should be measured according to the established methods. It is taken 
at the midpoint between the lower rib margin and the iliac crest. The circumference 
should preferably be measured on subjects while they are semi-clothed (i.e., waist 
uncovered with the subjects wearing underclothes only). If it is not possible to follow this 
procedure, the alternative is to measure the circumference on subjects without heavy 
outer garments with all tight clothing, including the belt, loosened and with pockets 
emptied. Subjects should stand with their feet close together (no more than 15 cm apart) 
with their weight equally distributed on each leg. Subjects should be asked to breathe 
normally and at the time of the reading of the measurements asked to breathe out gently. 
This will prevent subjects from contracting their muscles or from holding their breath. A 
plastic metric tape should be used. The length of the tape should be checked before 
starting the study and the length should be re-checked against a standard measure at least 
once a month and the tape should be replaced as appropriate. The two sides of the tape 
should be differently colored or have a scale only on 1 side. If the tape is uniformly 
colored, with reading on both sides, 1 side should be blanked out. The tape should be 
held firmly and its horizontal position should be ensured. The tape should be loose 
enough to allow the recorder to place 1 finger between the tape and the subject’s body. 
The importance of the tightness of the tape should be emphasized. It is recommended that 
the observer sits beside the subject while the readings are taken. Three measurements will 
be performed and recorded. 
 
11.3.1.4 Blood Pressure 
SBP and DBP will be measured using a calibrated device. The device will be a mercury 
sphygmomanometer with a cuff appropriate to the subject’s arm girth (obesity cuff). If 
not available, another device may be used which is calibrated carefully in proportion to a 

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mercury sphygmomanometer. Aneroid manometer is not recommended. The calibration 
of the device will be according to the site-specific guidelines and requirements. The same 
model of device will be used for each subject throughout the study. Blood pressure 
should be measured under standardized conditions, on the same arm. Both SBP and DBP 
should be recorded. The disappearance of sound (Korotkov phase V) should be used for 
the diastolic reading. Blood pressure should be measured in both supine position (after 
the subject has rested comfortably for at least 5 min) and standing position (after 2 min). 
At the Screening Visit, supine blood pressure should be checked in both arms on two 
consecutive readings separated by 2 min. The arm with the higher SBP will be 
determined at this visit based on the mean of two consecutive readings, and blood 
pressure should be measured in this arm throughout the study. At each other visit, two 
readings of supine blood pressure separated by 2 min should be recorded. 
 
11.3.1.5 Heart Rate 
Heart rate (pulse) will be measured over 1 min at the time of the second measurement of 
supine blood pressure and at the time of the measurement of standing blood pressure and 
the results will be recorded. 
 
11.3.1.6 Electrocardiogram 
ECG will be obtained using a 12-lead cardiograph. The maintenance of the device will be 
according to the site-specific guidelines and requirements. ECG will be performed after a 
15-min rest in supine position. 
 
11.3.1.7 Binge Eating Disorder 
The questionnaire on eating and weight patterns-revised (QEWP-R) abbreviated version 
will be used to identify subjects with binge eating (Appendix 1). Subjects are excluded 
from enrollment if the answer to question 11 is yes except if they are considered as mild 
binge eaters according to the Investigator’s assessment. 
 
11.3.1.8 Food Intake 
Food intake will be assessed by food diary. The diary will include all the meals consumed 
during any 2 consecutive weekdays and 1 weekend day before the visit. The assessment 
will include global food intake (including fluid intake), carbohydrate intake, fat intake, 
protein intake, and fiber intake. 
 
11.3.1.9 Food Habits 
Food habits will be assessed by a questionnaire (Appendices 2 and 3). 
 
11.3.1.10 Satisfaction 
A questionnaire will record the thoughts of the subjects regarding the investigational 
product (Appendix 3). The questionnaire will be completed by the subjects at the last 
treatment visit. 
 
11.3.1.11 Impact of Weight on Quality of Life 
The IWQOL questionnaire will ask subjects at selected sites about the impact of weight 
on their quality of life (Appendix 4). 

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11.3.1.12 Adverse Events 
All AEs and SAEs will be recorded (see Section 13). 
 
11.3.2 Biological 
11.3.2.1 Blood Parameters and Genomic Tests 
Blood samples will be collected by venipuncture and shipped to the local or central 
laboratory as per laboratory instructions (provided in a laboratory manual). 
 
Insulin resistance will be measured by HOMA-IR (15), which is calculated by 
multiplying fasting serum insulin (μU/mL) by fasting plasma glucose (mmol/L) and 
dividing by 22.5. 
 
Serum amylase results will be reported as total serum amylase and pancreatic serum 
amylase. 
 
Genomic tests will include the analysis of copy number variation of AMY1 gene (gene 
encoding salivary amylase) and additional analysis of several genes involved in obesity 
and type 2 diabetes (BDNF, CAPN10, FTO, KCNJ11, LEPR, MC4R, NEGR1, NPC1, 
PCSK1, PPARG, SH2B1, SLC16A13, and TCF7L2 genes). Blood samples for the 
extraction and analysis of deoxyribonucleic acid will be shipped to the central laboratory 
as per laboratory instructions. The results of genomic tests together with the results of 
serum amylase will be correlated to weight-related and metabolic parameters at baseline 
and their evolution during the study, in different populations. 
 
The total blood requirement per subject for all blood samplings will be approximately  
70 mL over approximately 31 weeks. An additional 25 mL of blood per subject will be 
drawn during the entire study at sites where vitamins should be measured and 5 mL of 
blood per subject will be drawn at a single visit for genomic tests. 
 
11.3.2.2 Urine Parameters 
Urine samples will be collected from a morning spot. The tests will be performed at the 
Investigator’s site (pregnancy test, drug screen). The subjects should empty their bladder 
(and discharge the urine) around 6 am, drink approximately 1 glass of water, and wait 
approximately 2 h before the urine samplings. 
 
Urine drug screen will detect amphetamines, barbiturates, cannabinoids, cocaine 
metabolites, opiates, and phencyclidine. 
 
12. VISITS 
12.1 Schedule 
This is an outpatient study (see Section 2 Study Flow Chart). The assessments of Visit 1 
(Screening Visit) can be done over several days within the screening period. Visit 13 

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should occur 2 days after Visit 12. The other visits can take place within ± 2 days (up to 
Visit 9) and ± 3 days (after Visit 9) of the schedule. 
 
Visit 13 should be avoided during the extended holiday period of December/January (the 
last week of December and the first 2 weeks of January). To reach this objective, Visit 2 
should not be scheduled during the last 3 weeks of July. 
12.2 Assessments 
The following procedures will be performed (see Section 11 Study Endpoints): 
 
12.2.1 Visit 1 (Screening Visit; Day -21 to -1) 
 Informed consent (women of childbearing potential are requested to use a 
medically approved contraceptive method during the entire study) 
 Demographic characteristics (gender, age, ethnic origin) 
 Menopausal status (and estrogen replacement therapy status) 
 Smoking status 
 Medical history 
 Physical examination 
 Height 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 ECG 
 Binge eating disorder (QEWP-R) 
 Dietary interview (calculation of the energy requirement) 
 Serum pregnancy test (women of childbearing potential only) 
 TSH 
 Urine drug screen (test performed at the Investigator’s site) 
 HbA1c 
 Hematology 
 Blood chemistry 
 Previous (within 1 month) and concomitant medication records 
 AEs and SAEs records 
 
12.2.2 Visit 2 (Baseline Visit; Day 0) 
 Physical examination 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary prescription) 
 Food intake 
 Food habits 

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 IWQOL 
 Serum amylase (blood can be collected at any of the Visits 2, 3, 4, 5, 9, or 13) 
 Genomic tests (blood can be collected at any of the Visits 2, 3, 4, 5, 9, or 13) 
(tests not mandatory) 
 Serum pregnancy test (women of childbearing potential only) 
 Urine pregnancy test (women of childbearing potential only) (test performed at 
the Investigator’s site) 
 Serum insulin 
 HbA1c 
 Serum CRP 
 Hematology 
 Blood chemistry 
 Vitamins 
 Concomitant medication record 
 Randomization 
 Dispensation of study product (administration begins the following day) 
 AEs and SAEs records 
 
12.2.3 Visit 3 (First Double-Blind Visit; Day 8 ± 2) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Plasma glucose 
 Serum insulin 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.4 Visit 4 (Second Double-Blind Visit; Day 15 ± 2) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Plasma glucose 
 Serum insulin 
 Serum albumin 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 

