Randomized, Double-Blind, Sham-Controlled, Prospective, Multi-Center Pilot Study to Evaluate the Safety and Effectiveness of Duodenal Mucosal Resurfacing Using the Revita™ System in the Treatment of Type 2 Diabetes
Phase: NA
Conditions: Type 2 Diabetes
Sponsor: Fractyl Health Inc.

 
 
 
 
 
 
March 22, 2022 
 
Clinicaltrials.gov 
 
To Whom it May Concern: 
 
Following please find the final protocol for the study titled “Randomized, Double-Blind, Sham-
Controlled, Prospective, Multi-Center Pilot Study to Evaluate the Safety and Effectiveness of 
Duodenal Mucosal Resurfacing Using the Revita™ System in the Treatment of Type 2 Diabetes”, 
version date 9Jul2020, NCT03653091. 
 
 
Sincerely, 
 
 
 
Sarah Hackett 
Sr. Director of Clinical Operations 
Fractyl Health 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fractyl Health Inc. I 17 Hartwell Street I Lexington, MA 02421
 
DocuSign Envelope ID: 819B4C9E-9E17-4D80-A94F-9C59AD7DA034

 
 
Randomized, Double-Blind, Sham-Controlled, 
Prospective, Multi-Center Pilot Study to Evaluate 
the Safety and Effectiveness of Duodenal Mucosal 
Resurfacing Using the Revita™ System in the 
Treatment of Type 2 Diabetes 
 
The Revita™ US Pilot Study 
 
Protocol Number: C-40000  
 
 
 
Sponsor: 
Fractyl Laboratories 
17 Hartwell Avenue 
Lexington MA 02421 
 
 
 
 
 
Version 3.0   
Date 9 July,2020 
 
 
Confidential  
 
 
 
 
 
 
 
Do Not Copy 
 
This investigational protocol contains confidential information for use by the principal investigators and their designated 
representatives, including IRBs and/or Ethics Committees, participating in this clinical investigation. It should be held 
confidential and maintained in a secure location. It should not be copied or made available for review by any unauthorized 
person or firm. 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 2 of 96 
Sponsor Protocol Approval Page 
  
STUDY TITLE: 
Randomized, Double-Blind, Sham-Controlled, 
Prospective, Multi-Center Pilot Study to Evaluate the 
Safety and Effectiveness of Duodenal Mucosal 
Resurfacing Using the Revita™ System in the 
Treatment of Type 2 Diabetes  
 
The Revita™ US Pilot Study 
 
PROTOCOL NUMBER: 
C-40000  
 
VERSION NUMBER: 
3.0 
 
 
 
 
 
We, the undersigned, have read and approve the protocol specified above and agree on 
its content. 
 
Sarah Hackett, BS 
Director of Clinical Operations  
Fractyl Laboratories 
USA 
  
  
Date: 
Sanobar Parkar, MD, MPH 
Medical Director, Clinical Development 
Fractyl Laboratories 
USA 
 
 
Date: 
Kelly White, PharmD 
Executive Director, Clinical 
Development 
Fractyl Laboratories 
USA 
 
 
Date: 
Juan Carlos Lopez-Talavera, MD, PhD 
Chief Medical Officer 
Fractyl Laboratories 
USA 
 
  
 
Date: 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 3 of 96 
Investigator Protocol Approval Page 
 
Randomized, Double-Blind, Sham-Controlled, Prospective, Multi-Center Pilot 
Study to Evaluate the Safety and Effectiveness of Duodenal Mucosal Resurfacing 
Using the Revita™ System in the Treatment of Type 2 Diabetes 
 
The Revita™ US Pilot Study 
 
C-40000 
 
Protocol Version 3.0 
 
I hereby agree to participate in this evaluation of the Fractyl Revita™ System Sponsored 
by Fractyl Laboratories, Inc. (here in after “Study Sponsor”).  I agree to conduct this 
investigation according to the requirements of the protocol provided by the Study Sponsor 
in accordance with applicable local regulations, and in accordance with the conditions 
imposed by the reviewing Institutional Review Board (IRB).  I agree to supervise all use 
of the investigational devices and to ensure appropriate informed consent is obtained 
from all subjects prior to inclusion in this study. 
 
I understand that this investigation will be monitored by the Study Sponsor and/or a 
designee employed by the Study Sponsor. This monitoring will involve periodic inspection 
of my investigational site and ongoing review of the data that are submitted by me to the 
Study Sponsor.   
 
I am aware that the Study Sponsor reserves the right to discontinue this investigation at 
any time. 
 
I understand this study protocol and trial results are confidential, and I agree not to 
disclose any such information to any person other than a representative of the Study 
Sponsor, the IRB/EC, or regulatory authorities without the prior written consent of the 
Study Sponsor. 
 
Accepted by: 
 
 
 
_________________________________       _________________________ 
Principal Investigator 
 
 
 
  Date 
 
 
______________________________________________________________ 
Printed Name 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 4 of 96 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ........................................................................................ 22 
1.1 
Type 2 Diabetes (T2D) 
22 
1.2 
Existing Treatment Options 
22 
1.3 
Summary of Limitations of Current Therapies 
24 
1.4 
Emerging Metabolic Role in the Gut 
25 
1.5 
Fractyl RevitaTM System 
26 
1.6 
DMR Procedure 
27 
1.7 
Clinical Experience 
28 
1.8 
Risk Analysis 
29 
2 
STUDY DESIGN ......................................................................................... 33 
2.1 
Overview 
33 
2.2 
Number of Study Sites and Subjects 
34 
2.3 
Intended Use 
34 
2.4 
Study Objectives 
34 
2.5 
Study Workflow 
35 
2.6 
Study Duration 
36 
2.7 
Study Endpoints 
36 
2.8 
Blinding 
37 
2.9 
Control of Bias and Validity 
37 
3 
STUDY POPULATION ................................................................................ 38 
3.1 
Subject Selection 
38 
3.2 
Duration of Subject Participation 
38 
4 
SCREENING PERIOD AND ELIGIBILITY CRITERIA................................. 39 
4.1 
Selection Criteria 
39 
5 
STUDY VISITS ........................................................................................... 43 
5.1 
Visit 1: Screening (Pre-Medication Run-In) 
43 
5.2 
Visit 2: Baseline (Post Medication Run-In) 
44 
5.3 
Visit 3: Procedure (within 21 days from Visit 2) 
46 
5.4 
Visit 4: Day 7 Telephone Call (+/-2 days) 
50 
5.5 
Visit 5: Day 14 Telephone Call (+/-2 days) 
50 
5.6 
Visit 6: Week 4 (Day 28) Clinic Visit (+/- 7 days) 
51 
5.7 
Visit 7: Week 8 (Day 56) Telephone Call (+/- 2 days) 
52 
5.8 
Visit 8: Week 12 (Day 84) Clinic Visit (+/- 7 days) 
53 
5.9 
Visit 9: Week 15 (Day 105) Telephone Call (+/- 2 days) 
54 

 
Protocol # C-40000 Version 3.0 
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5.10  Visit 10: Week 18 (Day 126) Clinic Visit (+/- 7 days) 
54 
5.11  Visit 11: Week 21 (Day 147) Telephone Call (+/- 2 days) 
55 
5.12  Visit 12: Week 24 (Day 168) Clinic Visit (+/- 7days) 
56 
5.13  Visit 3C: Crossover to DMR Visit (+21 days from Visit 12) 
59 
5.14  COVID-19 Exceptions 
59 
5.15  Unscheduled Visits 
59 
5.16  Subject Withdrawal & Early Termination 
59 
6 
STUDY PROCEDURES & ASSESSMENTS .............................................. 60 
6.1 
Demographics/Medical History/Physical Exam 
60 
6.2 
Body Weight, Blood Pressure & Targeted Physical Exam 
61 
6.3 
Blood Analysis 
61 
6.4 
Electrocardiogram 
62 
6.5 
Renal Function 
62 
6.6 
MRE 
62 
6.7 
Lifestyle Counseling 
63 
6.8 
SF-36 Quality of Life Questionnaire 
63 
6.9 
PROMIS® (Patient-Reported Outcomes Measurement Information System) 63 
6.10  Subject Self-Monitoring of Blood Glucose (SMBG) and Glycemia Diary 
63 
6.11  Management of Glycemia and Antidiabetic Medication 
64 
6.12  Concomitant Medications 
69 
7 
STUDY MANAGEMENT ............................................................................. 69 
7.1 
Regulatory Compliance 
69 
7.2 
Institutional Review Board (IRB) Review 
69 
7.3 
Study Records 
70 
7.4 
Study Reports 
71 
7.5 
Device Accountability 
73 
7.6 
Protocol Deviations 
73 
7.7 
Investigational Site Termination 
73 
7.8 
Adverse Event Reporting 
73 
7.9 
Data Monitoring Committee (DMC) 
80 
7.10  Clinical Events Committee (Adjudication Committee) 
81 
8 DATA MANAGEMENT AND STATISTICAL CONSIDERATIONS .................. 82 
8.1 82 
7.11  Data Collection and Quality Control 
82 
8.1.1 82 

 
Protocol # C-40000 Version 3.0 
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8.2 Statistical Considerations 
84 
9       REFERENCES ......................................................................................... 89 
APPENDIX 1: SCHEDULE OF ASSESSMENTS – DMR CASES ..................... 92 
APPENDIX 2: SCHEDULE OF ASSESSMENTS – SHAM CASES................... 94 
APPENDIX 3: MAXIMUM APPROVED DAILY DOSE OF NON-INSULIN 
GLUCOSE LOWERING AGENTS .............................................................. 96 
 
 
 
 
 
 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 7 of 96 
Protocol Version 3.0 Rationale for Changes 
Section 
Change 
Rationale for Change 
2.1  
Subject enrollement # of changes from 
18 to 9  
Amended to reflect actual number of 
subjects enrolled. 
2.1 
Both treatment arms will be followed up 
for a total of 48 weeks to 24 weeks  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
2.1 
Telephone visits 30 and 42 removed  
and in-clinic visits 36 and 48 post 
procedure visits removed.  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
2.2 
Enrollement # changed from 18 to 9  
Amended to reflect actual number of 
subjects enrolled. 
2.4  
Removed study objective to assess the 
effect of DMR on glycemic endpoint 48 
weeks after the randomized procedure 
for durability of effect determination  
Amended study objective to eliminate 48 
week glycemic endpoint in DMR arm. 
2.7.1 
Removed secondary endpoint proportion 
of DMR-treated subjects with an A1c 
improvement from baseline at 24 weeks 
that maintain an A1c improvement at 48 
weeks   
Eliminated 48 week secondary 
endpoints in DMR arm. 
2.7.1 
Removed additional endpoint interest 
A1c change from baseline to Week 48 
by visit over time, DMR only 
 
Eliminated 48 week additional endpoints 
of interest in DMR arm. 
2.7.1 
Removed additional endpoint interest 
FPG change from baseline to Week 48 
by visit over time, DMR only 
 
Eliminated 48 week additional endpoints 
of interest in DMR arm. 
2.7.1 
Removed additional endpoint interest 
UACR change from baseline to Week 48  
by visit over time, DMR only  
 
Eliminated 48 week additional endpoints 
of interest in DMR arm. 
2.7.1 
Removed additional endpoint interest 
ALT and AST change from baseline to 
Week 48 by visit over time, DMR only 
Eliminated 48 week additional endpoints 
of interest in DMR arm. 
3.1 
Subject enrollement # of changes from 
18 to 9 
Amended to reflect actual number of 
subjects enrolled. 
3.2  
Updated the total anticipated duration of 
subject participation in the clinical study 
for a subject randomized to DMR will be 
up to a maximum of 33 weeks from 57 
weeks (maximum of 6 weeks between 
Screening and Baseline, maximum of 3 
weeks between Baseline and 
Procedure, and 24 weeks from 48 
weeks of follow up post procedure). 
Revised total study duration to reflect 
the elimination of follow ups out to Week 
48 for DMR arm. 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 8 of 96 
Section 
Change 
Rationale for Change 
5.12.11 
Added following language under AE for 
Week 24 visit “Subjects with an ongoing 
possibly and probably device and 
procedure related AEs reported at week 
24 follow up visit will be followed until 
resolution. This will also also include 
AEs (signs and symptoms) reported 
during 24 week follow up period but 
without a definitive diagnosis and/or 
attribution of the cause at this visit” 
This language is added to ensure all 
ongoing AEs or those without diagnosis 
or causality will be followed until 
resolution for subject safety reason. 
5.14  
Added COVID-19 Expectations for the 
study  
Added language around COVID-19 
exceptions to endpoint assessments and 
crossover procedures.   
5.14 
Removed Visit 13 Week 30 telelphone 
call  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
5.15 
Removed Visit 14 Week 36 In Clinic Visit  Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
5.16 
Removed Visit 15 Week 42 telelphone 
call 
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
5.17 
Removed Visit 16 Week 48 In Clinic Visit 
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
6.7  
Subjects will be provided lifestyle 
counseling to Week 24 (visit 12)  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
6.8  
SF-36 Quality of Life Questionnaire 
assessment removed at Week 48 visit  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
6.9 
PROMIS questionnaire removed at 
Week 48 visit  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
6.11 
Anti Diabetic Regimen will be followed 
through 24 week Visit 12 instead of 
Week 48 Visit 16  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
6.11.1 
Hyperglycemia Management from week 
24 to week 48 will not be followed  
Amended for elimination of follow ups 
out to Week 48 in DMR arm. 
7.9 
Added “All possibly and probably device 
and procedure related AEs reported 
during 24 weeks follow up will be 
followed until resolution. This will also 
also include resolution of all AEs (signs 
and symptoms) reported upto 24 weeks 
for which there is not yet a definitive 
diagnosis and/or attribution of cause by 
the 24 weeks follow up visit”. 
This is added to ensure safety of all 
subjects with ongoing AE(signs and 
symptoms) during 24 week followup or 
without diagnosis or causality at their 
last or week 24 follow up visit. 
7.12.2  
Sample size decreased from 18 to 9 
subjects  
Amended to reflect actual number of 
subjects enrolled. 
7.12.5 
Removed safety population analysis 
through 48 weeks post-DMR; this will 
include the 48 weeks of the study for 
patients receiving DMR from the start of 
the study. Results will be presented 
separately for the first 24 weeks and the 
24-48 weeks.   
Revised analysis of safety population 
due to elimination of follow ups out to 
Week 48. 