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 AEs and SAEs records 
 
12.2.5 Visit 5 (Third Double-Blind Visit; Day 29 ± 2) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Plasma glucose 
 Serum insulin 
 Serum albumin 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.6 Visit 6 (Fourth Double-Blind Visit; Day 43 ± 2) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.7 Visit 7 (Fifth Double-Blind Visit; Day 57 ± 2) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.8 Visit 8 (Sixth Double-Blind Visit; Day 71 ± 2) 
 Weight 

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 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.9 Visit 9 (Seventh Double-Blind Visit; Day 85 ± 2) 
 Physical examination 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Serum pregnancy test (women of childbearing potential only) 
 Serum insulin 
 TSH (subjects on replacement therapy with thyroid hormones or preparations 
only) 
 HbA1c 
 Serum CRP 
 Hematology 
 Blood chemistry 
 Vitamins 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 Reinforcement of study-related instructions 
 
12.2.10 Visit 10 (Eighth Double-Blind Visit; Day 113 ± 3) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 

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12.2.11 Visit 11 (Ninth Double-Blind Visit; Day 141 ± 3) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Concomitant medication record 
 Investigational product accountability 
 Dispensation of study product 
 AEs and SAEs records 
 
12.2.12 Visit 12 (Tenth Double-Blind Visit; Day 169 ± 3) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Food intake 
 Food habits and satisfaction 
 Concomitant medication record 
 Investigational product accountability 
 AEs and SAEs records 
 
12.2.13 Visit 13 (First Follow-up Visit; Day 171; 2 days after Visit 12) (Last visit if 
entering extension study) 
 New informed consent (subjects entering extension study) 
 Physical examination 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 IWQOL 
 Serum pregnancy test (women of childbearing potential only) 
 Serum insulin 
 HbA1c 
 Serum CRP 
 Hematology 
 Blood chemistry 
 Vitamins 
 Concomitant medication record 
 AEs and SAEs records 
 

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12.2.14 Visit 14 (Second Follow-up Visit; Day 197 ± 3) 
 Weight 
 Waist circumference 
 Vital signs (supine and standing blood pressure and heart rate) 
 Dietary interview (dietary check) 
 Concomitant medication record 
 AEs and SAEs records 
 
12.3 Definition of Source Data 
The list of information considered as source data that must be shown in the subject’s 
chart is provided in Appendix 5. 
 
13. SAFETY MONITORING AND REPORTING 
13.1 Adverse Event and Device Deficiency 
13.1.1 Investigational Product in this Clinical Study 
In this clinical study, the investigational product, Gelesis100, is considered as a medical 
device. Therefore, all safety monitoring and reporting procedures are governed by 
medical device guidelines and regulations. 
 
13.1.2 Definitions 
An AE is any untoward medical occurrence (sign, symptom, illness, abnormal laboratory 
value, or other medical event) in a subject, whether or not related to the investigational 
medical device. This includes events related to the procedures involved (any procedure in 
the Clinical Investigation Plan). 
 
A SAE is any AE that: 
- led to death 
- resulted-in a life-threatening condition 
- resulted-in a permanent impairment of a body structure or a body function 
- required inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 h 
(elective hospitalizations and/or hospitalizations for treatment of pre-existing conditions 
that did not worsen from baseline are not considered AEs and should not be reported as 
SAEs) 
- resulted-in a medical or surgical intervention to prevent permanent impairment to a 
body structure or a body function 
- led to fetal distress, fetal death or a congenital abnormality, or birth defect 
 
A device deficiency is an inadequacy of the medical device with respect to its identity, 
quality, durability, and safety (e.g., use errors and inadequate labeling). Medical device 

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deficiency can lead to an adverse device effect (ADE) or a serious ADE (SADE) (see 
below). 
 
For the purpose of this study and for reporting purposes, all device deficiencies that could 
have led to SAEs, if suitable action had not been taken or intervention had not been 
made, or if circumstances had been less fortunate, will also be considered as SAE. 
An ADE is an AE with a reasonable causal relationship to the use of the investigational 
medical device (i.e., an AE assessed as either “most probably related” or “possibly 
related” to the use of medical device) (see Section 13.1.3). 
 
An unanticipated ADE (UADE) is an ADE not previously reported or an ADE that 
occurs with specificity, severity, frequency, or outcome that is not consistent with the 
current Investigator’s Brochure (8). 
 
A SADE is a SAE with a reasonable causal relationship to the use of the investigational 
medical device (i.e., a SAE assessed as either “most probably related” or “possibly 
related” to the use of medical device). For Canada, this definition is equivalent to the 
Canadian definition of an incident. 
 
An unanticipated SADE (USADE) is a SADE not previously reported or an SADE that 
occurs with specificity, severity, frequency, or outcome that is not consistent with the 
current Investigator’s Brochure. In US, this definition is equivalent to the definition of an 
UADE in Medical Device Reporting regulation at Title 21. 
 
13.1.3 Adverse Event and Device Deficiency Recording, Assessment, and Reporting 
Procedure 
All AEs regardless of seriousness or relationship to the investigational medical device 
including those occurring during the screening period (after the signature of the Informed 
Consent Form) are to be recorded in the appropriate electronic CRF. 
 
AEs reported by subject will be discussed in details and recorded by the Investigator at 
each visit. AEs will be collected until 28 days after the last administration of the 
investigational medical device (i.e., until subject terminates his/her participation in the 
study). 
 
The Investigator should specify the date of onset, severity, action taken with respect to 
the investigational medical device, corrective treatment, outcome, and whether or not 
there is a reasonable possibility that the AE may have been caused by the use of the 
investigational medical device. 
 
AEs are graded as follows: 
 Mild: sign or symptom, usually transient, requiring no special treatment and 
generally not interfering with usual activities. 

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 Moderate: sign or symptom, which may be ameliorated by simple therapeutic 
measures, may interfere with usual activity. 
 Severe: sign or symptom intense or debilitating and interfering with usual 
activities without being immediately life-threatening. Recovery is usually aided 
by therapeutic measures. 
 Very severe: sign or symptom life-threatening. Urgent intervention indicated. 
 
The assessment of the relationship of an AE to the use of the medical device is a clinical 
decision based on all available information at the time of the completion of the electronic 
CRF: 
 Most probably related: follows a reasonable temporal sequence from medical 
device use, and cannot be reasonably explained by known characteristics of the 
subject’s clinical data. 
 Possibly related: follows a reasonable temporal sequence from medical device 
use, but could have been produced by the subject’s clinical state regardless of the 
medical device. 
 Probably not related: temporal association is such that the medical device use is 
not likely to have had any reasonable association with the observed event. 
 Not related: no relationship to the use of the medical device is perceived. 
 
Abnormalities of vital signs and laboratory results are to be recorded as AEs only if they 
are considered by the Investigator as clinically significant (symptomatic, requiring 
corrective treatment, leading to discontinuation, or fulfilling a seriousness criteria). 
 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the 
Screening Visit should be recorded as medical/surgical history. 
 
In this study, the following events will be reported to the authorities on expedited basis: 
 All SAEs (including SADEs) will be expeditiously reported to the relevant 
European Regulatory Authorities and the Ethics Committees. 
 All newly discovered pregnancies will be expeditiously reported, if required by 
the local regulations. 
 All suspected USADEs will be expeditiously reported to the US Food and Drug 
Administration (FDA) and the US Institutional Review Boards. 
 All incidents occurring in Canada will be expeditiously reported to Health 
Canada. 
 
All device deficiencies are to be recorded in the appropriate electronic CRF. 
 
13.1.4 Anticipated Adverse Device Effects 
The ADEs anticipated with the administration of Gelesis100 in overweight or obese 
subjects include nausea, dyspepsia (heartburn), abdominal distension (bloating), 
flatulence, abdominal pain, diarrhea, defecation urgency, and constipation. These AEs 

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were observed in the FLOW study. A comprehensive list of anticipated ADEs is provided 
in the Investigator’s Brochure (8). 
 
13.1.5 Risk Analysis 
The Sponsor has established and maintains a process for identifying hazards associated 
with the use of its products, estimating, evaluating, controlling these risks and monitoring 
the effectiveness of the control. Detailed information regarding risk analysis is available 
in the Investigator’s Brochure (8). 
 
13.1.6 Precautions to Minimize Risk 
To minimize technical and medical complications, the investigational medical device 
should be used only as instructed in the Clinical Investigation Plan. This includes: 
- administering the prescribed amount of medical device before lunch and dinner (3 
capsules) 
- drinking the prescribed volume of water (approximately 100 mL + 500 mL) at the 
prescribed timing before meal 
- consuming food at the prescribed timing (20 to 30 min after medical device 
administration) 
 
13.2 Pregnancy 
In case of pregnancy, the investigational medical device use must be discontinued and the 
Sponsor informed. Every effort should be made to follow up the pregnancy until its 
outcome is available. 
 
The Contract Research Organization (CRO) Clinical Safety will provide the Investigator 
with the Pregnancy Reporting Form for completion. If the pregnancy is to be terminated, 
the anticipated date of termination should be provided. 
 
13.3 Responsibilities for Adverse Event and Pregnancy Reporting 
13.3.1 Responsibilities of the Investigator 
- to inform the Sponsor about all AEs 
- to inform the Sponsor about all SAEs, newly discovered pregnancies or pregnancy 
outcomes, within 24 h of awareness of the events, by: 
 entering the information about the event into the electronic CRF 
 in case the Investigator does not receive an automatic notification from the 
electronic CRF system of successful SAE submission or electronic CRF data 
entering is not possible: 
- printing the completed section of the electronic CRF (or in case completion of 
electronic CRF is not possible, completion of paper SAE form) 
- signing the completed SAE form 

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- sending the scanned SAE form by e-mail to the CRO Clinical Safety at 
pharmacovigilance@easthorn.eu (or in case sending a scan is not possible, faxing 
it to the CRO Clinical Safety at +420 244 462 271) 
- to inform the Sponsor about all device deficiencies 
- to make every effort to follow up the subject to a satisfactory resolution of the safety 
event or until the end of the study 
- to respond to follow-up requests from the Sponsor/CRO Clinical Safety 
 
13.3.2 Responsibilities of the Sponsor 
- to ensure that: 
 all AEs are recorded and reviewed with the Investigators 
 all SAEs are reported to the relevant European Regulatory Authorities/Ethics 
Committees as required by the local regulations 
 all newly discovered pregnancies are reported as required by the local regulations 
 all suspected USADEs are reported to the FDA/Institutional Review Boards as 
required by the US regulations 
 all SADEs/incidents are reported to Health Canada as required by the Canadian 
regulations 
 all device deficiencies are recorded and reviewed with the Investigators 
- during the course of the study, inform in writing all Investigators about all SAEs 
occurring at any of the participating sites 
- to collect and maintain records of all AEs, device deficiencies, and pregnancies 
 
14. TREATMENT/STUDY DISCONTINUATION 
14.1 Temporary Treatment Discontinuation 
The subjects may discontinue the study treatment for a period not exceeding 3 days for a 
valid medical reason, at the discretion of the Investigator. 
 
14.2 Permanent Treatment/Study Discontinuation 
14.2.1 Reasons 
The subject may withdraw from the treatment with the investigational product (and the 
study) at any time and irrespective of the reason. 
 
The Investigator will discontinue the investigational product (and the study) for the 
following reasons (after assessing their clinical relevance): 
- contraception cessation 
- pregnancy or wish of pregnancy 
- significant intolerance to the study product 
- an increase of ≥ 0.5% point (≥ 5.5 mmol/mol) in HbA1c from Baseline Visit in subjects 
with treated or untreated type 2 diabetes, or any increase if the new value falls in the 

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range of the exclusion criteria for HbA1c (see Section 8.4) after confirmation following a 
re-check at the next study visit (or before) 
- an increase of ≥ 10% in total cholesterol, LDL cholesterol, or triglycerides from 
Baseline Visit in subjects with elevated lipids at Baseline Visit, or any increase if the new 
values fall in the range of the exclusion criteria for lipids (see Section 8.4) after 
confirmation following a re-check at the next study visit (or before) 
- an increase of ≥ 10 mm Hg in supine SBP and/or supine DBP from Baseline Visit in 
subjects with treated or untreated hypertension, or any increase if the new values fall in 
the range of the exclusion criteria for blood pressure (see Section 8.4) after confirmation 
following a re-check at the next study visit (or before), based on the mean of two 
consecutive readings 
- poor subject compliance with the study procedures and recommendations and/or major 
protocol deviation 
- it is the best interest of the subject (including the need to add prohibited medications) 
 
The subject is withdrawn from the treatment and the study if the treatment arm is 
unblinded for emergency reasons (see Section 15.5.4.2) or for a reason other than the 
interim analysis before the end of the treatment. 
 
14.2.2 Procedures 
When confirmed, a permanent treatment/study discontinuation should be recorded by the 
Investigator in the appropriate electronic CRF and, if applicable, reported to the relevant 
Ethics Committee/Institutional Review Board. 
 
Every effort should be made to complete the clinical and laboratory evaluations required 
for Visits 12 and 13 as soon as possible (combined assessments). 
 
Subjects who have withdrawn from the treatment/study cannot be re-enrolled in the 
study. Their screening number and randomization number must not be re-used. 
 
15. STATISTICAL CONSIDERATIONS 
This section presents general information about statistical considerations and concepts 
such as randomization, stratification, statistical power, and sample size. There will also 
be a brief discussion on analysis methodology, as well as some data conventions. The 
detailed descriptions of statistical analysis methods and data conventions will be in a 
separate document, the Statistical Analysis Plan (SAP). Any post-hoc analyses will be 
identified in the final Clinical Study Report. 
 
15.1 Treatment Arms 
The following treatment arms will be assessed: 
- active: Gelesis100 2.25 g, twice daily 
- placebo: matching placebo containing sucrose, twice daily 

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15.2 Baseline and Visit Windows 
Baseline for a given parameter or endpoint is defined to be the last observation (obtained 
at either the Screening or Baseline Visit) taken before the first study product 
administration. The study visits and visit windows are Days 8 ± 2, 15 ± 2, 29 ± 2, 43 ± 2, 
57 ± 2, 71 ± 2, 85 ± 2, 113 ± 3, 141 ± 3, 169 ± 3, 171, and 197 ± 3. 
 
15.3 Description of Study Endpoints 
The details of the study endpoints are presented in Section 11. 
 
15.4 Sample Size Determination and Rationale 
For this clinical trial, a total of 460 subjects (230 per arm) will be randomized to have 
322 subjects complete the study (161 per arm) due to an anticipated dropout rate of 30%. 
This sample size will allow establishing both super-superiority and superiority with 
sufficient statistical power based on the primary endpoint of change in body weight from 
baseline. 
 
The sample size calculation, using PASS (16), is based on the assumption that there will 
be a clinically meaningful difference of at least 3.0% weight loss between the two arms 
after 24 weeks of treatment. This 3.0% is also being used as margin to establish the 
super-superiority (lower bound of the confidence interval of Gelesis100 effect ≥ 3.0% of 
placebo effect). With the above sample size, there is 85% statistical power for a 3.0% 
margin super-superiority (i.e., delta of at least 4.5%) with a common SD of 5.0% and a 
type I error rate of 0.05 (one-sided test). The statistical formula for the study hypothesis is 
as follows: 
H0: µplacebo - µGelesis100 < 3.0% 
HA: µplacebo - µGelesis100 ≥ 3.0% 
Where µplacebo is the mean percent change from baseline in the placebo arm and µGelesis100 is 
the mean percent change from baseline in the Gelesis100 arm. 
 
In addition, with the above sample size, there will be at least 90% statistical power to 
establish that the difference between the two arms is greater than 0 (i.e., the superiority 
with no margin), with a common SD of 5.0% and a type I error rate of 0.05 (two-sided 
tests), with the null hypothesis that the mean percent change from baseline in primary 
effectiveness endpoint is the same for both treatment arms and the alternative hypothesis 
that the Gelesis100 arm provides a different mean percent change in body weight than 
does the placebo arm. The statistical formula for the study hypothesis is as follows: 
H0: µplacebo - µGelesis100 = 0 
HA: µplacebo - µGelesis100 ≠ 0 
Where µplacebo is the mean percent change from baseline in the placebo arm and µGelesis100 is 
the mean percent change from baseline in the Gelesis100 arm. 
 

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15.5 Randomization, Stratification, Blinding, and Unblinding 
15.5.1 Randomization 
This is a multicenter randomized clinical trial with sites from different countries (US, 
Canada, and several European countries). Eligible subjects will be randomly assigned to 
the active arm or the placebo arm based on a randomization schedule. An individual 
independent of the clinical trial team will develop the randomization schedule. 
 