 
Protocol # C-40000 Version 3.0 
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Page 9 of 96 
Section 
Change 
Rationale for Change 
7.12.6 
Secondary efficacy endpoint proportion 
of DMR-treated subjects with an A1c 
improvement from baseline at 24 weeks 
that maintain an A1c improvement at 48 
weeks    
Eliminated 48 week secondary endpoint 
in DMR arm. 
7.12.6 
Additional Endpoint of Interest removed 
(i) 
A1c change from baseline to 
Week 48 by visit over time, DMR only 
(ii) 
FPG change from baseline to 
Week 48 by visit over time, DMR only 
(iii) 
UACR change from baseline to 
Week 48  by visit over time, DMR only  
(iv) 
ALT and AST change from 
baseline to Week 48 by visit over time, 
DMR only 
Eliminated 48 week additional endpoints 
of interest in DMR arm. 
Apprendix 
1  
Schedule of Assessments for visit #13 to 
16 removed  
Updated scheduled of assessments to 
reflect elimination of follow ups out to 
Week 48 in DMR arm. 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 10 of 96 
Protocol Summary 
 
Title: 
Randomized, Double-Blind, Sham-Controlled, 
Prospective, Multi-Center Pilot Study to Evaluate the 
Safety and Effectiveness of Duodenal Mucosal 
Resurfacing (DMR) Using the Revita™ System in the 
Treatment of Type 2 Diabetes (T2D) 
 
Short Title: 
The Revita™ US Pilot Study 
 
Protocol ID#: 
C-40000  
 
Device: 
The Fractyl Revita™ System is an endoscopic treatment 
consisting of a single catheter and console designed to lift the 
duodenal mucosa with saline followed by controlled 
circumferential hydrothermal ablation of the mucosa.   
 
Study Objectives: 
The study objectives are: 
 to assess the safety of the Fractyl Revita™ System for the 
treatment of subjects with  type 2 diabetes (T2D) 
suboptimally controlled on 2 to 3 oral antidiabetic 
medications (OADs) 
 
to assess the effect of Duodenal Mucosal Resurfacing 
(DMR) versus Sham procedures on glycemic endpoints 
24 weeks after the procedure 
 
Study Design: 
Randomized, double-blind sham-controlled prospective 
multicenter clinical investigation of subjects with T2D 
suboptimally controlled on 2 to 3 OADs, one of which must be 
metformin. Total post-randomization study duration will be up 
to 48 weeks. 
 
 Up to 6 Study Sites in the US 
 Maximum of 9 enrolled subjects, with 2:1 randomization 
scheme  
 4 week OAD Run-In Period to assess stability of blood 
glucose control in conjunction with medication compliance 
and lifestyle (diet, exercise) counseling 
 OADs will be held constant from start of Run-In Period 
through Week 24, with protocol pre-specified treatment 
algorithms for hypoglycemia and hyperglycemia. Note: 
Subjects on SU medications will be provided with specific 
instructions regarding their medication usage pre- and 
post-DMR/Sham procedure (See 5.3.1). 
 Following OAD Run-In Period, subjects will be scheduled 
for an endoscopic evaluation consisting of an assessment 

 
Protocol # C-40000 Version 3.0 
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Page 11 of 96 
of the esophagus, stomach, duodenum and associated 
structures to ensure there are no conditions that would 
exclude the subject from having the index procedure 
(DMR or Sham).   
 Following confirmation of eligibility during the endoscopic 
evaluation, subjects will be randomized to receive either 
the DMR or Sham procedure, and post-procedure, will 
return for follow-up visits as per visit schedule. 
 Unblinding will occur at Week 24: 
o Sham treatment arm subjects who accept the offer 
of crossover will receive DMR treatment at Week 
24 with a 24-week follow-up post-procedure  
o Their antidiabetic medications will be held 
constant from Week 24 through Week 48 
with protocol pre-specified treatment 
algorithms for hypoglycemia and 
hyperglycemia 
o Subjects will continue to receive lifestyle 
(diet, exercise) counseling 
o DMR treatment arm will continue to receive lifestyle 
(diet, exercise) counseling through Week 24.   
o Their antidiabetic medications will be 
managed with a protocol pre-specified 
rescue treatment algorithm consistent with 
current diabetes standard of care 
 In subjects randomized to the DMR treatment arm, an 
ablation site biopsy will be performed at Week 24  
 A Data Monitoring Committee (DMC) with pertinent 
expertise will monitor the safety of study subjects on an 
ongoing basis    
 A Clinical Events Committee (CEC) will adjudicate safety 
endpoints, and provide an unbiased assessment of 
adverse event (AE) relatedness and severity  
 
Indication for Use: 
The Revita™ System is intended to improve glycemic control 
in conjunction with diet and exercise in patients with T2D who  
are inadequately controlled with oral antidiabetic medications. 
 
Inclusion Criteria 
Screening Visit (Pre-Medication Run-In, Visit 1) 
1. Men and non-pregnant women 28-65 years of age 
2. Diagnosed with T2D for at least 3 years  
3. Hemoglobin A1C (A1C) of 7.5 - 9.5% (59 - 80 
mmol/mol) 
 
4. On two to three OADs (metformin plus one or two 
additional OADs) with two (see note below) at least at 

 
Protocol # C-40000 Version 3.0 
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Page 12 of 96 
half maximum labeled dose (or highest tolerated) with 
no changes in medication in the 12 weeks prior to the 
Screening Visit (Visit 1) (Refer to Table 8.3 of the 
American Diabetes Association [ADA] Standard of 
Medical Care in Diabetes 2018 for the maximum 
approved daily dose of non-insulin glucose lowering 
agents.) Note: For subjects on sulfonylurea (SU) 
glucose-lowering drugs for diabetes, the only SUs 
permitted in the study will be glipizide or glimepiride, 
and their doses below half maximum labeled dosing 
will not be an exclusion for study entry. Patients 
unwilling to reduce the dose of SU at the time of the 
DMR procedure as described by protocol will be 
excluded. 
5. Agree to use an additional glucose-lowering treatment 
(eg, liraglutide, other OAD with the exception of 
glyburide) if recommended by the study investigator in 
case of persistent hyperglycemia.   
6. Agree not to donate blood during their participation in 
the study 
7. Able to comply with study requirements and 
understand and sign the Informed Consent Form 
8. Women of childbearing potential (WOCBP) must be 
using two acceptable methods of contraception 
throughout the study 
9. Women must not be breastfeeding 
 
Baseline Visit (Post Medication Run-In, Visit 2) 
1. WOCBP must have a negative urine pregnancy test at 
Baseline Visit 
 
Exclusion Criteria 
Screening Visit (Pre-Medication Run-In, Visit 1) 
1. Diagnosed with Type 1 Diabetes (T1D)  
2. Probable insulin production failure, defined as fasting 
C Peptide serum <1 ng/mL (333pmol/l) 
3. History of diabetic ketoacidosis or hyperosmolar 
nonketotic coma 
4. Previous use of any types of insulin for >1 month (at 
any time, except for treatment of gestational diabetes) 
5. Current use of injectable medications for diabetes 
(insulin, glucagon-like peptide-1 receptor agonist [GLP-
1RA]) 
6. Current use of glyburide, a sulfonylurea (SU) glucose-
lowering drug for diabetes.  
7. Hypoglycemia unawareness or a history of severe 
hypoglycemia (more than 1 severe hypoglycemic 

 
Protocol # C-40000 Version 3.0 
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Page 13 of 96 
event, as defined by need for third-party-assistance, in 
the last year) 
8. Known autoimmune disease, including but not limited 
to celiac disease, or pre-existing symptoms of systemic 
lupus erythematosus, scleroderma or other 
autoimmune connective tissue disorders 
9. Previous GI surgery that could limit treatment of the 
duodenum such as Bilroth 2, Roux-en-Y gastric 
bypass, or other similar procedures or conditions  
10. History of chronic or acute pancreatitis 
11. History of diabetic gastroparesis 
12. Known active hepatitis or active liver disease  
13. Acute gastrointestinal illness in the previous 7 days 
14. Known history of irritable bowel syndrome, radiation 
enteritis or other inflammatory bowel disease, such as 
Crohn’s disease 
15. Known history of a structural or functional disorder of 
the esophagus that may impede passage of the device 
through the gastrointestinal tract or increase risk of 
esophageal damage during an endoscopic procedure, 
including Barrett’s esophagus, esophagitis, dysphagia, 
achalasia, stricture/stenosis, esophageal varices, 
esophageal diverticula, esophageal perforation, or any 
other disorder of the esophagus 
16. Known history of a structural or functional disorder of 
the esophagus, including any swallowing disorder, 
esophageal chest pain disorders, or drug refractory 
esophageal reflux symptoms 
17. Known history of a structural or functional disorder of 
the stomach, including gastric ulcer, chronic gastritis, 
gastric varices, hiatal hernia (> 2 cm), cancer or any 
other disorder of the stomach 
18. Known history of chronic symptoms suggestive of a 
structural or functional disorder of the stomach, 
including any symptoms of chronic upper abdominal 
pain, chronic nausea, chronic vomiting, chronic 
dyspepsia or symptoms suggestive of gastroparesis, 
including post-prandial fullness or pain, post-prandial 
nausea or vomiting or early satiety 
19. Known history of duodenal ulcer, intestinal diverticula 
(diverticulitis), intestinal varices, intestinal 
stricture/stenosis, small bowel obstruction, or any other 
obstructive disorder of the gastrointestinal (GI) tract 
20. Currently have ongoing symptoms suggestive of 
intermittent small bowel obstruction, such as recurrent 

 
Protocol # C-40000 Version 3.0 
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Page 14 of 96 
bouts of post-prandial abdominal pain, nausea or 
vomiting 
21. Active H. pylori infection (subjects with active H. pylori 
may continue with the screening process if they are 
treated with an appropriate antibiotic regimen)  
22. History of coagulopathy, upper gastrointestinal 
bleeding conditions such as ulcers, gastric varices, 
strictures, congenital or acquired intestinal 
telangiectasia  
23. Current use of anticoagulation therapy (such as 
warfarin) which cannot be discontinued for 7 days 
before and 14 days after the procedure  
24. Current use of P2Y12 inhibitors (clopidogrel, pasugrel, 
ticagrelor) which cannot be discontinued for 14 days 
before and 14 days after the procedure.  
25. Unable to discontinue non-steroidal anti-inflammatory 
drugs (NSAIDs) during treatment through 4 weeks 
following the procedure. Use of low dose aspirin is 
allowed. 
26. Current use of serotonergic medications (SSRI) 
27. Use of systemic glucocorticoids (excluding topical or 
ophthalmic application or inhaled forms) for more than 
10 consecutive days within 90 days prior to the 
Screening Visit. 
28. Use of drugs known to affect GI motility (e.g. 
Metoclopramide) 
29. Receiving weight loss medications such as Meridia, 
Xenical, or over the counter weight loss medications 
30. Untreated/inadequately treated hypothyroidism, 
defined as an elevated Thyroid Stimulating Hormone 
(TSH) level at Screening; if on thyroid hormone 
replacement therapy, must be on a stable dose for at 
least 6 weeks prior to Screening 
31. Persistent anemia, defined as Hemoglobin <10 g/dL 
32. Subjects who have donated blood or received a 
transfusion in the prior 3 months 
33. Subjects with conditions that alter red blood cell 
turnover 
34. Subjects with prosthetic joints   
35. Significant cardiovascular disease including known 
history of valvular disease, or myocardial infarction, 
heart failure, transient ischemic attack or stroke within 
the last 6 months  
36. Moderate or severe chronic kidney disease (CKD), 
with estimated glomerular filtration rate (eGFR) <45 

 
Protocol # C-40000 Version 3.0 
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Page 15 of 96 
ml/min/1.73m2 (estimated by Modification of Diet in 
Renal Disease [MDRD]) 
37. Known immunocompromised status, including but not 
limited to individuals who have undergone organ 
transplantation, chemotherapy or radiotherapy within 
the past 12 months, who have clinically-significant 
leukopenia, who are positive for the human 
immunodeficiency virus (HIV) or whose immune status 
makes the subject a poor candidate for clinical trial 
participation in the opinion of the Investigator 
38. Active systemic infection 
39. Active malignancy within the last 5 years (with the 
exception of treated basal cell or treated squamous 
cell carcinoma) 
40. Subjects with a personal or family history of medullary 
thyroid carcinoma 
41. Subjects with Multiple Endocrine Neoplasia syndrome 
type 2 
42. Not a candidate for surgery or general anesthesia 
43. Active illicit substance abuse or alcoholism 
44. Current smoker  
45. Participating in another ongoing clinical trial of an 
investigational drug or device 
46. Any other mental or physical condition which, in the 
opinion of the Investigator, makes the subject a poor 
candidate for clinical trial participation 
47. Unwilling or unable to perform self-monitoring of blood 
glucose (SMBG), complete the patient diary, or comply 
with study visits and other study procedures as 
required per protocol 
 
Baseline Visit (Post Medication Run-In, Visit 2) 
1. A1c post run-in phase < 7.5% (59 mmol/mol) or > 9.5% 
(86 mmol/mol)2. Any severe hypoglycemic event, 
defined as hypoglycemia requiring third-party 
assistance; or any clinically significant hypoglycemic 
event, defined as self-monitored or laboratory plasma 
glucose level < 54 mg/dL (3.0 mmol/L); or ≥ 2 glucose 
alert values ≤70 mg/dL (3.9 mmol/L), unless a clear 
correctable precipitating factor can be identified, since 
the Screening Visit (Visit 1) 
2. Uncontrolled hyperglycemia with a glucose level >270 
mg/dl (>15 mmol/L) after an overnight fast or >360 
mg/dl (>20 mmol/l) in a randomly performed 
measurement during Medication Run-In Period and 

 
Protocol # C-40000 Version 3.0 
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Page 16 of 96 
confirmed by a second measurement (not on the same 
day) 
3. Mean of 3 separate blood pressure measurements 
>180 mmHg (systolic) or >100 mmHg (diastolic) 
4. WOCBP with a positive urine pregnancy test at 
Baseline Visit 
 
Procedure (Visit 3)  
1. Active and uncontrolled GERD defined as grade III 
esophagitis or greater 
2. Abnormalities of the GI tract preventing endoscopic 
access to the duodenum 
3. Anatomic abnormalities in the duodenum that would 
preclude the completion of the DMR procedure, 
including tortuous anatomy 
4. Malignancy newly diagnosed by endoscopy 
5. Upper gastrointestinal conditions such as ulcers, 
polyps, varices, strictures, congenital or acquired 
intestinal telangiectasia 
 
Study Endpoints: 
Effectiveness Endpoints: 
 
Primary Endpoint:   
A1c change from baseline to Week 24, DMR vs Sham  
 
Secondary Endpoints:  
(i) 
A1c change from baseline to Week 24 by visit over 
time, DMR vs. Sham  
(ii) Fasting plasma glucose (FPG) change from baseline 
to Week 24, DMR vs. Sham  
(iii) FPG change from baseline to Week 24 by visit over 
time, DMR vs. Sham  
(iv) Urine Albumin-to-Creatinine Ratio (UACR) change 
from baseline to Week 24, DMR vs. Sham  
(v) Alanine Aminotransferase (ALT) and Aspartate 
Aminotransferase (AST) change from baseline to 
Week 24, DMR vs. Sham  
 
Additional Endpoints of Interest: 
(i) 
A1c change from Week 24 (pre-DMR) in Sham 
cross-over group to Week 48   
(ii) FPG change from Week 24 (pre-DMR) in Sham 
cross-over group to Week 48   
(iii) RAND Short Form (36) Health Survey (SF-36) 
change from baseline at Week 24 (prior to  
assessments or endoscopy) vs Sham 

 
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(iv) PROMIS® (Patient-Reported Outcomes 
Measurement Information System) change from 
baseline at Week 24 (prior to  assessments or 
endoscopy) vs Sham 
 
Safety Endpoints: 
 Event number and incidence of reported adverse 
events (AEs) and serious adverse events (SAEs), as 
well as device- and procedure-relatedness of AEs and 
SAEs, unanticipated adverse device effects (UADEs), 
and withdrawals due to AEs  
 Other safety  
o assessments including vital signs and weight, 
physical exam, laboratory values (FPG, HbA1c, 
ALT, AST and UACR), electrocardiogram [ECG]  
o Duodenal biopsy samples for histological 
evidence of mucosal regrowth, inflammation 
and fibrosis 
o Magnetic Resonance Imaging Enterography 
(MRE) to assess thermal injury in the duodenum 
 
Note: As a pilot evaluation, this study is not statistically 
powered and only descriptive statistics will be used to assess 
both primary and secondary endpoints. 
 