The randomization will be central and will use mixed blocks of 2 and 4 with a 1:1 ratio of 
active to placebo to ensure even distribution of active and placebo subjects. Each arm 
will include approximately 230 subjects. 
 
The randomization assignment will be made through an interactive web randomization 
system maintained by the CRO. The site representative will log into the eClinical system 
(developed by Clinical Research Technology, Srl.) and enter the information pertaining 
to the subject to be randomized, and will be notified of the next sequential randomized 
treatment. 
 
15.5.2 Stratification 
The following characteristics at the Screening Visit will be used as stratification factors at 
the time of randomization and the centralized randomization procedure will balance 
treatment arm assignments in each country or combination of countries for the following 
stratification factors: 
- male, BMI < 35, and normal fasting glucose 
- male, BMI < 35, and impaired/diabetic fasting glucose 
- male, BMI ≥ 35, and normal fasting glucose 
- male, BMI ≥ 35, and impaired/diabetic fasting glucose 
- female, BMI < 35, and normal fasting glucose 
- female, BMI < 35, and impaired/diabetic fasting glucose 
- female, BMI ≥ 35, and normal fasting glucose 
- female, BMI ≥ 35, and impaired/diabetic fasting glucose 
 
The selection of these stratification factors is based on the facts that gastric capacity has a 
tendency to be higher in male subjects and in subjects with higher BMI, and weight loss 
can be more important in subjects with higher fasting glucose (data from the FLOW 
study). 
 
15.5.3 Blinding 
As this is a double-blind trial, the study participants, the Investigators, all other study site 
personnel, the Monitoring Team involved in collecting the data, the Data Management 
Team involved in querying the clinical sites, and the Sponsor will be blinded to treatment 
assigned to the subject during the entire course of the study. Placebo capsules matching 

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the size, shape, color, and coating of Gelesis100 will be used for blinding the study 
treatment. 
 
The randomization lists containing the assignment of subjects to treatment arms will be 
securely provided to the person involved in randomizing the subjects (i.e., the 
WebMaster), who has no role in screening, qualifying, enrolling, or evaluating study 
subjects. No other study personnel other than the WebMaster and the randomization code 
generator will have access to the randomization codes for the study. 
 
15.5.4 Unblinding 
To maintain the study blind, treatment unblinding will occur only per the cases specified 
below. The unblinding will be performed after all clinical data have been received, data 
inconsistencies have been resolved, and the database has been locked, except for the case 
of the interim analysis by an independent statistician and the emergency unblinding 
including management of a suspected USADE/SADE. 
 
15.5.4.1 Unblinding for Interim Analysis 
An interim analysis is planned to be conducted when approximately 50% of the subjects 
have been randomized and completed Visit 13 (Week 24) or early terminated, whichever 
comes first. The details of this interim analysis are presented in Section 15.6. 
 
Unblinded treatment assignments for the interim analysis will only be given to the 
independent statistician. For this analysis, there will be no subject level unblinding to any 
other personnel in the study except the WebMaster and the randomization code generator. 
The summary tables will be unblinded to the treatment arm level and will be presented 
using masked treatment arms. Unblinding of treatment arms to the Data Monitoring 
Committee members will only occur per their request. 
 
15.5.4.2 Unblinding for Emergency 
Every attempt will be made to maintain the blind throughout the study. Breaking the 
blind prematurely will be allowed only under two circumstances: 
- when knowledge of the treatment assignment is essential for treating a subject in case of 
an emergency 
- as part of the management of a suspected USADE/SADE 
 
The unblinding of treatment assignment will be performed by: 
 
The Investigator in case of a suspected SADE if: 
 The information about the treatment assignment is essential for the subsequent 
treatment of the suspected SADE. 
 
Should the need for unblinding the code arise, the Sponsor’s Trial Monitor must be 
contacted immediately via phone and e-mail to approve the unblinding. This prior 
approval can be waived if there is a life-threatening situation requiring immediate 

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intervention. However, the Investigator must notify the Sponsor (or designee) as soon as 
possible following the unblinding event. 
 
The CRO Clinical Safety in case of a suspected USADE/SADE if: 
 The Regulatory Authorities/Ethics Committee/Institutional Review Board request 
the information about the treatment assignment. 
 The Sponsor needs the information about the treatment assignment for the 
evaluation of risk analysis. 
The CRO Clinical Safety performs such unblinding upon approval from the Sponsor. 
After unblinding, the CRO Clinical Safety Manager informs both the Sponsor and the 
Investigator about the study subject in question. 
 
The unblinding is performed by logging onto the eClinical system and entering the 
appropriate subject-specific information. The user will follow the prompts for emergency 
unblinding and will be notified of the treatment assignment on the screen. The date and 
reason for revealing the treatment assignment for the subjects will be captured in the 
eClinical system. Sponsor and CRO Clinical Safety will be notified of the unblinding. 
Sponsor’s Trial Monitor will follow up with the site in a case the site did not obtain prior 
approval to unblind. 
 
Subjects who are unblinded for emergency reasons will be discontinued from the 
treatment. 
 
15.5.4.3 Unblinding for Final Analysis 
Treatment unblinding and release of the randomization codes of the investigational 
product assignments for the study will occur if the trial is terminated or, at the time of 
database lock. That is after all randomized subjects have completed the study or 
discontinued from the study and all clinical data have been received and data 
inconsistencies have been resolved. 
 
15.6 Interim Analysis 
An interim analysis will be conducted when approximately 50% of subjects have been 
randomized and completed Visit 13 (Week 24) or early terminated, whichever comes 
first. 
 
The procedures for this interim analysis will be based on a standard operating procedure 
that has a well-established firewall to protect the integrity of the trial. The interim 
analysis will be performed by an independent statistician, who is not otherwise associated 
with the conduct of this trial. 
 
The main purpose of this interim analysis is to assess: 
- sample size re-assessment to evaluate the sample size estimations, which will serve in 
the planning of the remainder of the study 
- other parameters that the Data Monitoring Committee may request 

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15.6.1 Procedures for Interim Analysis 
 Cutoff dates for collection of electronic CRFs, data querying, database lock, and 
analysis are established based on an estimated target date of the approximately 
50% of subject completing 24 weeks of treatment or early terminated. 
 All data available by the cutoff date is entered, validated, queries generated and 
resolved or pending queries documented. 
 The database is locked. 
 The locked database is saved in a drive to which only the independent statistician 
responsible for the interim analysis has access. 
 
Using the data obtained in this interim analysis, the independent statistician will prepare 
safety summaries and calculate the following metrics for the primary endpoint: 
 Mean percent change at Week 24, the SD and the observed number of subjects in 
the active arm. 
 Mean percent change at Week 24, the SD and the observed number of subjects in 
the placebo arm. 
 The dropout rate at the time of the interim analysis for both arms. 
 The conditional power (CP) analysis of the study at the time of the interim 
analysis (17) (the method for this calculation is provided in below). 
 The revised sample size requirement based on this interim analysis (18) (the rule 
and method for sample size recalculation are provided below). 
 
15.6.2 Conditional Power Calculation 
The CP will be calculated according to the below formula using the mean percent 
changes in the active arm compared to placebo arm: 
 
CP (f1,z1) = Φ {z1/√𝑓1 (1 −𝑓1) – zα/√(1 −𝑓1)} 
where: 
 CP (f1,z1) is the CP at the interim analysis 
 Φ{.} is the cumulative distribution function of a standard normal distribution  
(μ = 0, σ2 = 1) 
 f1 is the fraction of subjects enrolled and used in the interim analysis before 
decision of increasing the sample size 
 zα is the upper α quintile for standard normal distribution 
 z1 is the standardized normal, the z score will be obtained from the following 
formula: 
 
            z1 = (µa - µc - 3)/√[𝜎𝑎2/ 𝑛𝑎+ 𝜎𝑐2/ 𝑛𝑐 ] 
            where: 
o µa = the mean percent changes at Week 24 for the subjects in the active 
arm 

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o µc = the mean percent changes at Week 24 for the subjects in the placebo 
arm 
o σa = the SD of percent changes at Week 24 for the subjects in the active 
arm 
o σc = the SD of percent changes at Week 24 for the subjects in the placebo 
arm 
o na = the number of subjects in the active arm used in the interim analysis 
o nc = the number of subjects in the placebo arm used in the interim analysis 
o a = the active arm 
o c = the placebo arm 
 
The resulting CP will be used to determine whether the sample size should be increased 
or remain unchanged. 
 
15.6.3 Rule and Method for Increasing Sample Size 
 If the CP < 36%, the sample size will not be increased and the study will continue 
as is. 
 If the CP is ≥ 36% and < 85%, the sample size may be adjusted to retain the 
original power of 85%. 
 If the CP is ≥ 85%, the study will continue as is. 
 
Regardless of the size of the CP, the study sample size will not be reduced. 
 
15.6.4 Data Provided to Data Monitoring Committee 
The Data Monitoring Committee will receive a statistical report. The details on the 
content of the report will be described in the Data Monitoring Committee charter. 
 
15.6.5 Stopping Rule 
The study will not be stopped for overwhelming effectiveness reasons. However, the 
Data Monitoring Committee may recommend stopping the study for safety reasons at any 
time during the trial. The Investigator may decide to stop the study for reasons described 
in Section 14.2.1. The Sponsor may also decide to stop the study for safety or other 
reasons at any time during the trial (see Section 22.1). 
 
15.6.6 Stopping Rule Provided to Sponsor by Data Monitoring Committee 
The Data Monitoring Committee will make recommendations to the Sponsor on the 
sample size adjustment and any safety concerns. 
 

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15.6.7 Type I Error Rate Adjustment 
There will be no type I error rate adjustment as there is no intention to stop the study for 
effectiveness benefit. In addition, the sample size is planned to be increased when the 
interim CP is promising and this will protect the type 1 error rate (18). 
 
15.7 General Statistical Considerations 
All collected study data will be presented in subject data listings. Statistical analyses will 
be performed using SAS® for Windows, version 9.3 or later. Descriptive statistics 
(number of observations, mean, SD, median, minimum, and maximum values) will be 
calculated by treatment arm for continuous variables. Frequencies and percentages will 
be presented by treatment arm for categorical variables. 
 
15.7.1 Analysis Populations 
15.7.1.1 Intention-to Treat Population 
The ITT population is defined as all randomized subjects. 
 
15.7.1.2 Per Protocol Population 
The per protocol (PP) population refers to all randomized subjects who were successfully 
randomized, treated, and stayed on their assigned treatment with no major protocol 
deviation. 
 
15.7.1.3 Safety Population 
The safety population is defined as any subject receiving the treatment after 
randomization. This population will be used for the analysis of safety parameters. 
 
15.7.2 Covariates 
For effectiveness analyses, the stratification factors and the respective baseline values for 
the endpoint will be used as covariates in the analysis models. 
 
15.7.3 Missing Data 
For effectiveness evaluation, missing data points will be imputed using multiple 
imputation approach. This approach is robust and the least biased for the missing at 
random cases. This method will be detailed in the SAP. 
 
15.7.4 Multiple Comparisons and Multiplicity 
For the co-primary endpoints, there will be no type I error adjustment. 
 
For the secondary endpoints, the Closed Test procedure will be used. All the secondary 
endpoints will be ordered prior to database lock and tested according to the order. 
 

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15.7.5 Subgroup Analysis 
Several subgroup analyses will be conducted for the stratification factors as well as the 
pre-specified secondary endpoints. Subgroup analyses will also be performed based on 
the results of serum amylase and genomic tests. The detail of these subgroup analyses 
will be presented in the SAP. 
 
15.8 Statistical Methods 
A SAP will be developed and approved before the database is locked. The SAP will 
present the detailed statistical methodology to be used in analyzing the effectiveness and 
safety data from this trial. 
 
All the effectiveness endpoints presented here will be conducted using both the ITT and 
the PP populations. All safety analyses will be conducted using the safety population. 
 
All data collected will be summarized according to the variable type: 
 Continuous data summaries will include: 
o Number of observations, mean, SD, median, minimum, and maximum 
values 
o ANCOVA with the stratification factors and the respective baseline values 
for the endpoint in the model for inferential statistics 
 Categorical data summaries will include: 
o Frequency counts and percentages 
o Logit model with the stratification factors and the respective baseline 
values for the endpoint in the model for inferential statistics 
 Time-dependent data: 
o Cox proportional hazards model will be used to analyze time-dependent 
data 
o Kaplan-Meier will be used to depict the time to event data 
 
15.8.1 Subject Disposition 
The disposition of all subjects who sign an Informed Consent Form will be provided. The 
numbers of subjects screened, randomized, completed, and discontinued during the study, 
as well as the reasons for all post-randomization discontinuations will be summarized by 
treatment arm. Disposition and reasons for study discontinuation will also be provided as 
a by-subject listing. 
 

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15.8.2 Demographics and Baseline Characteristics Analysis 
Demographic and baseline characteristic data will be summarized descriptively and/or 
presented as a by-subject listing for the safety population. In addition, all the known 
potential risk factors (e.g., diabetes, dyslipidemia, hypertension) will be tabulated and 
compared between the two treatment arms. 
 
15.8.3 Extent of Exposure to Study Product 
Extent of exposure to the study product will be summarized for each arm. 
 
15.8.4 Compliance with Diet, Life-Style, and Study Product 
Compliance with the diet and life-style recommendations and the intake of the study 
product will be summarized for each arm. 
 
15.8.5 Concomitant Medications/Therapies 
Concomitant medications/therapies will be summarized separately for the safety 
population. All prior and concomitant medications recorded in the electronic CRF will be 
coded to all matching Anatomic Therapeutic Classification codes using the most recent 
version of WHO Drug version. Descriptive summaries, by treatment arm, will be 
prepared using the coded term. All concomitant medications/therapies recorded in the 
electronic CRF will be listed. 
 
15.8.6 Effectiveness Analysis 
15.8.6.1 Primary Analysis 
The primary analysis will be conducted on the ITT population. 
 
Co-primary endpoints 
ANCOVA will be used to compare the percent change in weight from baseline to Day 
171 for the two treatment arms. The stratification factors and baseline weight will be 
included in the analysis and associated treatment difference, 95% confidence interval 
around the difference and P value for the treatment effect will be reported. 
 
The proportion of body weight responders will be presented descriptively by treatment 
arm. Responders in this case will be defined as those subjects who have achieved ≥ 5% 
reduction in body weight compared to baseline. In addition, the Logit model will be used 
to analyze the percent of responders, with the stratification factors and baseline weight in 
the model. 
 
To maintain the trial-wise type I error rate at 0.05, a closed test procedure will be used for 
the secondary and tertiary endpoints. The order of the endpoints will be as follows: 
 
 
 

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Secondary and tertiary endpoints 
Analysis of the secondary and tertiary endpoints will be summarized according to the 
variable type: 
- continuous data summaries will be based on ANCOVA or Mixed Model using the 
stratification factors and the respective baseline values for the endpoint as a covariate in 
the model 
- categorical data summaries will be based on Logit model using the stratification factors 
and the respective baseline values for the endpoint as a covariate in the model 
 
15.8.6.2 Supportive Analysis 
To assess the consistency of the primary analysis results, supportive analysis will be 
conducted using the PP population. Statistical methodology for the supportive analyses 
will be the same as that of the primary analysis, with the exception of the analysis 
population used. The PP population will be used for the supportive analysis while ITT 
population will be used for the primary analysis. 
 
15.8.6.3 Longitudinal Analysis 
Longitudinal data analyses will be conducted for selected endpoints; these will be pre-
specified in the SAP. 
 
15.8.7 Safety Assessments 
15.8.7.1 Adverse Events 
All AEs will be presented by number of episodes and by number of subjects experiencing 
the event in each arm with information on time of occurrence and duration. 
 
AEs (including ADEs) will be coded using the latest version of MedDRA. Treatment-
emergent AEs (TEAEs) are defined as events with an onset on or after the first 
randomized treatment. TEAEs will be summarized by treatment arm, System Organ 
Class, and Preferred Term. The following TEAEs summaries will be provided: 
- TEAEs by severity grade 
- TEAEs by relationship to study treatment 
 
In addition, separate summaries of SAEs (SADEs) and AEs (ADEs) resulting in 
discontinuation of study treatment will be presented. 
 
15.8.7.2 Physical Examination 
All physical examination clinically significant abnormal findings will be listed. 
 
15.8.7.3 Vital Signs 
All data from the vital signs assessments (blood pressure, heart rate) will be listed. The 
data will also be summarized and presented by treatment arm and timepoint. 
 