Study Assessments: 
 
 
 
 
 
 
 
A1c 
FPG 
ALT, AST 
UACR 
Duodenal mucosal biopsy 
MRE 
SF-36  
PROMIS®  
 
Study Sponsor: 
Fractyl Laboratories Inc. 
17 Hartwell Ave 
Lexington, MA 02421 USA 
 

 
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List of Abbreviations  
ACRONYM 
DESCRIPTION 
A1c 
Glycated Hemoglobin (HbA1c) 
ADA 
American Diabetes Association 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase  
 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CBC 
Complete Blood Count 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
DMC 
Data Monitoring Committee 
DMR 
Duodenal Mucosal Resurfacing 
DPP 
Diabetes Prevention Program 
DPP4 
Dipeptidyl peptidase-4 inhibitor 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
FPG 
Fasting Plasma Glucose 
GI 
Gastrointestinal 
GIP 
Gastric Inhibitory Peptide 
GLP-1 
Glucagon-like peptide 1 
GLP1-RA 
Glucagon-like peptide 1 receptor agonist 
HCP 
Health Care Provider 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
HOMA-IR 
Homeostatic Model Assessment of Insulin Resistance 
ICH 
International Conference on Harmonization 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IFU 
Instructions for Use 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IV 
Intravenous 
LDL 
Low Density Lipoprotein 
mg/dL 
Milligrams per Deciliter 
Mmol 
Millimoles 
mmol/L 
Millimoles per liter 
MRE 
MRI 
ng/mL 
MRI Enterography 
Magnetic Resonance Imaging 
Nanograms per milliliter 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OAD 
Oral antidiabetic medications 

 
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OD 
Outer diameter 
PROMIS® 
Patient-Reported Outcomes Measurement Information System 
pmol/l 
Picomole/liter 
PP 
Per Protocol 
PT 
Preferred term 
QA 
Quality Assurance 
QOL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
Sc 
subcutaneous 
SF-36 
Short Form (36) Health Survey by RAND 
SGLT2i 
Sodium-glucose cotransporter-2 inhibitor 
SMBG 
Self-Monitoring of Blood Glucose 
SOC 
System organ class 
SSRI 
Serotonergic medications 
SU 
Sulfonylurea 
TEAE 
Treatment Emergent Adverse Event 
TZD 
Thiazolidinedione 
T1D 
Type 1 Diabetes 
T2D  
Type 2 Diabetes  
TSH 
Thyroid Stimulating Hormone 
UACR 
Urine Albumin-to-Creatinine Ratio  
UADE 
Unanticipated Adverse Device Effect 
WOCBP 
Women of Childbearing Potential 
 
 
 

 
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List of Definitions 
Term 
Definition 
As-Treated (AT) 
Population 
The subset of ITT subjects who received at least one ablation 
or undergo the sham procedure.  This is the primary 
population for efficacy.  Subjects are analyzed according to 
the treatment received. 
 
End-of-study 
The end-of-study date is when all subjects have completed all 
study visits or have otherwise discontinued from the study. 
 
Enrolled Subject 
Study enrollment is defined as successful completion of the 
endoscopic evaluation, randomization, and initiation of the 
index procedure, DMR or sham. 
 
Fasting blood 
glucose level 
 
Blood sample obtained after an overnight fast of at least 8 
hours 
Hypoglycemic 
events 
A glucose alert value is defined as ≤ 70 mg/dL (3.9 mmol/L). 
Serious, clinically important hypoglycemia is defined as a 
plasma glucose of < 54 mg/dL (3.0 mmol/L ).  Severe 
hypoglycemia is defined as denoting severe cognitive 
impairment requiring external assistance for recovery. 
 
Intent-to-Treat (ITT) 
Population 
The ITT population includes all subjects who were 
randomized after the Medication Run-In phase.  This is the 
secondary analysis population for efficacy (no imputation will 
be made for missing data, given the nature of the study; i.e., 
analysis on this population will be performed using only 
available data).  Subjects are analyzed according to the 
treatment to which they were randomized. 
 
Medication Run-In 
Time period when subjects who have met the Screening 
criteria undergo the 4 week Medication Run-In period. 
 
On-Study Period 
Subject participation in the study will begin from the time of 
signing the informed consent and concludes after the last 
study visit is completed. 
 
Safety Population 
This population includes all subjects in whom randomized 
treatment was attempted. Subjects are analyzed according to 
the treatment received. 
 
Screening Period 
From the time the subject signs informed consent until the 
time of randomization will be considered a screening period. 
 

 
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Screen Failure 
Patient who signs the informed consent form and fails to 
meet all eligibility criteria. 
 
Subject 
Patient who participates in this study in any capacity will be 
referred to as the “subject”.        
                                                                     
Study Participation 
Duration 
From the time the first subject signs informed consent until 
their completion of the last study visit. 
 
Study Population 
The study population includes all subjects consented at the 
site. Within this population there are Screened, Medication 
Run In, and Safety populations. 
 
Study Reference 
Manual 
A general term for any information or guideline provided to 
the study sites on technical aspects or procedural details of 
the clinical study. 
 
 
 
 

 
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1 
Introduction 
 
 
1.1 Type 2 Diabetes (T2D) 
T2D is an endocrine disorder that is characterized by chronically elevated blood 
glucose (hyperglycemia) and subsequent vascular complications.  It is a global 
disease of pandemic proportions and, in the United States alone, there are over 
25 million patients with T2D and nearly 2 million newly diagnosed patients every 
year (1). T2D is the leading cause of blindness (due to diabetic retinopathy, 
20,000 cases/year), end-stage renal disease (due to diabetic nephropathy, 
50,000 cases/year), and amputation (due to diabetic neuropathy, 70,000 
cases/year) (2).   
 
T2D is a complicated condition and its characteristic feature, hyperglycemia, 
manifests through diminished insulin action in the body. This occurs through two 
main pathogenic drivers: (i) a failure of the pancreatic beta cells to secrete 
adequate insulin; and (ii) systemic resistance to insulin action (termed “insulin 
resistance”). In principle, some patients who are genetically predisposed to 
disease worsen their degree of insulin resistance through westernized lifestyle 
behaviors (i.e., excessive caloric consumption of a diet rich in fat and simple 
sugars, and insufficient physical activity). This insulin resistant state thus 
imposes a persistent and excessive insulin secretory demand on the pancreatic 
beta cells (3,4). Over time, the pancreatic beta cell is unable to sustain its 
capacity to maintain such a high level of insulin secretion, and overt insulin 
secretory failure ensues. The mismatch between the degree of insulin resistance 
and the insufficient pancreatic insulin production leads to the onset of frank 
hyperglycemia and clinical diabetes (5). Unfortunately, once established, the 
disease continues to run a progressive course as pancreatic beta cell reserve 
further and inexorably declines over time. This explains why treatment 
approaches to lower blood glucose early in the disease invariably fail in the face 
of progressive beta cell failure. This inevitably results in the typical patient 
requiring more treatment assistance over time, culminating in the advanced state 
of negligible beta cell secretory reserve and the need for insulin treatment by 
injection (6,7). Therefore, an ideal new treatment approach for T2D would 
intervene before pancreatic beta cell function has completely failed with the aim 
of improving insulin sensitivity, and delaying or reducing the progressive decline 
in insulin secretory capacity. 
 
1.2 Existing Treatment Options 
Existing treatment options for T2D include lifestyle modification, pharmacological 
therapy and bariatric surgery. 
 
 Lifestyle Modification 
Lifestyle modification (i.e. diet, exercise) is a well-established intervention that is 
a critical first treatment step in T2D clinical management. Under carefully 
controlled clinical trial conditions, intensive lifestyle modification exerts metabolic 
benefit in subjects with pre-T2D, as demonstrated in the Diabetes Prevention 

 
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Program (DPP)  (8,9) and in patients with T2D (10,11). However, lifestyle 
modification alone is a largely ineffective treatment approach in a real world 
setting in large part due to patient non-compliance over the long term (12).  
 
 Pharmacological Intervention  
Pharmacological intervention is the mainstay of diabetes management, with 
approximately 45 anti-diabetes therapeutics currently available in the US. 
Unfortunately, like lifestyle modification, patient non-compliance renders this 
extensive treatment resource only partially effective. As illustration, a large 
segment of the US T2D population remains in sub-optimal glycemic control 
despite access to a wide array of pharmacological options (13,14).  
Pharmacological treatment of T2D is predominantly founded on increasing insulin 
action to limit hyperglycemia.  This is accomplished by either (1) increasing 
insulin availability through stimulating endogenous secretion from the pancreatic 
beta cells or, in advanced disease, by exogenously administering insulin, or (2) 
increasing the body’s sensitivity to insulin action, in other words, insulin 
sensitization. Pharmacological intervention is also founded on pragmatic ease of 
implementation and patient acceptance, where orally administered therapies tend 
to be used earlier in the disease before graduating to the need for injectable 
therapies (i.e., Glucagon-like peptide 1 receptor agonist [GLP-1RA], insulins). 
 
Increasing insulin availability is realized through well-established 
pharmacological therapy classes, the sulphonylureas (SUs), GLP-1RAs, and 
insulin, but two of the three classes (SUs and insulin) do so with potential for 
causing abnormally excessive circulating insulin levels that can expose patients 
to the harmful effects of hypoglycemia. It is well-established that iatrogenic 
hypoglycemia in T2D, through use of either SU or insulin, is associated with 
detrimental consequences, namely cardiovascular complications and death (15-
18). It is also speculated that the excessive hyperinsulinemia observed with both 
treatment classes, in particular with exogenous insulin use, stimulates abnormal 
lipogenesis, and this results in weight gain through increased adiposity and 
increased abnormal fat deposition in critical end organs, such as the liver, 
thereby worsening co-existent fatty liver disease (19-21). 
 
Insulin sensitization can be elicited by well-established interventions (lifestyle 
[diet and exercise], metformin, thiazolidinediones [TZDs]) that result in an 
improvement in overall glycemia. This improvement in glycemia can be observed 
at all stages of T2D: in conjunction with insulin secretagogues or exogenous 
insulin later in the disease, or to prevent the progression of beta cell failure when 
used earlier in the disease (22). It is also recognized that insulin sensitization is 
often accompanied by metabolic benefits beyond glycemic control through 
positive effects observed in other insulin sensitive end organs (e.g., 
cardiovascular system, liver, and ovary) (23-25). With the TZD class as 
illustration, positive effects have been reported on blood pressure, improvements 
in fatty liver disease manifestations, and a return to ovulation in anovulatory 
females (26). 

 
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 Bariatric Surgery  
Bariatric surgery has emerged as an intervention that exerts striking 
improvements in glycemic control in subjects with T2D, seemingly in a weight-
independent manner, and highlights the important role of the gastrointestinal tract 
in regulating metabolic homeostasis (27,28).  It has been shown to exert durable 
improvements in glycemic control that are superior to that achieved with 
optimized pharmacological therapy (29,30). However, the notion of surgery itself 
and its attendant risks, as well as limited surgical capacity, limits the role of 
bariatric surgery to impact population-level disease. 
 
1.3 Summary of Limitations of Current Therapies 
A number of barriers are acknowledged as impediments to achieving optimal 
glycemic control in T2D with currently available treatment options at both the 
patient and population level.  
 
 By Patient Adherence/Compliance 
The treatment of T2D is notable in that the majority, if not all, of the available 
interventions require some level of compliance on the part of the individual 
patient on a daily basis (e.g., administering oral medications or injections, 
sometimes multiple times per day, exercising, eating healthy meals and snacks, 
blood glucose monitoring). Non-compliance therefore limits greatly the impact of 
lifestyle modification and most of the pharmacological therapies; and the more 
complex and labor intensive a given treatment (e.g., exogenous insulin) the more 
it diminishes real world impact (31). Bariatric surgery has emerged as a very 
different treatment approach involving a single point in time intervention that 
exerts a powerful impact on metabolism. It is of course counterbalanced by the 
short-term effects of an actual surgical procedure and the significant risk of post-
surgical complications, but it nevertheless offers a transformative treatment 
approach that circumvents many of the issues of patient compliance (32,33).    
 
 By Specific Treatment Approach 
Each pharmacological modality also comes with specific tolerability or adverse 
event considerations that become a particular impediment to their use and 
contribute to real world non-compliance. 
 
Treatment 
Impediment 
Metformin 
GI intolerability, certain exclusion criteria, rare lactic 
acidosis 
SUs 
Weight gain, hypoglycemia 
Dipeptidyl 
peptidase-4 
inhibitors 
(DPP4s) 
Pancreatitis risk, rare angioedema and arthralgia 
TZDs 
Weight gain, edema, heart failure, bladder cancer 
Acarbose 
GI intolerability 

 
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SGLT2i 
GU infection, rare ketoacidosis, amputations 
GLP-1RA 
GI intolerability, injections, risk of pancreatitis 
Insulin 
Weight gain, hypoglycemia, edema, injections, blood 
glucose monitoring 
 
 By Disease Progression and Treatment Continuum 
T2D is a progressive disease and currently available pharmacological therapies 
are not designed to address its core pathophysiological abnormalities, and this 
results in an inability to alter the inexorable course of the disease. In other words, 
pharmacological treatment has been largely designed to limit the metabolic 
manifestation of clinical diabetes (hyperglycemia) but without treating the actual 
underlying disease. The average patient therefore requires more 
pharmacological treatment over time to control hyperglycemia, culminating in the 
eventual transition to insulin treatment (34,35). The final step to insulin treatment 
is especially problematic in that subjects resist this final therapeutic step as the 
treatment itself carries great negative stigma; it is hard to implement in a real 
world setting especially among patients with multiple chronic diseases and 
multiple concomitant chronic medications (see above), and there are inherent 
harmful side effects of insulin therapy that are often experienced by the patient 
(e.g., hypoglycemia, fluid retention, weight gain) (36-38).  
 
In summary, the management of T2D, despite an extensive list of treatment 
modalities, is impeded, given that (i) patient non-compliance limits treatment 
success at all parts of the disease continuum, (ii) the available treatments only 
treat the metabolic consequence of the disease (hyperglycemia) and not the 
underlying disease itself, (iii) the available treatments are unable to safely correct 
hyperglycemia in a large segment of the population, and (iv) aversion to insulin 
use means patients suffer needlessly with prolonged hyperglycemia pre-insulin 
use.  
    
1.4 Emerging Metabolic Role in the Gut  
Recent bariatric surgery experience has provided an increasing body of evidence 
that the gut plays a critical metabolic role in T2D.  More specifically, the bypass 
of the duodenum or prevention of nutrient contact with the duodenal mucosal 
surface results in a prompt and sustained insulin sensitizing effect. This effect 
appears to be independent of the short-term calorie restriction and the later 
reduction in adipose fat mass that is observed in patients who have undergone 
bariatric surgery. 
 