 
 

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15.8.7.4 Laboratory Tests 
All laboratory values and their changes from baseline will be listed. Laboratory 
measurements will also be summarized as continuous variable and presented by treatment 
arm and timepoint. 
 
16. STUDY COMMITTEES 
16.1 Steering Committee 
To ensure the proper scientific completion of the study, a Steering Committee (Research 
Coordination Committee) will be established. The Committee will have 7 members. The 
Sponsor and the Principal Investigator will nominate 6 members for this Committee (2 
members from the Sponsor, 4 members from the investigational sites). An additional 
member will be nominated from the Monitoring Team of the CRO. 
 
The Steering Committee should follow the overall progress of the study, ensure smooth 
communication, seek to solve any unforeseen events affecting the study, and monitor the 
progress of the results. The Steering Committee will remain blinded throughout the study. 
 
16.2 Data Monitoring Committee 
To ensure the proper safety of the study, a Data Monitoring Committee will be 
established. The Committee will have 3 members (1 Chairman, 1 Clinical Investigator, 
and 1 Statistician). 
 
The responsibilities of the Data Monitoring Committee will be detailed in a charter. 
 
17. ETHICAL CONSIDERATIONS 
17.1 Principles 
The study will be conducted in accordance with the principles established by the 18th 
World Medical Assembly (Helsinki, 1964) and all applicable amendments established by 
the World Medical Assemblies and the International Conference on Harmonisation (ICH) 
guidelines for Good Clinical Practices (GCP), and in compliance with European Norm 
(EN) International Organization for Standardization (ISO) 14155:2011. 
 
17.2 Informed Consent 
The Investigator (or a designated representative) should fully inform the subject of all 
relevant aspects of the study. Prior to the study start, the written Informed Consent Form 
must be dated and signed by the subject and by the person who conducted the informed 
consent discussion. The Informed Consent Form will be translated to the state language 
of the country where the trial will be conducted in accordance with language 
requirements in US, Canada, and the EEA [status: 1/2007]. The subject will receive the 

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original or the copy of the translated, dated, and signed Informed Consent Form. Any 
new significant findings will be communicated to the subject. 
 
17.3 Ethics Committee/Institutional Review Board 
The Investigator must submit this Clinical Investigation Plan (together with the Informed 
Consent Form, the Investigator’s Brochure, the Investigator’s curriculum vitae, and any 
other relevant document) to the appropriate Ethics Committee/Institutional Review Board 
after the approval by the Sponsor, and is required to forward to the Sponsor a copy of the 
written and dated favorable opinion signed by the Chairman of the Ethics 
Committee/Institutional Review Board with information on the composition of the 
Committee/Board. The investigational product will not be released at the study site and 
the study will not start until this copy has been received by the Sponsor. 
 
Submission in Europe can be done by the Investigator or the Sponsor (or designee). 
 
Responsibility for coordinating with Ethics Committee/Institutional Review Board is 
defined in the Investigator/Sponsor (CRO) Contract. 
 
During the course of the study, any amendment to the Clinical Investigation Plan or any 
update to the Investigator’s Brochure will be sent to the Ethics Committee/Institutional 
Review Board. Any revision to the Clinical Investigation Plan or the Informed Consent 
Form must be approved by the Ethics Committee/Institutional Review Board prior to 
implementation, unless there is a safety issue for the study subject. 
 
Any additional requirements imposed by the Regulatory Authorities or the Ethics 
Committee/Institutional Review Board should be followed. 
 
If requested, a summary of the study outcome will be sent to the Ethics 
Committee/Institutional Review Board at the end of the trial. 
 
17.4 Confidentiality 
All information provided by the Sponsor or produced during the study is confidential. 
The Investigator and the Sub-Investigators agree to keep this information confidential 
and not to disclose it to any third party without the prior written approval of the Sponsor. 
The Ethics Committee/Institutional Review Board members have also the same 
obligation of confidentiality. 
 
18. ADMINISTRATIVE AND REGULATORY PROCEDURES 
18.1 Laws 
The study will be conducted in compliance with laws, regulations, and guidelines of the 
countries where the study is conducted (US, Canada, Europe). 

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18.2 Clinical Trials Registration 
This trial will be registered in appropriate clinical trial database(s) consistent with federal 
law and regulation, FDA guidance, and WHO mandate. 
 
18.3 Curriculum Vitae 
An updated copy of the curriculum vitae of the Investigator and the Sub-Investigators 
will be provided to the Sponsor prior to the start of the study. 
 
18.4 Record Retention 
The Investigator must maintain confidential all study documentation and prevent 
accidental or premature destruction of the documents. 
 
The documents should be retained at least 15 years after the completion of the study. If 
archiving can no longer be ensured by the Investigator, the Sponsor should be informed 
and a mutually agreed upon alternative should be proposed. The Investigator must notify 
the Sponsor prior to destroying any document before the 15-year period. 
 
18.5 Data Protection 
The Sponsor should treat the subject’s personal data and the Investigator’s personal data 
in compliance with all applicable laws and regulations, and take all appropriate measures 
to protect the data and prevent access to the data by an unauthorized third party. 
 
18.6 Insurance 
The Sponsor certifies that it has a liability insurance policy covering the subjects and the 
liability of the Investigator and Sub-Investigators. The insurance policy is in accordance 
with local laws and requirements. 
 
The insurance of the Sponsor does not relieve the Investigator and Sub-Investigators of 
any obligation to maintain their own liability insurance policy as required by applicable 
law. 
 
18.7 Financial Arrangements 
The sponsor is providing financial support and material through contracts with sites 
participating in the study. Study subjects may be provided reimbursement for reasonable 
travel expenses and accommodation associated with the completion of study visits, when 
appropriate under local regulation. 
 

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19. CLINICAL INVESTIGATION PLAN AMENDMENTS 
Any amendment to the Clinical Investigation Plan requires a written favorable opinion 
from the Ethics Committee/Institutional Review Board prior to its implementation, unless 
there are overriding safety reasons. In case a change to the Informed Consent Form 
becomes necessary following the amendment, the Investigator must receive a favorable 
opinion from the Ethics Committee/Institutional Review Board prior to the 
implementation of the change. 
 
20. CLINICAL INVESTIGATION PLAN DEVIATIONS 
A Clinical Investigation Plan deviation (protocol deviation) is any change or alteration to 
the procedures stated in the Clinical Investigation Plan, Informed Consent Form, study 
materials (e.g., questionnaires), or recruitment process originally approved by the Ethics 
Committee/Institutional Review Board. 
 
Major protocol deviation is any intentional or unintentional change from the approved 
Clinical Investigation Plan that adversely affects the risk/benefit ratio of the study, the 
rights, safety, or welfare of the study subjects or others, or the integrity of the study 
(ability to draw conclusions from the study data), such as any deviation from subject 
inclusion and exclusion criteria or subject informed consent procedures, study medication 
dispensing error, etc. 
 
Minor protocol deviation is any deviation that does not have the potential to negatively 
impact the willingness of the subjects to participate in the study, the safety of the study 
subjects, or the integrity of study, such as incomplete/inadequate subject testing 
procedures, non-compliance with medication regimens, visits performed outside of 
specified visit windows, etc. 
 
The Investigator is not allowed to deviate from the Clinical Investigation Plan except 
under emergency circumstances to protect rights, safety, and well-being of the study 
subjects. 
 
All protocol deviations are to be reported to the Sponsor. Major protocol deviations are to 
be reported according to local regulations. 
 
21. STUDY MONITORING 
21.1 Responsibilities of the Sponsor 
The Sponsor is responsible to Regulatory Authorities for ensuring the proper conduct of 
the study (ethical aspects, compliance, integrity and validity of the data recorded). The 
main duty of the Monitoring Team is to help the Sponsor (and the Investigator) to 
achieve this objective. A Monitoring Plan will be prepared before the start of the study. 
During the study, the Monitoring Team will contact the site at regular intervals (by 
monitoring visits, phone calls, e-mails, letters, or fax) to review the study progress and 

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discuss any relevant issue. The Monitoring Team must check the electronic CRF entries 
against the source documents. 
 
21.2 Responsibilities of the Investigator 
The Investigator should accept and sign the Clinical Investigation Plan. The Investigator 
is responsible to conduct the study in accordance with the Clinical Investigation Plan, the 
ICH guidelines for GCP, the EN ISO 14155:2011, and the applicable regulatory 
requirements. The Sub-Investigators appointed to assist the Investigator will be under 
direct responsibility of the Investigator. The Investigator agrees to provide reliable data 
as requested by the Clinical Investigation Plan (through electronic CRF and query) in an 
accurate and legible manner and to ensure direct access to source documents to the 
Sponsor’s representatives. 
 
22. PREMATURE DISCONTINUATION OF THE STUDY OR 
PREMATURE CLOSE-OUT OF A SITE 
22.1 Decided by the Sponsor 
The Sponsor may decide to discontinue the study or to close the site for the following 
reasons: 
- the number of subjects who have completed the study is considered sufficient 
- the Sponsor has information on the investigational product leading to a doubt about the 
benefit/risk ratio 
- the aim of the study is no longer of interest 
- the Investigator has not included sufficient number of subjects in the study after a 
reasonable period of time mutually agreed upon 
- the presence of breach by the Investigator of a fundamental obligation 
 
The Sponsor must notify the Investigator in writing and also inform the Regulatory 
Authorities and the Ethics Committee/Institutional Review Board. 
 
22.2 Decided by the Investigator 
The Investigator must notify the Sponsor (prior notice of 30 days) of this decision and 
give 
the 
reason 
in 
writing. 
The 
Regulatory 
Authorities 
and 
the 
Ethics 
Committee/Institutional Review Board should also be informed. 
 
The Regulatory Authorities or the Ethics Committee/Institutional Review Board may 
suspend or prematurely terminate participation in a clinical investigation at the 
investigation sites for which they are responsible. 
 
The Investigator or authorized designee should promptly inform the enrolled subjects at 
the site in case of discontinuation/termination of the study. 
 

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23. PROPERTY RIGHTS 
All information, documents, and investigational product provided by the Sponsor remain 
the property of the Sponsor. All the results arising from the study remain the property of 
the Sponsor. 
 
All inventions, formulations, and discoveries that are developed, conceived, and/or made 
by the CRO and/or the Investigator based on confidential information received from the 
Sponsor and that are specific to programs, projects, and/or products of the Sponsor will 
be the sole and exclusive property of the Sponsor. 
 
24. COMMUNICATION AND PUBLICATION OF RESULTS 
The Sponsor has the right to communicate and publish the results of the study at any time 
by proposing authorship to relevant authors from the Investigator’s Team. The 
Investigator has the right to communicate and publish the results of the study by 
proposing authorship to relevant authors from the Sponsor’s Team and after obtaining 
written approval of the manuscript from the Sponsor. The results of the study will be 
submitted for presentation at scientific meetings and/or publication in scientific journals. 
The Sponsor has the right to postpone a presentation/publication for a period not 
exceeding 18 months after the availability of the study results. 
 
25. 
QUALITY 
ASSURANCE 
AUDITS 
AND 
REGULATORY 
INSPECTIONS 
The Clinical Trial described in this Clinical Investigation Plan will be subject to Quality 
Assurance evaluations in order to ensure that the trial is performed and the data are 
generated, documented (recorded), and reported in compliance with the ICH E6 GCP 
principles, EN ISO 14155:2011, and the applicable regulatory requirements. The 
Investigator may be audited by the Sponsor’s Quality Assurance Auditor periodically in 
accordance with Clinical Quality Assurance audit plan. The audit plan will be discussed 
by the Sponsor and the Investigator. The Investigator agrees to allow the auditors to have 
direct access to the study records for review. The confidentiality of the data audited 
should be respected by all parties. The Investigator should immediately inform the 
Sponsor about the planned audit and the outcome of the audit by the Regulatory 
Authorities. Corrective actions should be implemented for all problems found during the 
audit. 
 
The Investigator agrees to allow direct access to source data/documents, including subject 
journals, during monitoring, auditing and/or inspection by the Regulatory Authorities and 
the Ethics Committee/Institutional Review Board. 
 
 

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26. REFERENCES 
 
1. Bessesen DH. Update on obesity. J Clin Endocrinol Metab, 2008, 93, 2027-2034. 
 
2. Prentice AM. The emerging epidemic of obesity in developing countries. Int J 
Epidemiol, 2006, 35, 93-99. 
 
3. Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med, 1993, 119, 655-660. 
 
4. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes, 1992, 16, 
397-415. 
 
5. Bays HE. Current and investigational antiobesity agents and obesity therapeutic 
treatment targets. Obes Res, 2004, 12, 1197-1211. 
 
6. Pories WJ. Bariatric surgery: risks and rewards. J Clin Endocrinol Metab, 2008, 93, 
S89-S96. 
 
7. Sallet JA, Marchesini JB, Paiva DS, et al. Brazilian multicenter study of the 
intragastric balloon. Obes Surg, 2004, 14, 991-998. 
 
8. Gelesis100 Investigator’s Brochure. February 2016. 
 
9. Heshmati HM, Tacchino R, Ron E, Sannino A, Zohar Y. Attiva, a novel 
superabsorbent biodegradable hydrogel, increases the feeling of satiety in humans. In: 
Program of the 19th Annual Meeting and Clinical Congress of the American Association 
of Clinical Endocrinologists, April 21-25, 2010; Boston, MA, USA. Abstract #605. 
 
10. Astrup A, Kristensen M, Gnessi L, Watanabe M, Svacina S, Matoulek M, Hlubik P, 
Stritecka H, Contaldo F, Pasanisi F, Heshmati HM, Zohar Y, Ron ES, Sannino A, 
Demitri C, Saponaro C. Oral administration of Gelesis100, a novel hydrogel, 
significantly decreases body weight in overweight and obese subjects. In: Program of the 
Joint Meeting of the International Congress of Endocrinology and the Endocrine Society, 
June 21-24, 2014; Chicago, IL, USA. Abstract #0897. 
 
11. Geliebter A, Yahav EK, Gluck ME, Hashim SA. Gastric capacity, test meal intake, 
and appetitive hormones in binge eating disorder. Physiol Behav, 2004, 81, 735-740. 
 
12. American Diabetes Association. Nutrition recommendations and interventions for 
diabetes. A position statement of the American Diabetes Association. Diabetes Care, 
2007, 30 (Suppl 1), S48-S65. 
 
13. Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, Holzmeister LA, 
Hoogwerf B, Mayer-Davis E, Mooradian AD, Purnell JQ, Wheeler M. Evidence-based 

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nutrition principles and recommendations for the treatment and prevention of diabetes 
and related complications. Diabetes Care, 2002, 25, 148-198. 
 
14. Harris JA, Benedict FG. A biometric study of basal metabolism in man. Washington, 
DC: Carnegie Institute of Washington, 1919, Publication 279. 
 
15. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. 
Homeostasis model assessment: insulin resistance and beta-cell function from fasting 
plasma glucose and insulin concentrations in man. Diabetologia, 1985, 28, 412-419. 
 
16. PASS 14 Power Analysis and Sample Size Software. NCSS, LLC. Kaysville, Utah, 
USA, ncss.com/software/pass, 2015. 
 
17. Chen YHJ, DeMets DL, Lan KKG. Increasing the sample size when the unblinded 
interim result is promising. Statist Med, 2004, 23, 1023-1038. 
 
18. Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statist Med, 2011, 30, 3267-3284. 
 

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27. APPENDICES 
 

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27.1 Appendix 1: Binge Eating Disorder 
 
QUESTIONNAIRE ON EATING AND WEIGHT PATTERNS-REVISED 
(QEWP-R) – ABBREVIATED VERSION 
Last Name _____________________ 
First Name ________________ M.I. ______ 
Subject Number _________________ 
Date _______________________________ 
________________________________________________________________________ 
 
Thank you for completing this questionnaire. Please circle the appropriate number or response, or 
write in information where asked. You may skip any question you do not wish to answer. 
 