DMR, using the Revita™ System, is designed to mimic the metabolic benefit of 
the duodenal exclusion component of bariatric surgery, thereby eliciting an 
insulin sensitizing effect.  The clinical data gathered thus far indicate that DMR 
exerts a likely insulin sensitizing effect as evidenced by a lowering of 
Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), an insulin 
sensitizing metabolic signature by metabolomics testing (e.g., lowering of α-
hydroxybutyrate, diacylglycerol, and peroxidase activity), and other related insulin 

 
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sensitizing biomarker effects (including lowered hepatic transaminases and 
urinary albumin). 
 
Unlike bariatric surgery, which involves an anatomical bypass of the duodenum 
and therefore no exposure of ingested nutrients to the surface of that portion of 
the GI tract, DMR is designed to ablate and resurface the duodenal mucosal 
surface, thus allowing nutrients to be exposed to a resurfaced local mucosa. This 
infers that the duodenal mucosa surface is in some way abnormal in insulin 
resistant T2D subjects and is therefore emanating a potential ‘insulin resisting’ 
effect.  This notion is supported by multiple lines of evidence:  
 
(i) 
the duodenum undergoes a maladaptive hypertrophic response when 
exposed to unhealthy nutrients (i.e., fat, simple sugars);  
(ii) 
this change appears to be associated with an augmented insulin resistant 
signal emanating from this portion of the bowel;  
(iii) this signal appears to be persistent and reversible in T2D, as revealed in 
patients after bariatric surgery:  in patients in whom metabolic improvement 
has been established after surgery, the acute re-exposure of the bypassed 
duodenum to nutrients quickly restores the insulin resistant, hyperglycemic,  
dysmetabolic condition that had existed pre-surgery; and 
(iv) ablation technology applied to other tissue surfaces has shown that the 
natural tissue response to ablation is re-growth with subsequent healthy 
tissue surface formation (39-41) 
 
Taken together, there is a strong rationale that the duodenal mucosa of T2D 
subjects is in some way abnormal and that subjects would likely reap metabolic 
benefit if the local duodenal mucosa is resurfaced through an ablation technique.  
Preliminary clinical data gathered in ~100 patients treated with the Revita™ 
System (discussed in Section 1.7) suggest that DMR does indeed exert a 
glycemic improvement in T2D subjects, which appears to be mediated through 
an insulin sensitizing mechanism. The goal of the proposed pilot study is to 
further advance the DMR clinical evidence in T2D subjects in a controlled clinical 
setting to better characterize its safety and effectiveness profile. 
 
The Fractyl Revita™ System has achieved CE-marking and allows physicians to 
safely and effectively ablate the duodenal mucosa in patients with T2D. This 
procedure decreases hyperglycemia in these patients, thereby positively 
impacting their abnormal metabolic state. Further study of the Fractyl Revita™ 
System in patients with T2D will add important new data regarding tolerability, 
efficacy and safety of the DMR procedure compared to a sham-treated control 
group, provide both a short- and longer-term metabolic and safety perspective, 
and better characterize the intended user population.  
 
1.5 Fractyl RevitaTM System 
The Fractyl Revita™ System consists of two main components:  the Revita™ 
Catheter and a Console.  

 
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Revita™ Catheter: 
The Revita™ Catheter is a sterile, single use device that is delivered transorally 
over a guidewire into the duodenum using standard techniques, by a therapeutic 
endoscopist, and performs two functions: 1) injects saline into the submucosa of 
the duodenum to create a thermal barrier while also lifting the mucosa with saline 
to create a more uniform surface for ablation; and 2) ablates the mucosal surface 
using heated water recirculating inside a balloon.  
 
To achieve its function, the Revita™ Catheter is constructed of a multi-lumen 
shaft with a balloon affixed to its distal end. Affixed to the outside of the balloon 
are three narrow shafts, each with a port, that are used to draw a vacuum when 
placing the saline during the mucosal lifting portion of the procedure. Within each 
shaft is a fluid lumen with a miniaturized needle affixed to the distal end. Each 
needle is wholly contained within the port ensuring its safe use. During the 
mucosal lift, the tissue is drawn into the needle port, and saline is injected into 
the submucosal space through the needles.  The proximal end of the shaft is 
fitted with a handle and saline and vacuum lines that are affixed to a console unit 
to control its function.  The catheter is available with a 24 mm outer diameter 
(OD) balloon.  
 
Console: 
The console is a reusable electro-mechanical piece of equipment and provides 
precisely controlled functionality to the catheter to perform the submucosal lift 
and hot fluid ablation steps of the procedure.  The console continuously monitors 
its performance to detect fault conditions and mitigate risks to the patient. The 
console is controlled by the user through the use of a software user interface 
monitor. Prior to use, the console is fitted with a sterile single use line set that 
serves as the pathway for the saline to be placed into the duodenal submucosa 
during the procedure.  
 
1.6 DMR Procedure 
The DMR procedure using the Revita™ System is completed in the endoscopy 
suite or in an operating room using either general anesthesia by a physician who 
is trained in therapeutic endoscopic procedures involving the use of a guidewire. 
The patient is positioned in the left lateral decubitus position used for endoscopic 
procedures or preferred position as dictated by the site’s requirements for 
endoscopic procedures. A standard endoscope is used to complete an initial 
endoscopic evaluation and a guidewire is delivered past the ligament of Treitz to 
assist in delivering the catheter. Anti-peristaltic agents may be used during the 
procedure. Catheter delivery and device location for treatment is verified using 
fluoroscopic guidance. The use of fluoroscopy is limited to use during catheter 
placement and verification of location during treatment.  Based on data collected 
during earlier clinical investigations, the duration of radiation exposure is 
approximately equivalent to that delivered during an endoscopic retrograde 
cholangiopancreatography procedure, which is a common endoscopic procedure 

 
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with an acceptable safety profile. The total procedure time is approximately 30 
minutes.    
 
Mucosal Lift and Ablation Procedure 
The Revita™ catheter is placed in the proximal duodenum distal to the papilla. 
Both mucosal lift and mucosal ablation of the duodenum are commonly 
performed in the endoscopy suite, and the Revita™ System is designed to 
enable a highly controlled lift and ablation of the post-papillary duodenum.  Using 
the console interface, the balloon is inflated and vacuum delivered to draw  the 
intestinal mucosal tissue into the ports located on the balloon. The actuator on 
the handle is moved to advance the needle into the submucosal space within 
each of the ports. The console delivers saline colored with methylene blue or 
similar dye into the submucosa through the needles within the lumens of the 
catheter resulting in complete circumferential lift of the mucosa. Once complete, 
the ablation cycle is started and hot water is circulated into the balloon to 
complete an ablation of the previously expanded tissue. The balloon is deflated 
and the catheter repositioned distally to the next segment to be treated. The 
process of expansion, ablation and repositioning is repeated until the needed 
length is treated. A full DMR procedure is defined as 5 complete ablations 
representing 10 axial centimeters of circumferentially ablated tissue in the 
duodenum. The Revita™ catheter and endoscope are then removed.  
 
1.7 Clinical Experience 
A first in human clinical investigation (C-10000) began in August 2013 at a single 
site in Santiago, Chile and enrolled 57 subjects. The objective of this 
investigation was to evaluate initial feasibility and the safety profile of the DMR 
procedure using the Revita™ System, and its effect on subjects with T2D. 
Efficacy was evaluated with FPG and A1c levels. Safety data included 
volunteered/elicited AEs and their relatedness to the study device or procedure.     
Early in the course of the study, three SAEs of duodenal stenosis were reported. 
All resolved without sequelae. As corrective action, procedural and catheter 
modifications were implemented with no further reports of stenosis across the 
entire Revita™ clinical program to date. An additional SAE of jejunal perforation 
during catheter placement and prior to ablation, was noted. The most frequent 
AEs were GI-related (abdominal distention, abdominal pain, change of bowel 
habit and diarrhea). They occurred early following the procedure, were 
predominately mild in severity, and resolved early during the post-operative 
period, all without sequelae. Although the study was conducted primarily to 
demonstrate safety, A1c and FPG lowering and HOMA-IR improvement 
suggested significant improvement in the metabolic derangements of diabetes 
(42).  
 
A second single arm, open label evaluation has enrolled 46 subjects in Europe 
and South America (C-20000). The objective of this multi-center trial  was to 
verify that the results seen in C-10000 at a single center were generalizable to a 
broader population across Europe, in addition to South America . There were no 

 
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device-related SAEs. One procedure-related SAE, a transient low grade fever 
(38°) with C-reactive protein (CRP) elevation, occurred the day after DMR and 
required one extra day of hospitalization.  Consistent with the C-10000 study, the 
most frequent AEs were GI-related, occurring early post procedure; they were 
transient and generally mild. Effectiveness was demonstrated by a robust mean 
improvement in A1c of 1.0% at 24 weeks, with 71.1% of subjects achieving an 
improvement of at least 0.5%; mean FPG lowering of 35.7 mg/dL; a durable 
glycemic response over 52 weeks of observation; and a clinically-relevant 
decrease in HOMA-IR.   
 
C-30000, a randomized double-blind sham-controlled prospective multicenter 
clinical investigation in up to 120 T2D subjects was initiated in Europe and Brazil 
in Q2 2017, and includes mechanistic studies as well as safety and effectiveness 
assessments. 
 
1.8 Risk Analysis 
There are certain residual risks associated with the use of the Fractyl Revita™ 
System and the DMR procedure. AEs that may result from the DMR System 
include those commonly associated with gastrointestinal endoscopy procedures, 
as well as device-related AEs: potential acute and chronic adverse 
consequences of the device-induced duodenal ablation treatment, or those 
resulting from device malfunction, device user error, selected materials, device 
design or device construction.  Some AEs may be associated with both the 
procedure and the device. In addition, device malfunctions may occur which may 
or may not result in a device-related AE. The Instructions for Use (IFU) provide a 
listing of these device-related residual risks. Below is a listing of these risks, the 
means by which they may be minimized, as well as a justification for conducting 
the study. 
 
 Procedure Risks 
Potential AEs associated with the endoscopic procedure and sedation include 
the following (in alphabetical order):  
• 
Abdominal cramps, discomfort, or pain 
• 
Allergic or adverse reaction to sedation or anesthesia 
• 
Abdominal bloating 
• 
Cardiac or respiratory arrest 
• 
Death  
• 
Delayed gastric emptying  
• 
Dental injury 
• 
Difficulty swallowing 
• 
Digestive tract injury or perforation 
• 
Fever 
• 
Gastrointestinal bleeding 
• 
Headache 
• 
Hyperglycemia 
• 
Hypoglycemia 

 
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• 
Hypotension 
• 
Hypoxia 
• 
Impaired judgment or reactions 
• 
Indigestion 
• 
Infection 
• 
Injury to esophagus 
• 
Laryngospasm 
• 
Mucosal injury to GI tract  
• 
Nausea  
• 
Pancreatitis 
• 
Perforation 
• 
Pneumoperitoneum 
• 
Pulmonary aspiration 
• 
Sore or irritated throat  
• 
Vomiting 
 
Many of these risks and complications associated with the procedure are similar 
to those associated with other commonly performed endoscopic procedures with 
sedation, such as duodenal biopsies and endoscopic mucosal resection.   
 
 Device Risks 
 Potential AEs associated with the device include the following: 
  
 Abdominal cramps, discomfort, or pain 
 Abscess formation 
 Allergic reaction to the device materials or methylene blue  
 Death  
 Delayed gastric emptying  
 Diarrhea 
 Digestive tract injury 
 Duodenal stenosis 
 Fever 
 Gastric dumping syndrome 
 Gastritis 
 Gastrointestinal bleeding 
 Hyperglycemia 
 Hypoglycemia 
 Infection 
 Mucosal injury to GI tract  
 Nausea  
 Nutritional malabsorption 
 Pancreatitis 
 Perforation 
 Stomach or duodenal obstruction  
 Stricture  

 
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 Structural damage to the GI tract 
 Thermal damage to the duodenum wall or surrounding structures 
 Ulcer 
 Vomiting 
 
Device malfunctions that lead to device-related AEs include: 
 
 Console delivers incorrect ablation time and temperature profile resulting 
in GI tract injury or perforation 
 Hole in hot fluid catheter balloon resulting in leakage of hot fluid that 
results in GI tract injury or perforation  
 Lost catheter component in the GI tract or wall that results in GI tract injury 
or perforation 
 
Device malfunctions that may or may not result in device-related AEs include: 
 Component degradation  
 Device breakage  
 Device disarticulation  
 
 Minimizing Study Risks 
The following steps have been taken to minimize risks associated with the 
procedure and the use of the Fractyl Revita™ System: 
 
 The tissue or fluid contacting materials used in the construction of the 
Revita™ Catheter are known medical-grade materials that are well-
characterized and have a long history of use. In addition, biocompatibility 
testing has proven that the materials are safe. 
 The device design uses known technologies including sub-mucosal 
injection and hot fluid balloon to complete the procedure. Similar 
technologies are currently in use for such accepted procedures as 
endoscopic mucosal resection and treatment of menorrhagia.  
 The device design has been rigorously tested in the laboratory, animal 
models and clinical trials to characterize its performance and confirm the 
safety and performance of the procedure. 
 All endoscopists receive detailed training in the use of the Fractyl Revita™ 
System and the DMR procedure. The training includes hands-on use of 
the system in a lab setting. 
 
 Justification for Investigation 
As with any medical device developed for use in a procedure, there are risks 
associated with the Fractyl Revita™ System and the DMR procedure. Many of 
these risks are similar to those seen with other endoscopic devices that are 
passed either over the wire or through an endoscope for treatment in the 
esophagus, stomach or duodenum. The risk profile of such devices in the hands 
of experienced therapeutic endoscopists has improved dramatically over time 
with dedicated training, implementation of best practices in therapeutic technique 

 
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(e.g. use of endoscopic guidewires), improved endoscopic visualization, and 
improved fluoroscopic capabilities in endoscopic suites. From a procedural 
standpoint, devices such as achalasia-pneumodilatation balloons, injection 
needles, RF ablation devices and endoscopic mucosal resection systems have 
shown a satisfactory history of safe and effective clinical use. Attempts have 
been made to limit procedural risks by limiting study participation to subjects in 
general good health as per the stringent inclusion/exclusion criteria, having the 
DMR procedure conducted only by physicians and procedural teams trained in 
advanced therapeutic endoscopic procedures, and by conducting didactic and 
hands-on animal labs. In addition, appropriate steps have been taken to minimize 
the risks associated with the device design and materials, as listed above.   
 