1. Age ________ years 
2. Sex: 1  Male     2  Female 
3. What is your ethnic/racial background? 
1. Black (not Hispanic) 
2. Hispanic 
3. White (not Hispanic) 
4. Asian 
5. Other (please specify) 
________________________ 
 
4. How far did you get in school? 
1. Grammar school, junior high school or less 
2. Some high school 
3. High school graduate or equivalency (GED) 
4. Some college or associate degree 
5. Completed college 
 
5. How tall are you? 
              ________ cm (in) 
6. How much do you weigh now? 
              ________ kg (lbs) 

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7. What has been your highest weight ever (when not pregnant)? 
              ________ kg (lbs) 
8. Have you ever been overweight by at least 4.5 kg (10 lbs) as a child or 6.8 kg (15 lbs) as an 
adult (when not pregnant)? 
              1  Yes     2  No or not sure 
IF YES: How old were you when you were first overweight (at least 4.5 kg (10 lbs) as a child or 
6.8 kg (15 lbs) as an adult)? If you are not sure, what is your best guess? 
              ________ years 
9. How many times (approximately) have you lost 9 kg (20 lbs) or more – when you weren’t 
sick – and then gained it back? 
1. Never 
2. Once or twice 
3. Three or four times 
4. Five times or more 
 
10. During the past six months, did you often eat within any two-hour period what most people 
would regard as an unusually large amount of food? 
              1  Yes     2  No 
IF NO: SKIP TO QUESTION 15 
 
11. During the times when you ate this way, did you often feel you couldn’t stop eating or control 
what or how much you were eating? 
              1  Yes     2  No 
IF NO: SKIP TO QUESTION 15 
 
12. During the past six months, how often, on average, did you have times when you ate this way 
– that is, large amounts of food plus the feeling that your eating was out of control? (There 
may have been some weeks when it was not present – just average those in). 
1. Less than one day a week 
2. One day a week 
3. Two or three days a week 
4. Four or five days a week 
5. Nearly every day 

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13. Did you usually have any of the following experiences during these occasions? 
a. Eating much more rapidly than usual?                                   
Yes     No 
b. Eating until you felt uncomfortably full?                         
Yes     No 
c. Eating large amounts of food when you didn’t feel physically hungry? 
                                                      
 
 
 
Yes     No 
d. Eating alone because you were embarrassed by how much you were eating? 
                                                      
 
 
 
Yes     No 
e. Feeling disgusted with yourself, depressed, or feeling very guilty after overeating? 
                                                                                             
Yes     No 
 
14. Think about a typical time when you ate this way – that is, large amounts of food plus the 
feeling that your eating was out of control. 
a. What time of day did the episode start? 
1. Morning (8 am to 12 noon) 
2. Early afternoon (12 noon to 4 pm) 
3. Late afternoon (4 pm to 7 pm) 
4. Evening (7 pm to 10 pm) 
5. Night (after 10 pm) 
 
b. Approximately how long did this episode of eating last, from the time you started to eat 
to when you stopped and didn’t eat again for at least two hours 
              _____ hours ______ minutes 
 
c. As best you can remember, please list everything you might have eaten or drunk during 
that episode. If you ate for more than two hours, describe the foods eaten and liquids 
drunk during the two hours that you ate the most. Be specific – include brand names 
where possible and amounts as best you can estimate. (For example: 198 g (7 oz) Ruffles 
potato chips; 1 cup Breyer’s chocolate ice cream with 2 teaspoons hot fudge; two 237-mL 
(8-fl oz) glasses of Coca-cola, 1½ ham and cheese sandwiches with mustard). 
 
 
 
 
d. At the time this episode started, how long had it been since you had previously finished 
eating a meal or snack? 
              _____ hours ______ minutes 

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15. In general, during the past six months, how upset were you by overeating (eating more than 
you think is best for you)? 
1. Not at all 
2. Slightly 
3. Moderately 
4. Greatly 
5. Extremely 
 
16. In general, during the past six months, how upset were you by the feeling that you couldn’t 
stop eating or control what or how much you were eating? 
1. Not at all 
2. Slightly 
3. Moderately 
4. Greatly 
5. Extremely 
 
 
 

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27.2 Appendix 2: Food Habits 
 
QUESTIONNAIRE ON FOOD HABITS BEFORE TREATMENT 
Last Name _____________________ 
First Name ________________ M.I. ______ 
Subject Number _________________ 
Date _______________________________ 
________________________________________________________________________ 
 
Thank you for completing this questionnaire. Please circle the appropriate letter. You may skip any 
question you do not wish to answer. 
 
1. Do you eat meat, like beef chicken or pork? 
a. Yes, every day or almost every day 
b. Yes, but not every day 
c. I hardly eat those foods 
d. I never eat those foods 
 
2. Are you a vegetarian or a vegan? 
a. I am a vegetarian 
b. I am a vegan 
c. I am not a vegetarian or a vegan 
 
3. Do you eat breakfast? 
a. Yes, every day 
b. Yes, but not every day 
c. Only once or twice a week 
d. I almost never eat breakfast 
 
4. Which statement best describes your eating habits regarding main meals? 
a. I eat almost every day breakfast lunch and dinner 
b. I eat almost every day lunch and dinner but not breakfast 
c. I eat almost every day breakfast and lunch but not dinner 
d. I eat almost every day breakfast and dinner but not lunch 
e. I do not eat regular meals and I eat when I am hungry 
 
 
 

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5. Which statement best describes your eating habits regarding snacks? 
a. I usually do not eat much during the meals and I like to have snacks during the day 
b. I eat most of my food during the meals but I also have three or more snacks during the 
day 
c. I eat most of my food during the meals and I have not more than two snacks during the 
day 
d. I eat most of my food during the meals and I usually do not have snacks during the day 
 
 
 

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27.3 Appendix 3: Food Habits and Satisfaction 
 
QUESTIONNAIRE ON FOOD HABITS AND SATISFACTION AFTER 
TREATMENT 
Last Name _____________________ 
First Name ________________ M.I. ______ 
Subject Number _________________ 
Date _______________________________ 
________________________________________________________________________ 
 
Thank you for completing this questionnaire. Please circle the appropriate letter or write in 
information where asked. You may skip any question you do not wish to answer. 
 
Food Habits 
1. Do you eat meat, like beef chicken or pork? 
a. Yes, every day or almost every day 
b. Yes, but not every day 
c. I hardly eat those foods 
d. I never eat those foods 
 
2. Are you a vegetarian or a vegan? 
a. I am a vegetarian 
b. I am a vegan 
c. I am not a vegetarian or a vegan 
 
3. Do you eat breakfast? 
a. Yes, every day 
b. Yes, but not every day 
c. Only once or twice a week 
d. I almost never eat breakfast 
 
4. Which statement best describes your eating habits regarding main meals? 
a. I eat almost every day breakfast lunch and dinner 
b. I eat almost every day lunch and dinner but not breakfast 
c. I eat almost every day breakfast and lunch but not dinner 
d. I eat almost every day breakfast and dinner but not lunch 
e. I do not eat regular meals and I eat when I am hungry 
 

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5. Which statement best describes your eating habits regarding snacks? 
a. I usually do not eat much during the meals and I like to have snacks during the day 
b. I eat most of my food during the meals but I also have three or more snacks during the 
day 
c. I eat most of my food during the meals and I have not more than two snacks during the 
day 
d. I eat most of my food during the meals and I usually do not have snacks during the day 
 
 
Satisfaction 
1. Would you recommend these capsules to a relative or a friend who wants to lose weight? 
a. Yes 
b. No 
 
2. On a scale of 1 to 10, how would you rate your experience using these capsules? (10 
being very positive and 1 being very negative) ____ 
 
Please explain why you gave this rating: 
________________________________________________________________________ 
 
What did you like about the capsules? 
________________________________________________________________________ 
 
What did you not like about the capsules? 
________________________________________________________________________ 
 
3. Would you like to continue receiving these capsules? 
a. Yes 
b. No 
 
If No, please explain why: 
________________________________________________________________________ 
 
4. If you were to continue taking the same amount of active product in this study, would 
you prefer to take smaller capsules but in a larger number? (Please see the real examples 
before answering the question) 
a. Yes, I would prefer smaller capsules, but more of them (e.g., 4 or 5 capsules each time) 
b. No, I would prefer the current size capsules and continue with 3 capsules each time 
 
 

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27.4 Appendix 4: Impact of Weight on Quality of Life 
 
QUESTIONNAIRE ON IMPACT OF WEIGHT ON QUALITY OF LIFE 
(IWQOL) 
Last Name _____________________ 
First Name ________________ M.I. ______ 
Subject Number _________________ 
Date _______________________________ 
________________________________________________________________________ 
 

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27.5 Appendix 5: List of Source Data 
 
Subject’s identity 
Pathology studied, date of diagnosis 
Medical history, associated diseases (date of onset) 
Dates of administration of the study product 
Previous and concomitant medications 
A statement that the Informed Consent Form was signed by the subject 
Dates of participation in the study 
Dates of study visits 
Assessments performed during the study (including questionnaires) 
AEs and SAEs (and follow-up) 
Date of dropout (and reason)