The medical consequences and morbidity associated with T2D have been well 
studied and documented, and include microvascular and macrovascular 
complications such as renal failure, blindness, peripheral neuropathy, 
amputation, increased risk of myocardial infarctions, stroke, and peripheral 
vascular disease. A successful DMR procedure is expected to lower A1c in T2D 
patients with inadequate glycemic control despite the use of oral glucose-
lowering medications, given its potential for increasing insulin sensitivity and 
action, thereby decreasing glucose toxicity and enabling more effective glycemic 
control. In addition to its beneficial effect on the pathophysiological drivers of 
metabolic dysfunction, the DMR procedure has a key therapeutic advantage in 
that its effectiveness is not compliance-dependent, in contrast to all other 
currently available T2D therapies. Because poor adherence to medications is a 
significant barrier to glycemic control in the general population, a DMR procedure 
which does not require daily compliance with additional medications may prove 
to be particularly helpful in achieving superior real world results, as has been 
observed with bariatric surgery. In conjunction with an appropriate lifestyle  (eg, 
healthy diet, exercise), a DMR procedure performed in patients who have not 
achieved target glycemic goals with their current regimen of OADs should help 
optimize glycemic control and support endogenous beta cell function. Removing 
compliance as an impediment to glycemic control, and given its mechanistic 
plausibility, the DMR procedure and device offer an important new therapy to 
patients with T2D to help reduce the morbidity and end-organ damage from this 
debilitating chronic illness.    
 
As noted above, there are potential benefits associated with the DMR procedure, 
and the risks associated with the device and procedure have been identified and 
minimized where possible. Thus, the benefit/risk profile associated with the 
Revita™ System warrants further clinical research and justifies this investigation. 
 
 
 

 
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2 
Study Design 
 
2.1 Overview 
In two clinical trials conducted to date, the Fractyl Revita™ System has been 
studied as an open-label device intervention without a pre-specified control arm. 
Additionally, the first randomized, double-blind, sham controlled study was 
initiated in Q2, 2017 in Europe and South America and is in the process of being 
closed out. 
 
The US Pilot study is a prospective, randomized, double-blind (subject and 
endocrinologist), 24-week, sham-controlled, multi-center, pilot trial  in a maximum 
of 9 enrolled subjects with T2D suboptimally controlled on 2 to 3 OADs, one of 
which must be metformin. The randomization scheme will be 2:1 DMR 
treatment:Sham procedure. Total post-randomization study duration will be 24 
weeks for DMR subjects and 48 weeks for Sham subjects who undergo the 
crossover procedure within 21 days of Week 24 visit. 
 
All eligible subjects will participate in a 4-week antidiabetic medication Run-In 
Period before randomization to the index procedure to assess stability of blood 
glucose control in conjunction with medication compliance and lifestyle (diet, 
exercise) counseling. OADs will be held constant from start of Run-In Period 
through Week 24, with protocol pre-specified treatment algorithms for 
hypoglycemia and hyperglycemia.  
 
Following the medication run-in period, subjects will be scheduled for an 
endoscopic evaluation consisting of an assessment of the esophagus, stomach, 
duodenum and associated structures to ensure there are no conditions that 
would exclude the subject from having the index procedure (DMR or Sham).  
   
Following confirmation of subject eligibility during the endoscopic evaluation, 
subjects will be randomized to receive the DMR or Sham procedure. Post 
procedure the subjects will be required to return for follow-up visits as per visit 
schedule. 
 
Both treatment arms will be followed up for a total of 24 weeks from the index 
procedure and will continue to receive lifestyle counseling through the end of the 
study. At the Week 24 Visit, subjects randomized to the DMR treatment arm will 
have an ablation site biopsy and will be followed for an additional 24 weeks. At 
the Week 24 Visit, the Sham treatment arm will be provided the opportunity to 
cross-over to receive the DMR treatment. Sham subjects will then repeat all 
study visits from the DMR procedure through 24 weeks post crossover. Sham 
subjects that choose not to crossover and have the DMR study will be withdrawn 
from the study.  
  
On an ongoing basis, study subjects will be provided with healthy lifestyle 
counseling to educate them on the importance of exercise and diet in relation to 

 
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blood glucose control.  They will receive blood glucose meters at the Screening 
Visit and will be instructed how to perform  self-monitoring of blood glucose 
(SMBG) at a schedule as outlined in Section 6.10. Subjects will be provided 
diaries in which they will record any changes in medication use, SMBG results, 
and any symptoms of hypoglycemia or hyperglycemia. 
 
Study assessments include: A1c, FPG, ALT, AST, UACR, Duodenal mucosal 
biopsy, MRE, SF-36 Questionnaire, PROMIS®.  
 
Subject follow up visits conducted by telephone will occur at 7 and 14 days and 
at Weeks 8,15 and 21   post procedure. Subject follow up visits conducted in 
clinic will occur at Week 4, 12, 18 and 24 post procedure. A summary of the 
assessments and data collection requirements is presented in Appendix 1 (DMR) 
and Appendix 2 (Sham).     
 
2.2 Number of Study Sites and Subjects 
Up to 6 sites in the US will participate in the study. The total study enrollment is a 
maximum of 9 enrolled subjects in a randomized scheme of 2:1 (DMR:Sham)  
 
2.3 Intended Use 
The Fractyl Revita™ System is intended to improve glycemic control in 
conjunction with diet and exercise in patients with T2D who are inadequately 
controlled with oral antidiabetic medications.  
 
2.4 Study Objectives 
The study objectives are: 
 to assess the safety of the Fractyl Revita™ System for the treatment of 
subjects with T2D suboptimally controlled on 2 to 3 oral antidiabetic 
medications  
 to assess the effect of DMR versus Sham procedures on glycemic 
endpoints 24 weeks after the procedure 
 
 
 
 

 
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2.5 Study Workflow 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Subjects randomized to DMR who do not receive any ablations during the DMR procedure will 
have all clinical findings documented, and will be followed for safety through the Week 4 
visit and then discontinued from the study. 
 
**Subjects randomized to Sham who crossover to DMR but do not receive any ablations during 
the DMR procedure will have all clinical findings documented, and will be followed 
through the Week 4 post crossover visit and then discontinued from the study. 
 
+Subjects that choose not to crossover from sham to DMR will be discontinued from the study 
and the End of Study Electronic Case Report Forms (eCRFs) will be completed. 
 
 
Screened 
Protocol-specified Inclusion/Exclusion criteria 
Did not meet Study Eligibility 
Criteria – Screen Failure 
Medication Run In 
(4 weeks) 
Did not meet post Run-In Study 
Eligibility Criteria – Screen Failure 
Endoscopic Evaluation  
(Per Protocol) 
Failed Endoscopic Evaluation – 
Screen Failure  
Randomized (ITT) 
2:1 (DMR to Sham) 
Crossover to DMR 
(Within 21 Days after Week 24)  
Did not undergo  
DMR** + 
DMR Arm  
Sham Arm 
Did not undergo  
DMR* 
Did not undergo 
sham procedure 
End of Study  
(Week 24 follow-up post randomized DMR treatment / Week 24 follow-up Post Crossover) 
Follow up visits  
(Day 7 - Week 24 Post Crossover) 
Follow up visits  
(Day 7 – Week 24) 

 
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2.6 Study Duration 
It is anticipated that the overall duration of this investigation will be approximately 
23 months including subject enrollment, collection of follow-up assessments, and 
data analysis. The study will be initiated at each institution following approval of 
the respective independent Institutional Review Board (IRB) and after a Site 
Initiation Visit has been performed. Enrollment of subjects will take approximately 
four (4) months based on six (6) sites accruing a maximum of 9 enrolled 
subjects. Subjects will be follow for 24 weeks after initial randomization to 
DMR/Sham procedure or following Sham crossover to DMR procedure. Final 
data collection, analysis and final study report will take an additional 4 months.   
 
2.7 Study Endpoints 
This study is designed as a multi-center pilot evaluation of safety and 
effectiveness of the DMR procedure. It is not powered to demonstrate a 
statistically significant difference in effectiveness parameters between the 
treatment groups, and these endpoints will not formally define subject and study 
success. Instead, the results of this evaluation will be used to better understand 
the safety profile of the DMR procedure and to examine the reduction in A1c to 
aid in powering the future pivotal study which will serve as the basis for 
marketing authorization in the US.  
 
 Effectiveness Endpoints 
 
Primary Endpoint 
A1c change from baseline to Week 24, DMR vs Sham  
 
Secondary Endpoints 
(i) 
A1c change from baseline to Week 24 by visit over time, DMR vs. Sham 
(ii) 
FPG change from baseline to Week 24, DMR vs. Sham 
(iii) 
FPG change from baseline to Week 24 by visit over time, DMR vs. Sham 
(iv) 
UACR change from baseline to Week 24, DMR vs. Sham 
(v) 
ALT and AST change from baseline to Week 24, DMR vs. Sham 
 
Additional Endpoints of Interest 
(i) 
A1c change from Week 24 (pre-DMR) in Sham cross-over group to Week 
48   
(ii) 
FPG change from Week 24 (pre-DMR) in Sham cross-over group to Week 
48   
(iii) 
Short Form (36) Health Survey Version 2 (SF-36) change from baseline at 
Week 24 (pre- assessments and endoscopy) vs Sham 
(iv) 
Promis® (Patient-Reported Outcomes Measurement Information System) 
change from baseline at Week 24 (pre- assessments and endoscopy) vs 
Sham 
 
 Safety Endpoints 

 
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 Event number and incidence of reported AEs and SAEs, as well as device- 
and procedure-relatedness of AEs and SAEs, UADEs, and withdrawals due 
to AEs  
 Other safety  
 assessments including vital signs and weight, physical exam, 
laboratory values (FPG, HbA1c, ALT, AST and UACR), ECG 
 Duodenal biopsy samples for histological evidence of mucosal 
regrowth, inflammation and fibrosis 
 MRE to assess thermal injury to the duodenum. 
 
2.8 Blinding 
In this study, the endocrinologist and the associated site personnel and the 
subjects will be blinded to the treatment through the Week 24 follow-up visit, as 
will the Sponsor study team (except the proctors and technichians who will be 
present at the procedure).  While the endoscopist will not be blinded to individual 
treatments, he or she will be blinded to cohort level data and will not be 
responsible for the diabetes management of the subjects. At the Week 24 Visit, 
the subjects, the endocrinologist and the blinded study site staff, as well as the 
blinded Sponsor study team will be unblinded. 
 
Subjects who received the Sham treatment will be offered the option to crossover 
and undergo the DMR procedure at the Week 24 Visit post randomization.   
 
Sham-treated subjects who do not choose to crossover and receive DMR will be 
discontinued (withdrawn) from the study and the End of Study eCRFs will be 
completed. 
 
No study staff, associated hospital personnel, or study subjects will be informed 
of the randomization assignments until the scheduled time of unblinding at Week 
24, and care will be taken to minimize the risk of inadvertent premature 
unblinding.  The unblinding occurs after all assessments have been conducted at 
the Week 24 Visit. 
 
2.9 Control of Bias and Validity 
The following measures have been included in the study to control bias and 
increase study validity: 
 The study design utilizes multiple investigators and multiple study sites. 
 The study design utilizes objective endpoints that are measured in a central 
laboratory using validated methodology, these include A1c and  FPG. 
Standardized methods and protocols for performing and evaluating tests and 
examinations have been incorporated into the study protocol.   
 The use of a randomized controlled study design minimizes the bias in the 
findings and is considered the gold standard to demonstrate the true 
treatment effect. 
 The study monitor will review data collection forms as they are received from 
the study sites to assure there are no missing or incorrect data.  Missing or 

 
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incorrect data are queried and corrected in the database.  Site re-training will 
take place as required to ensure compliance with the protocol.   
 The DMC will evaluate SAEs and other pertinent safety parameters to ensure 
unbiased ongoing safety surveillance.  
 The CEC will adjudicate SAEs, and provide an unbiased assessment of AE 
relatedness and severity. Employing an independent body to oversee AE 
causality provides added validity to the assessment of study safety endpoints, 
reduces potential Sponsor or Investigator bias, and increases the consistency 
of all safety determinations.  
 
3 
Study Population 
 
3.1 Subject Selection 
A maximum of 9 subjects at up to six (6) study sites in the US will be enrolled into 
this clinical study. The clinical study population will be comprised of males and 
females, 28 - 65 years of age who satisfy all of the inclusion and exclusion 
criteria, as defined in Section 4.1. All subjects taking part in this clinical study 
must undergo the informed consent process. Subjects must be allowed adequate 
time to review the consent, have any questions answered, and make a voluntary 
decision to participate in the clinical study. Each subject must sign and date the 
IRB-approved Informed Consent Form (ICF) before any clinical study-related 
procedures are performed. A copy of the signed ICF will be provided to the 
subject for his/her records. A subject’s participation in the clinical study begins 
with the signing and dating of the ICF.  
 
Study sites may utilize a number of methods to recruit potential subjects into the 
study including evaluation of existing subjects from their clinical practice, referrals 
from other physicians and recruitment via external advertising. Advertising 
materials need to be reviewed and approved by the IRB before use.   
 
 Initial Subject Identification 
Potential subjects are identified by the Investigator or their designee(s) through 
medical record review, referring physicians, and inquiries from interested 
subjects. Subjects may be pre-screened using a telephone screening script to 
evaluate potential eligibility for the study. If the subject meets the study’s basic 
entry criteria as verified over the telephone using the screening script or through 
medical record review, the subject is invited to attend an office visit for potential 
inclusion in the study and consent to participate in the study by signing the ICF. 
 
 
 
 
 
3.2 Duration of Subject Participation 
The total anticipated duration of subject participation in the clinical study for a 
subject randomized to DMR will be up to a maximum of 33 weeks (maximum of 6 
weeks between Screening and Baseline, maximum of 3 weeks between Baseline 
and Procedure, and 24 weeks of follow up post procedure). 

 
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The total anticipated duration of subject participation in the clinical study for a 
subject randomized to Sham will be up to a maximum of 60 weeks (maximum of 6 
weeks between Screening and Baseline, maximum of 3 weeks between Baseline 
and Procedure, 24 weeks (to max of 27 weeks) to Crossover and 24 weeks of 
follow up post crossover procedure). 
 
  
 
4 
Screening Period and Eligibility Criteria 
The screening period will be completed in 3 phases and the eligibility confirmed 
at each of these visits: Screening (Visit 1, Pre-Medication Run-In), Baseline (Visit 
2, Post-Medication Run-In) and Procedure (Visit 3). The inclusion criteria and 
additional exclusion criteria for each visit are listed by visit in the following section 
below. 
 
4.1 Selection Criteria 
Selection criteria will be assessed and eligibility confirmed over the first 3 study 
visits: at the initial Screening Visit (Visit 1), at Baseline (Visit 2), and during the 
endoscopic evaluation at the Procedure Visit (Visit 3). Details of any subject who 
is screened for the study but is found to be ineligible at any of these 3 visits, 
based on medical history, medication use, physical exam, laboratory or ECG 
findings, will be considered a screen failure and the data collected must be 
entered in the Screening/Enrollment Log and documented in the eCRF. Screen 
Failure subjects will be informed by a telephone call from the site staff that they 
are ineligible for continued study participation. 
 
 Inclusion Criteria  
 
Screening Visit (Pre-Medication Run-In, Visit 1) 
1. Men and non-pregnant women 28-65 years of age 
2. Diagnosed with T2D for at least 3 years  
3. A1C of 7.5 - 9.5% (59-80 mmol/mol) 
4. BMI ≥ 28 and ≤ 40 kg/m2 
5. On two to three oral OADs (metformin plus one to two additional OADs) with 
two (see note below) at least at half maximum labeled dose (or highest 
tolerated) with no changes in medication in the 12 weeks prior to the 
Screening Visit (Visit 1) (Refer to ADA Standard of Medical Care in Diabetes 
2018, Table 8.3 for the maximum approved daily dose of non-insulin glucose 
lowering agents) (43). Note: For subjects on sulfonylurea (SU) glucose-
lowering drugs for diabetes, the only SUs permitted in the study will be 
glipizide or glimepiride, and their doses below half maximum labeled dosing 
will not be an exclusion for study entry. Patients unwilling to reduce the dose 
of SU at the time of the DMR procedure as described by protocol will be 
excluded. 
6. Agree to use an additional glucose-lowering treatment (eg, liraglutide, other 
OAD with the exception of glyburide) if recommended by the study 
investigator in case of persistent hyperglycemia.   

 
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7. Agree not to donate blood during their participation in the study 
8. Able to comply with study requirements and understand and sign the 
Informed Consent Form 
9. Women of childbearing potential (WOCBP) must be using two acceptable 
methods of contraception throughout the study 
10. Women must not be breastfeeding 
 
Baseline Visit (Post Medication Run-In, Visit 2) 
1. WOCBP must have a negative urine pregnancy test at Baseline Visit 
 
 Exclusion Criteria 
 
Screening Visit (Pre-Medication Run-In, Visit 1) 
1. Diagnosed with Type 1 Diabetes (T1D)  
2. History of diabetic ketoacidosis or hyperosmolar nonketotic coma 
3. Probable insulin production failure, defined as fasting C Peptide serum <1 
ng/mL (333pmol/l) 
4. Previous use of any types of insulin for >1 month (at any time, except for 
treatment of gestational diabetes) 
5. Current use of injectable medications for diabetes (insulin, GLP-1RA) 
6. Current use of glyburide, a sulfonylurea (SU) glucose-lowering drug for 
diabetes  
7. Hypoglycemia unawareness or a history of severe hypoglycemia (more than 1 
severe hypoglycemic event, as defined by need for third-party-assistance, in 
the last year) 
8. Known autoimmune disease, including but not limited to celiac disease, or 
pre-existing symptoms of systemic lupus erythematosus, scleroderma or 
other autoimmune connective tissue disorder 
9. Previous GI surgery that could limit treatment of the duodenum such as 
Bilroth 2, Roux-en-Y gastric bypass, or other similar procedures or conditions  
10. History of chronic or acute pancreatitis 
11. History of diabetic gastroparesis 
12. Known active hepatitis or active liver disease  
13. Acute gastrointestinal illness in the previous 7 days 
14. Known history irritable bowel syndrome, radiation enteritis or other 
inflammatory bowel disease, such as Crohn’s disease 
15. Known history of a structural or functional disorder of the esophagus that may 
impede passage of the device through the gastrointestinal tract or increase 
risk of esophageal damage during an endoscopic procedure, including 
Barrett’s esophagus, esophagitis, dysphagia, achalasia, stricture/stenosis, 
esophageal varices, esophageal diverticula, esophageal perforation, or any 
other disorder of the esophagus 
16. Known history of a structural or functional disorder of the esophagus, 
including any swallowing disorder, esophageal chest pain disorders, or drug 
refractory esophageal reflux symptoms 

 
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17. Known history of a structural or functional disorder of the stomach including 
gastroparesis, gastric ulcer, chronic gastritis, gastric varices, hiatal hernia (> 2 
cm), cancer or any other disorder of the stomach 
18. Known history of chronic symptoms suggestive of a structural or functional 
disorder of the stomach, including any symptoms of chronic upper abdominal 
pain, chronic nausea, chronic vomiting, chronic dyspepsia or symptoms 
suggestive of gastroparesis, including post-prandial fullness or pain, post-
prandial nausea or vomiting or early satiety 
19. Known history of duodenal ulcer, intestinal diverticula (diverticulitis), intestinal 
varices, intestinal stricture/stenosis, small bowel obstruction, or any other 
obstructive disorder of the GI tract 
20. Currently have ongoing symptoms suggestive of intermittent small bowel 
obstruction, such as recurrent bouts of post-prandial abdominal pain, nausea 
or vomiting 
21. Active H. pylori infection (Subjects with active H. pylori may continue with the 
screening process if they are treated with an appropriate antibiotic regimen)  
22. History of coagulopathy, upper gastrointestinal bleeding conditions such as 
ulcers, gastric varices, strictures, congenital or acquired intestinal 
telangiectasia  
23. Current use of anticoagulation therapy (such as warfarin) which cannot be 
discontinued for 7 days before and 14 days after the procedure  
24. Current use of P2Y12 inhibitors (clopidogrel, pasugrel, ticagrelor) which 
cannot be discontinued for 14 days before and 14 days after the procedure.  
25. Unable to discontinue non-steroidal anti-inflammatory drugs (NSAIDs) during 
treatment through 4 weeks following the procedure. Use of low dose aspirin is 
allowed.  
26. Current use of serotonergic medications (SSRI) 
27. Use of systemic glucocorticoids (excluding topical or ophthalmic application or 
inhaled forms) for more than 10 consecutive days within 90 days prior to the 
Screening Visit 
28. Use of drugs known to affect GI motility (e.g. Metoclopramide) 
29. Receiving weight loss medications such as Meridia, Xenical, or over the 
counter weight loss medications 
30. Untreated/inadequately treated hypothyroidism, defined as an elevated 
Thyroid-Stimulating Hormone (TSH) level at Screening; if on thyroid hormone 
replacement therapy, must be on stable dose for at least 6 weeks prior to 
Screening 
31. Persistent Anemia, defined as Hemoglobin <10 g/dL 
32. Subjects who have donated blood or received a transfusion in the prior 3 
months 
33. Subjects with conditions that alter red blood cell turnover 
34. Subjects with prosthetic joints   
35. Significant cardiovascular disease including known history of valvular 
disease, or myocardial infarction, heart failure, transient ischemic attack or 
stroke within the last 6 months 

 
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36. Moderate or severe chronic kidney disease (CKD), with estimated glomerular 
filtration rate (eGFR) <45 ml/min/1.73m2 (estimated by MDRD) 
37. Known immunocompromised status, including but not limited to individuals 
who have undergone organ transplantation, chemotherapy or radiotherapy 
within the past 12 months, who have clinically-significant leukopenia, who are 
positive for the human immunodeficiency virus (HIV) or whose immune status 
makes the subject a poor candidate for clinical trial participation in the opinion 
of the Investigator 
38. Active systemic infection 
39. Active malignancy within the last 5 years (with the exception of treated basal 
cell or treated squamous cell carcinoma) 
40. Subjects with a personal or family history of medullary thyroid carcinoma 
41. Subjects with Multiple Endocrine Neoplasia syndrome type 2 
42. Not a candidate for surgery or general anesthesia 
43. Active illicit substance abuse or alcoholism 
44. Current smoker  
45. Participating in another ongoing clinical trial of an investigational drug or 
device 
46. Any other mental or physical condition which, in the opinion of the 
Investigator, makes the subject a poor candidate for clinical trial participation 
47. Unwilling or unable to perform SMBG, complete the patient diary, or comply 
with study visits and other study procedures as required per protocol 
 
Baseline Visit (Post Medication Run-In, Visit 2) 
1. A1c post Run-In Phase < 7.5% (59 mmol/mol) or > 9.5% (86 mmol/mol) 
2. Any severe hypoglycemic event, defined as hypoglycemia requiring third-
party assistance; or any clinically significant hypoglycemic event, defined as 
self-monitored or laboratory plasma glucose level < 54 mg/dL (3.0 mmol/L); or 
≥ 2 glucose alert values ≤70 mg/dL (3.9 mmol/L), unless a clear correctable 
precipitating factor can be identified, since the screening visit (Visit 1) 
3. Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15 mmol/L) 
after an overnight fast or >360 mg/dl (>20 mmol/l) in a randomly performed 
measurement during Medication Run-In Period and confirmed by a second 
measurement (not on the same day)  
4. Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or 
>100 mmHg (diastolic) 
5. WOCBP with a positive urine pregnancy test at Baseline Visit 
 
Procedure (Visit 3)  
 
1. Active and uncontrolled GERD defined as grade III esophagitis or greater 
2. Abnormalities of the GI tract preventing endoscopic access to the duodenum 
3. Anatomic abnormalities in the duodenum that would preclude the completion 
of the DMR procedure, including tortuous anatomy 
4. Malignancy newly diagnosed by endoscopy 
5. Upper gastrointestinal conditions such as ulcers, polyps, varices, strictures, 
congenital or acquired intestinal telangiectasia 

 
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5 
Study Visits 
 
5.1 Visit 1: Screening (Pre-Medication Run-In) 
When the subject comes into clinic for the Screening Visit, the Informed Consent 
procedure is completed.  
 
 Informed Consent 
The informed consent shall inform the subject as to the objective and procedures 
of the study and possible risks involved. The subject will be informed about 
his/her right to withdraw from the study at any time and for any reason without 
sanction, penalty, or loss of benefits to which the subject is otherwise entitled, 
and that withdrawal from the study will not jeopardize their future medical care.  
The contents of the Informed Consent Form (ICF) will be discussed with the 
subject allowing adequate time for questions. If a subject is willing to participate 
in the study, they will indicate their willingness by signing the form. A signed copy 
of the ICF will be given to each subject in the study. The site must make a note in 
the subject’s medical record that consent was given, and the date and time at 
which the form was signed. 
 
 Demographics, Medical History and Full Physical Exam 
As outlined in Section 6.1, subject demographics, medical history and a full 
physical exam will be completed by the Investigator or designated study site 
personnel.  
 
 Blood Analysis 
As outlined in Section 6.3, subjects will have sufficient blood drawn to complete 
the required tests.  
 
Subjects with test results outside acceptable ranges that are indicative of an 
underlying condition that would compromise their participation in the study based 
on the protocol-specified Exclusion Criteria or Investigator expertise will be 
excluded from the study and considered to be Screen Failures.  
 
 H. pylori Test 
As outlined in Section 6.3, a blood sample will be drawn to complete testing of 
H.pylori on all potential subjects. 
 
Participants with active H. pylori may continue with the screening process if they 
are treated with an appropriate antibiotic regimen (A positive result will not be 
considered and Adverse Event). 
 
 ECG 
As outlined in Section 6.4, a 12-lead ECG will be performed  on all potential 
subjects. 
 

 
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 Lifestyle Counseling 
As outlined in Section 6.7, the subject will be provided with diabetic nutrition, 
healthy lifestyle and exercise guidance during this visit that is consistent with the 
standards of the American Diabetes Association (ADA) in order to educate them 
on the importance of a healthy lifestyle to blood glucose control.   
 
 Medication Run-In Period 
Individuals who meet all the Inclusion Criteria and none of the Exclusion Criteria 
at the Screening Visit (Visit 1) will be eligible to start the 4 week Medication Run-
In. Subjects will be instructed to continue their OAD regimen without change. The 
intent of the Medication Run-In Period is to verify a subject’s medication regimen 
and associated compliance, and to assess stability of glycemic control to ensure 
a stable baseline for subsequent comparisons. 
 
 SMBG / Glycemia Diary 
As outlined in Section 6.10, subjects will be provided with a home blood glucose 
meter, taught to perform SMBG (per the schedule outlined in Section 6.10) and 
asked to record the glucose values in the Glycemia Diary provided by the site. 
Subjects will be instructed to record the occurrence and blood glucose values (if 
possible) of all hypoglycemic episodes. They will also record their daily OAD 
intake. 
 
 Concomitant Medication 
As outlined in Section 6.12, a complete list of all medications a subject is 
currently taking will be recorded by the Investigator or designated study site 
personnel.  
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any reported/elicited adverse events or as dictated by 
blood tests and office evaluation will be recorded in the eCRF.  AEs are collected 
from the time the ICF is signed.   
 
5.2 Visit 2: Baseline (Post Medication Run-In) 
Subjects will come into the clinic for the Baseline Visit after completing a 
minimum of a 4 week (28 day) Medication Run-In.  This visit must occur 4-6 
weeks (28 – 42 days) after the Screening Visit (Visit 1).  
 
At this visit, subjects will be assessed for the following additional Inclusion 
Criteria: 
1. WOCBP must have a negative urine pregnancy test at Baseline Visit 
 
At this visit, subjects will be assessed for the following additional Exclusion 
Criteria: 
1. A1c post Run-In Phase < 7.5% (59 mmol/mol) or > 9.5% (86 mmol/mol) 
2. Any severe hypoglycemic event, defined as hypoglycemia requiring third-
party assistance; or any clinically significant hypoglycemic event, defined as 

 
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self-monitored or laboratory plasma glucose level < 54 mg/dL (3.0 mmol/L); or 
≥ 2 glucose alert values ≤70 mg/dL (3.9 mmol/L), unless a clear correctable 
precipitating factor can be identified, since the Screening Visit (Visit 1) 
3. Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15 mmol/L) 
after an overnight fast or >360 mg/dl (>20 mmol/l) in a randomly performed 
measurement during Medication Run-In Period and confirmed by a second 
measurement (not on the same day)  
4. Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or 
>100 mmHg (diastolic). 
5. WOCBP with a positive urine pregnancy test 
 
At the end of the Baseline Visit, the endoscopic procedure will be scheduled for 
subjects who are still eligible for study participation. The maximum time allowed 
between the Baseline Visit (Visit 2) and the Endoscopic Procedure Visit (Visit 3) 
is 21 days. Provide subjects on SU medications with specific instructions 
regarding their medication usage pre- and post-DMR/Sham procedure (See 
5.3.1). 
 
The study procedures outlined below will be performed at this Baseline (Post 
Medication Run-In) Visit in all subjects.  
 
 Body Weight, Blood Pressure & Targeted Physical Exam  
As outlined in Section 6.2, weight and blood pressure will be measured in all 
subjects.  A symptom-directed physical examination will be performed if new 
signs or symptoms are reported by a subject.  Abnormal findings noted at the 
previous physical exam will be reevaluated and any abnormal findings recorded. 
 
 Pregnancy Test  
A urine pregnancy test for WOCBP will be performed by a local laboratory.   
 
 Blood Analysis 
As outlined in Section 6.3, subjects continuing to be screened for study inclusion  
will have sufficient blood drawn to complete the standard blood analysis and 
forwarded to a central laboratory for analysis.  
 
A subject with test results outside acceptable ranges that are indicative of an 
underlying condition that would compromise their participation in the study based 
on the protocol-specified Exclusion Criteria or Investigator expertise will be 
excluded from the study and considered to be a Screen Failure.  
 
 Renal Function 
As outlined in Section 6.5, urinary albumin and creatinine levels will be analyzed 
to determine the UACR for evaluation of  kidney function.  A urine sample will be 
collected (at the same time as the fasting blood sample) from the subject and 
forwarded to a central laboratory for analysis.    
 

 
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 MRE 
As outlined in Section 6.7, subjects will undergo a MRE. 
 
 Lifestyle Counseling 
As outlined in Section 6.7, a member of the nutrition staff will query the subject 
regarding his/her adherence to a healthy lifestyle regimen, and provide the 
subject with advice regarding improvement in his/her diet and exercise regimen, 
if needed.  Subjects will be reminded of the importance of a healthy lifestyle to 
blood glucose control.   
 
 SF-36 Quality of Life Questionnaire 
As outlined in Section 6.8, subjects will complete the SF-36 for a health status 
and QOL assessment.    
  
 PROMIS® Patient Reported Outcomes 
As outlined in Section 6.9, subjects complete PROMIS® questionnaires to 
evaluate physical health.   
 
 OAD Use, SMBG / Glycemia Diary Review 
The subject’s Glycemia Diary will be  reviewed by the study site personnel for the 
occurrence of any exclusionary glycemic events, and OAD adherence. Subjects 
who meet the hypoglycemia or hyperglycemia exclusion criteria as outlined in 
Section 5.2 be excluded from the study. 
 
Subjects still eligible for the study will continue to perform SMBG, record 
occurrence of hypoglycemia, and continue their OADs without any changes 
through Visit 3 (Procedure).  
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication use reported by the subject 
will be recorded. Any changes in medication will be recorded on the medication 
log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any reported adverse events by the subject or dictated 
by blood tests or office evaluation will be recorded.   
 
5.3 Visit 3: Procedure (within 21 days from Visit 2) 
The procedure visit will consist of endoscopy, randomization of eligible subjects, 
and the completion of the index procedure (DMR or Sham).  All assessments are 
to be completed during a single clinic visit.  This visit may not occur more than 21 
days after the Baseline Visit (Visit 2).   
 
 Endoscopic Evaluation 
Prior to the procedure, subjects who are on SU medication will be instructed by 
the site regarding specific pre- and post-procedure (DMR or Sham) SU 

 
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management.  They will be asked to take half their regular dose of SUs the day 
before the procedure, and omit taking any SU the day of the procedure.  On the 
day of the procedure,the subject will undergo endoscopy with an assessment of 
the esophagus, stomach, duodenum and associated structures in order to ensure 
there are no conditions that would exclude the subject from receiving the index 
procedure (DMR or Sham).   
 
The following additional exclusion criteria should be assessed via endoscopy 
prior to subject study enrollment: 
 
1. Active and uncontrolled GERD defined as grade III esophagitis or 
greater 
2. Abnormalities of the GI tract preventing endoscopic access to the 
duodenum 
3. Anatomic abnormalities in the duodenum that would preclude the 
completion of the DMR procedure, including tortuous anatomy 
4. Malignancy newly diagnosed by endoscopy 
5. Upper gastrointestinal conditions such as ulcers, polyps, varices, 
strictures, congenital or acquired intestinal telangiectasia 
 
Any subject found to have the conditions listed in the Exclusion Criteria above 
will be considered a Screen Failure and will be excluded from further study 
participation. 
 
 Randomization 
Following confirmation of subject eligibility during the endoscopic evaluation, the 
subject will be randomized using electronic assignment via a web-based system  
at a 2:1 ratio to: 
 
DMR Procedure  
 
Sham Procedure  
 
The endocrinologist and the associated site personnel and the subjects will be 
blinded to the treatment through the Week 24 follow-up visit, as will the Sponsor 
study team (except the proctors and technichians who will be present at the 
procedure).  While the endoscopist will not be blinded to individual treatments, he 
or she will be blinded to cohort level data and will not be responsible for the 
diabetes management of the study subjects.  
 
Immediately following randomization, paracetamol, acetaminophen or equivalent 
will be administered to prevent pain after the procedure and to minimize the risk 
of premature unblinding.  
 
 Subject Enrollment 
Study enrollment is defined as successful completion of the endoscopic 
evaluation, randomization, and initiation of the index procedure, DMR or Sham. 
 

 
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All subjects who are enrolled in the study will be required to adhere to the follow-
up schedule outlined in this protocol.  
 
 Duodenal Mucosal Resurfacing Procedure 
The DMR procedure using the Revita™ System utilizes an over the wire 
endoscopic approach to ablate the duodenum as detailed in the Instructions for 
Use (IFU) and Operators Manual supplied with the study materials. Training will 
also be provided by Fractyl in advance of initiating the study.  
 
The procedure may be completed in an endoscopic suite or in an Operating 
Room depending on the facilities and support at each investigative site. All 
subjects will be monitored before and during anesthetization by general 
anesthesia or conscious sedation per each facility’s standard protocol. A 
complete DMR procedure is defined as 5 complete ablations representing 10 
axial centimeters of circumferentially ablated tissue in the duodenum.   
 
During the DMR procedure, a measurement is made by the endoscopist to 
approximate the distance in centimeters from the papilla to the proximal edge of 
the first completed ablation. This data will be used to assist the endoscopist in 
the location for the biopsies at the Week 24 Visit. 
 
For subjects randomized to DMR who do not receive any ablations during the 
DMR procedure, due to items such as tortuous anatomy precluding distal 
catheter delivery or erosive duodentitis, all clinical findings noted during the 
procedure will be documented in the medical record and in the CRFs. If the 
diameter of the subject’s duodenum prohibits the use of the single Revita 
catheter it will be noted in the medical record and in the CRFs. The subjects will 
be followed for safety through the Week 4 visit and then discontinued from the 
study. 
 
 Sham Procedure  
The Sham procedure will consist of placing the Revita™ Catheter as described 
above into the duodenum for a minimum of 30 minutes and then removing it from 
the patient.  
 
 Post-Procedure Care & Discharge  
Unforeseen events (findings or procedures) may occur during either the DMR or 
Sham procedures. These unforeseen events are those that are not planned as 
part of this procedure (e.g., a drop in oxygen saturation or evidence of intestinal 
bleeding, etc.). Unforeseen events that are emergent in nature should be 
recorded as adverse events and the investigator should reassess the subject’s 
suitability for continued participation in this study.  
 
Immediately following the procedure, the subject will be transported to the 
Recovery Area and monitored according to the hospital/physician protocol for 
endoscopic procedures. The subject may be released from the Recovery Room 

 
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to the nursing unit when they have met the hospital’s criteria for discharge from 
the Recovery Area. Immediate postoperative care will be dictated by the hospital 
or physician’s standard care protocol regarding post-anesthesia recovery.  
 
Prior to discharge, all subjects will be examined and evaluated for the presence 
of any AEs that may have occurred between the time of the procedure and 
discharge. A subject’s hospital stay can be extended based on need as 
determined by the Investigator. Subjects may be discharged when they meet the 
discharge criteria following the local sedation protocol and discharge 
requirements. 
 
 Post-Procedure Glucose and Diet Management  
For people with diabetes, any procedure that causes them to miss a meal or 
change their usual meal plan will require special planning to safely manage blood 
glucose. Subjects will be specifically instructed on appropriate post-procedure 
diet and glycemic management prior to discharge.  Intensified glucose monitoring 
will be implemented during this period, as discussed in Section 6.10. Subjects 
will be instructed to maintain adequate caloric intake and hydration during the 
entire post-procedure period. Guidelines for post-procedure, 2-week diet are as 
follows. The day of the procedure, abstinence of food is maintained (water is 
allowed but must be sipped). On Days 1–3 after the procedure, the subject may 
drink clear liquids such as tea, chicken broth and skimmed (fat-free) milk. Day 4-
6 post-procedure, the subject should begin to eat a soft diet such as chicken or 
beef soup (broth with herbs and semolina), nonfat yogurt, and tea and sugar-free 
gelato. Day 7-14 of the diet, the subject may expand their diet to include foods 
such as stew, fruit puree, yogurt and soda crackers. Training of the site 
personnel regarding the principles of nutritional management during this peri- 
and post-procedure period will be performed at every site prior to subject study 
entry. Site personnel training will include the composition and adequacy of 
dietary intake, attention to appropriate hydration, and relevance of intake to 
glycemic control. 
 
Following the DMR/Sham procedure, subjects on SU medications will be 
instructed to restart their medicines in an incremental fashion (step-wise increase 
to pre-procedure dose) guided by how well their dietary intake is progressing (eg, 
tolerability of full soft diet, calorie intake) and by their blood glucose levels as 
noted during their intense glucose monitoring efforts (refer to section 6.10 for 
additional instructions on SMBG and section 6.11 for additional instructions on 
Management of Glycemia and Antidiabetic Medication).  
 
After finishing the 14 day diet, a standard diabetic diet, outlined by the registered 
dietitian, will be resumed as tolerated. 
 
 OAD Use, SMBG and Glycemia Diary Review 

 
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As outlined in Sections 6.10 and 6.11, subjects will continue on their standard 
OAD regimen post-procedure, and record OAD use, blood glucose levels, and 
any hypoglycemia in the Glycemia Diary. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation will be recorded in the eCRF. Those 
that occur after the DMR or Sham procedure will be considered to be Treatment-
Emergent Adverse Events (TEAEs).    
 
5.4 Visit 4: Day 7 Telephone Call (+/-2 days) 
At Day 7 post-procedure, the subject will be contacted via telephone; no 
office/clinic visit is required. The following reminders will be given and information 
collected during the call: 
 
 Post-Procedure Diet Reminder 
The subjects will be reminded about the specific 14 day post-procedure diet.   
     
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels (as outlined in Section 
6.10 and section 6.11). For subjects who had been on SU medications prior to 
the DMR/Sham procedure, a review of dietary as well as glycemic and 
medication history will be performed to assess adequacy of their current SU dose 
and to provide further dosing recommendations, as needed.  
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF.  
 
5.5 Visit 5: Day 14 Telephone Call (+/-2 days) 
At Day 14 post-procedure, the subject will be contacted via telephone; no 
office/clinic visit will be required. The following reminders will be given and 
information collected during the call: 
 
 Post-Procedure Diet Reminder 

 
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The subjects will be reminded to discontinue the specific 14-day post-procedure 
diet. As outlined in Section 6.7, subjects will return to a standard diabetic diet as 
tolerated, as outlined by the study nutritionist.  
   
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels (as outlined in Section 
6.10 and section 6.11). For subjects who had been on SU medications prior to 
the DMR/Sham procedure, a review of dietary as well as glycemic and 
medication history will be performed to assess adequacy of their current SU dose 
and to provide further dosing recommendations, as needed until patient resumes 
to the pre-procedue SU dose based on investigator clinical judgment. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject is 
recorded. Any changes in medication are recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
5.6 Visit 6: Week 4 (Day 28) Clinic Visit (+/- 7 days) 
The following evaluations will be completed at the Week 4 Visit: 
 
 Body Weight, Blood Pressure & Targeted Physical Exam  
As outlined in Section 6.2, weight and blood pressure will be measured in all 
subjects. A symptom-directed physical examination will be conducted if new 
signs or symptoms are reported by a subject. Abnormal findings noted at the 
previous physical exam will be reevaluated and any abnormal findings recorded. 
 
 Blood Analysis  
As outlined in Section 6.3, subjects will have sufficient blood drawn to complete 
the standard blood analysis and forwarded to a central laboratory for analysis.  
 
 Lifestyle Counseling 
As outlined in Section 6.5, a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed.  Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control.   
    
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 

 
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The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects will continue to take antidiabetic medication 
without any changes to the regimen unless rescue criteria are met. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
 Blinding Assessment  
The subject will be asked about treatment assignment and the response will be 
recorded in the eCRF. 
 
5.7 Visit 7: Week 8 (Day 56) Telephone Call (+/- 2 days) 
At Week 8 post-procedure, the subject will be contacted via telephone; no 
office/clinic visit will be required. The following reminders will be given and 
information collected during the call: 
 
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects will continue to take  antidiabetic medication 
without any changes to the regimen unless rescue criteria are met. 
 
 Lifestyle Counseling 
As outlined in Section 6.7, a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed.  Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  

 
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As outlined in Section 7.8 any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
5.8 Visit 8: Week 12 (Day 84) Clinic Visit (+/- 7 days) 
The following evaluations will be completed at the Week 12 Visit:  
 
 Body Weight, Blood Pressure & Targeted Physical Exam  
As outlined in Section 6.2, weight and blood pressure will be measured in all 
subjects.  A symptom-directed physical examination will be conducted if new 
signs or symptoms are reported by a subject. Abnormal findings noted at the 
previous physical exam will be reevaluated and any abnormal findings recorded 
 
 Blood Analysis  
As outlined in Section 6.3, subjects will have sufficient blood drawn to complete 
the standard blood analysis and forwarded to a central laboratory for analysis.  
 
 Renal Function 
As outlined in Section 6.5, urinary albumin and creatinine levels will be analyzed 
to determine the UACR for evaluation of kidney function.  A urine sample will be 
collected (at the same time as the fasting blood sample) from the subject and 
forwarded to a central laboratory for analysis.    
 
 MRE 
As outlined in Section 6.7, subjects will undergo a MRE. 
 
 Lifestyle Counseling 
As outlined in Section 6.7, a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed.  Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control.   
  
 SF-36 Quality of Life Questionnaire 
As outlined in Section 6.8, subjects will complete the SF-36 for a health status 
and QOL assessment.    
  
 PROMIS® Patient Reported Outcomes 
As outlined in Section 6.9, subjects complete PROMIS® questionnaires to 
evaluate physical health.   
 
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 

 
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As outlined in Section 6.11, subjects will continue to take antidiabetic medication 
without any changes to the regimen unless rescue criteria are met. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
 Blinding Assessment  
The subject will be asked about treatment assignment and the response will be 
recorded in the eCRF. 
 
5.9 Visit 9: Week 15 (Day 105) Telephone Call (+/- 2 days) 
At Week 15 post-procedure, the subject will be contacted via telephone; no 
office/clinic visit will be required. The following reminders will be given and 
information collected during the call: 
 
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects will continue to take oral antidiabetic 
medication without any changes to the regimen unless rescue criteria are met. 
 
 Lifestyle Counseling 
As outlined in Section 6.7, a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed.  Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
5.10 Visit 10: Week 18 (Day 126) Clinic Visit (+/- 7 days) 
The following evaluations will be completed at the Week 18 Visit:  

 
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 Body Weight, Blood Pressure & Targeted Physical Exam  
As outlined in Section 6.2, weight and blood pressure will be measured in all 
subjects. A symptom-directed physical examination will be conducted if new 
signs or symptoms are reported by a subject. Abnormal findings noted at the 
previous physical exam will be reevaluated and any abnormal findings recorded. 
 
 Blood Analysis  
As outlined in Section 6.3, subjects will have sufficient blood drawn to complete 
the standard blood analysis and forwarded to a central laboratory for analysis.  
 
 Lifestyle Counseling 
As outlined in Section 6.7 a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed. Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control.   
  
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects will continue to take oral antidiabetic 
medication without any changes to the regimen unless rescue criteria are met. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
5.11 Visit 11: Week 21 (Day 147) Telephone Call (+/- 2 days) 
At Week 21 post-procedure, the subject will be contacted via telephone; no 
office/clinic visit will be required. The following reminders will be given and 
information collected during the call: 
 
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 

 
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 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects will continue to take oral antidiabetic 
medication without any changes to the regimen unless rescue criteria are met. 
 
 Lifestyle Counseling 
As outlined in Section 6.7, a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed. Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control. 
 
 Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
 
5.12 Visit 12: Week 24 (Day 168) Clinic Visit (+/- 7days) 
All subjects and the site endocrinologist and staff will be unblinded at this visit.  
 
The following evaluations will be completed at the Week 24 Visit (with the 
exception of Endoscopic Assessment which can be completed within 7 days of 
the Week 24 Visit):  
 
 Body Weight, Blood Pressure & Targeted Physical Exam  
As outlined in Section 6.2, weight and blood pressure will be measured in all 
subjects. A symptom-directed physical examination will be conducted if new 
signs or symptoms are reported by a subject. Abnormal findings noted at the 
previous physical exam will be reevaluated and any abnormal findings recorded 
 
 Blood Analysis  
As outlined in Section 6.3, subjects will have sufficient blood drawn to complete 
the standard blood analysis and forwarded to a central laboratory for analysis.  
 
 ECG 
As outlined in Section 6.4, a 12-lead ECG will be performed. 
 
 Renal Function 
As outlined in Section 6.5, urinary albumin and creatinine levels will be analyzed 
to determine the UACR for evaluation of kidney function. A urine sample will be 
collected (at the same time as the fasting blood sample) from the subject and 
forwarded to a central laboratory for analysis.    
   
 Lifestyle Counseling  

 
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As outlined in Section 6.7 a member of the nutrition staff will query the subjects 
regarding their adherence to a healthy lifestyle regimen, and provide them with 
advice about improving their diet and exercise regimen, if needed. Subjects will 
be reminded of the importance of a healthy lifestyle to blood glucose control. 
 
 SF-36 Quality of Life Questionnaire 
As outlined in Section 6.8, subjects will complete the SF-36 for a health status 
and QOL assessment.    
   
 PROMIS® Patient Reported Outcomes 
As outlined in Section 6.9, subjects complete PROMIS® questionnaires to 
evaluate physical health.   
 
 OAD and Rescue Medication Use, SMBG, and Glycemia Diary 
Review 
The subject’s Glycemia Diary will be reviewed by the study site personnel for 
OAD adherence, the addition of rescue medication for hyperglycemia, the 
occurrence of any hypoglycemia event, and SMBG levels. 
 
 Management of Glycemia and Antidiabetic Medication 
As outlined in Section 6.11, subjects continue to take all antidiabetic medication 
without any changes to the regimen unless rescue criteria are met. Subjects in 
the Sham treatment arm on SUs who are unblinded, and are offered and accept 
to undergo the DMR procedure, will be provided with specific peri-procedural 
instructions regarding their SU dosing (see Section 5.12.13). 
 
 
Concomitant Medication 
As outlined in Section 6.12, all concurrent medication reported by the subject will 
be recorded. Any changes in medication will be recorded on the medication log. 
 
 
Adverse Events (AEs)  
As outlined in Section 7.8, any AEs reported by or elicited from the subject, or 
dictated by blood tests or office evaluation, will be recorded in the eCRF. 
Subjects with an ongoing possibly and probably device and procedure related 
AEs reported at week 24 follow up visit will be followed until resolution. This will 
also also include AEs (signs and symptoms) reported during 24 week follow up 
period but without a definitive diagnosis and/or attribution of the cause at this 
visit. 
 
 
 
For Subjects Treated with the DMR Procedure Only 
Endoscopy and Endoscopic Evaluation  
A follow up endoscopic evaluation to visually examine the treatment site and 
adjacent tissues will be conducted after all Week 24 Visit assessments are 
complete and within 7 days of visit 12 / week 24. A video of the procedure will be 
obtained, as well as any Investigator notes detailing their observations. 

 
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Biopsy  
During the 24 week follow-up endoscopy, ablation site biopsies will be taken to 
evaluate the mucosal tissue that has regrown post DMR procedure.     
 
During the index DMR procedure, the endoscopist approximated the distance in 
centimeters from the papilla to the proximal edge of the first completed ablation. 
This distance was documented at the time of the procedure and will be available 
to the endoscopist during the follow-up endoscopy. Biopsies will be taken from 
within the first ablation zone whose length is defined as the proximal edge, as 
determined above, to a distance of 2.0 cm distal which corresponds to the length 
of the Revita™ Catheter ablation balloon. This technique will ensure biopsies are 
taken from a location that was previously ablated.   
 
A total of 4 biopsies will be taken from the ablation zone, with one biopsy taken 
from each circumferential quadrant on the lumen. A single biopsy from the un-
ablated tissue proximal to the papilla will serve as a control. 
In addition, the Investigator will take biopsies in any ablated area where the 
tissue appears abnormal under endoscopic visualization. 
 
Biopsies will be taken using large capacity, radial jaw forceps and placed in 10% 
formalin containers labeled with subject ID and sample location.  
 
Samples will be embedded in paraffin, and thin samples of each biopsy will be 
stained (hematoxylin and eosin; trichrome) to assess mucosal regrowth, 
inflammation and fibrosis using a 0-4 ordinal scoring system. The following 
assessments will be made comparing the ablated biopsies to the control: 
 Villous Formation 
 Acute Inflammation 
 Chronic Inflammation 
 Fibrosis 
The biopsy specimen will be analyzed at a central pathology laboratory in 
accordance with Good Laboratory Practice Regulations under the direction of a 
Board Certified Pathologist.  
 
 
For Subjects Treated with the Sham Procedure 
At the Week 24 Visit, all subjects initially treated with the Sham Procedure will 
have the same evaluations as the subjects in the DMR treatment group listed 
above, except for the 24 Week Follow-up endoscopy, endoscopic evaluation and 
biopsy. For subjects who accept the offer to crossover, the Endoscopy / DMR 
procedure will be scheduled within 21 days of this Week 24 Visit.  During the time 
between the Week 24 Visit and the crossover to DMR (Visit 3C), medications 
should be held stable. Prior to the procedure, subjects who are on SU medication 
will be instructed by the site regarding specific pre- and post-procedure SU 
management.  They will be asked to take half their regular dose of SUs the day 
before the procedure, and omit taking any SU the day of the procedure.   

 
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Note: Subjects that choose not to crossover from sham to DMR will be 
discontinued (withdrawn) from the study and the End of Study eCRFs will be 
completed. 
 
5.13 Visit 3C: Crossover to DMR Visit (+21 days from Visit 12) 
This visit is for Sham subjects only. The endoscopy and the DMR procedure will 
be completed at this visit. A video of the procedure will be obtained, as well as 
any Investigator notes detailing their observations.  
 
Once a Sham subject is treated with the DMR procedure, these subjects 
complete follow-up study Visits 4 (Day 7) through 12 (Week 24) as described in 
the protocol in Sections 5.4 through 5.12 (which are referred to as Visits 4C – 
12C for the Sham crossover group). These visits after the crossover to DMR 
include the exact same assessments as the initial visits and these crossover 
subjects will now be following the same visit schedule as a subject that was 
initially randomized to DMR.   
 
Note: Subjects randomized to Sham who crossover to DMR but do not receive 
any ablations during the DMR procedure will have all clinical findings 
documented, and will be followed through the 4 week post crossover visit and 
then discontinued from the study. 
 
5.14 COVID-19 Exceptions 
Due to the COVID-19 pandemic, in-clinic assessments, follow up endoscopic 
evaluations, biopsies and crossover procedures may not be offered to subjects 
unless the following criteria are met: 
 It is safe for subjects, site staff, and Sponsor Proctor (for crossover visits 
only) to travel to the study site during the given window  
 The study site allows on-site clinical research activities and elective 
procedures 
 
If both of these criteria are not met and subjects are unable to be seen on site, 
the study team will contact subjects via telephone to collect adverse events and 
concomitant medication changes through Week 24.     
 
 
5.15 Unscheduled Visits 
An unscheduled visit can occur at any time during the study. All unscheduled 
visits will be documented in the source documentation and in the eCRF. 
 
5.16 Subject Withdrawal & Early Termination 
All subjects initially randomized to the DMR procedure will be followed for 24 
weeks post-procedure.  All subjects initially randomized to the Sham procedure 
will be followed for 24 weeks, crossover to DMR and be followed for 24 weeks 
post crossover.  While study withdrawal is discouraged, subjects may withdraw 

 
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from the study at any time, with or without reason, and without prejudice to 
further treatment.  Reasonable efforts will be made by the investigational site to 
obtain a final data set from the subject, corresponding to data captured at Visit 
12.  Reasons for withdrawal include physician discretion, subject choice to 
withdraw consent, loss to follow-up and death, as described below.   
 
 Physician Discretion: the investigator determines that, for medical 
reasons, it is in the best interest of the subject to discontinue 
participation in the study.  If an AE or SAE occurs that could affect the 
subject’s safety or well-being, this should be documented in the eCRF 
as a reason for a subject’s study participation discontinuation. 
 Lost to Follow-Up:  Unable to locate the subject despite documented 
attempts to notify via telephone, email or mail.    
 Subject Withdrawal:  The subject requests to terminate his/her 
involvement in the study, therefore withdrawing his/her consent to 
participate in the study (the investigator must thoroughly document the 
reasons for termination, making all effort to obtain information about 
possible underlying AEs leading to the decision to withdraw from study 
participation).  
 Death:  If possible, an autopsy and/or death certificate should be 
obtained in order to document the cause of death. 
 
All subjects enrolled in the clinical study (including those withdrawn from the 
clinical study or lost to follow-up) shall be accounted for and documented. If a 
subject withdraws from the clinical investigation, the reason(s) shall be 
documented in the eCRF. All AEs ongoing at time of study end will be followed 
up until resolution or deemed to be chronic or stable. Withdrawn subjects will not 
be replaced.  
 
6 
Study Procedures & Assessments 
 
6.1 Demographics/Medical History/Physical Exam 
Subject demographics, medical history and a full physical exam are completed 
by the physician or assigned medical personnel. If necessary, the subject’s HCP 
may be asked to provide medical records about the subject’s medical history. 
Specific parameters to be captured include: 
 Demographic information, including date of birth, sex, race, and ethnicity 
 Diabetes history, including duration, prior therapy, current therapy 
 History of macrovascular complications: coronary heart disease, 
cerebrovascular disease, and peripheral arterial disease 
 Microvascular complications: retinopathy, nephropathy, and neuropathy 
 Concurrent health conditions 
 Previous surgeries/treatments 
 Physical exam findings with a focus specifically for T2D, including: 
- 
Vital signs:  pulse, blood pressure 

 
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- 
Height, weight 
- 
Fundoscopic exam 
- 
Thyroid palpation 
- 
Abdominal exam 
- 
Heart and lung auscultation 
- 
Deep tendon reflex and sensation (vibration, pinprick) assessment in 
distal lower extremities 
- 
Skin examination 
 
6.2 Body Weight, Blood Pressure & Targeted Physical Exam  
Weight and blood pressure will be obtained in all subjects.   
 Body weight will be measured to the nearest 0.1 kg on a calibrated 
scale in the morning before breakfast after a visit to the lavatory with 
the subject in light clothing with shoes removed. 
 
 Blood pressure will be measured in a sitting position in duplicate (in 
same arm) after 15 min of rest. Note: For Eligibility assessment, use 
the mean of 3 separate blood pressure measurements >180 mmHg 
(systolic) or >100 mmHg (diastolic). 
 
A symptom-directed physical examination will be conducted if new signs or 
symptoms are reported by the subject.  Abnormal findings noted at the previous 
physical exam will be reevaluated and any abnormal findings recorded.  
 
6.3 Blood Analysis 
Subjects will have sufficient fasting blood drawn to complete the following tests in 
a schedule as outlined in Appendix 1 & 2. As indicated in the table below, the test 
name will have the associated specific evaluations included.  
 
All blood drawn for analysis should be performed after at least an 8-hour 
overnight fast. 
 
Test Name 
Evaluation to be Included 
Complete Blood Count 
White Blood Cell Count  
White Blood Cell Differential 
Total Hemoglobin 
Hematocrit 
Platelet Count 
Blood Chemistry  
Blood Urea Nitrogen 
Calcium 
Chloride 
Creatinine & calculated eGFR 
Potassium 
Sodium 
Albumin 
Liver Panel 
ALT 

 
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AST 
Total Bilirubin 
Alkaline Phosphatase 
Ferritin 
Pancreatic Enzymes 
Amylase 
Lipase 
Thyroid Stimulating 
Hormone (TSH) 
Same 
Fasting Lipid Panel 
Total Cholesterol 
High Density Lipoprotein (HDL) 
Low Density Lipoprotein (LDL) 
Triglycerides 
Fasting Plasma Glucose 
Same 
Glycosylated hemoglobin 
(A1c) 
Same 
Fasting C-Peptide 
Same 
Fasting Insulin 
Same 
H.pylori 
(Screening Visit Only) 
Same 
 
At the Screening visit, subjects with test results outside acceptable ranges that 
are indicative of an underlying condition that would compromise their 
participation in the study, based on protocol-specified Exclusion Criteria or the 
Investigator’s expertise, will be excluded from the study and considered to be 
Screen Failures. All out-of-range laboratory values obtained during the course of 
the study will be deemed as clinically significant or not clinically significant by the 
investigator. Clinically significant values will be considered AEs and recorded as 
such on the eCRFs, as described in Section 7.8. 
 
Blood samples will be analyzed at a central laboratory. 
 
6.4 Electrocardiogram 
A 12-lead ECG will be performed in a schedule as outlined in Appendix 1 & 
2.  Clinically relevant abnormal findings will be reported as AEs, if they are newly 
discovered after inclusion in the study. 
 
6.5 Renal Function 
Urinary albumin and creatinine levels will be obtained to evaluate renal function.  
A urine sample will be collected (at the same time as the fasting blood sample) 
from the subject and forwarded to a central laboratory for analysis. Analyses will 
include albumin, creatinine and albumin/creatinine ratio.  
 
6.6 MRE 
Subjects will undergo MRE as outlined in Appendix 1 & 2 at the Baseline (Visit 2) 
to evaluate the duodenum and at Week 12 (Visit 8) to assess the entire 10 cm 
length of treated duodenum for thermal injury. Clinically-relevant abnormal 

 
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findings will be reported as AEs, if they are newly discovered after inclusion in 
the study. 
 
6.7 Lifestyle Counseling 
Subjects will be provided with standard diabetic nutrition, healthy lifestyle and 
exercise guidance that is consistent with ADA standards at Screening, and from 
Baseline (Visit 2) up to Week 24 (Visit 12) to educate them on the importance of 
diet in relation to blood glucose control.  Compliance with diet and lifestyle 
recommendations will be discussed with the subject throughout the study and 
specifically in the case of insufficient glycemic control. The details are provided in 
the Study Reference Manual. 
 
6.8 SF-36 Quality of Life Questionnaire 
Subjects will complete an assessment of health status and quality of life, the SF-
36 Questionnaire, at Baseline, and Weeks 12 and 24. These measures rely upon 
patient self-reporting. The SF-36 asks 36 questions to measure functional health 
and well-being from the patient's point of view. It is a practical, reliable and valid 
measure of physical and mental health that can be completed in five to ten 
minutes. 
 
6.9 PROMIS® (Patient-Reported Outcomes Measurement Information System) 
Subjects will complete the PROMIS® at Baseline, 12 and 24 Week Visits. 
PROMIS® is a set of person-centered measures that will be used to evaluate 
and monitor physical health in subjects. For the purposes of this study, the 
gastrointestinal symptom domains were chosen including nausea/vomiting, 
gas/bloating, diarrhea and belly pain. 
 
6.10 Subject Self-Monitoring of Blood Glucose (SMBG) and Glycemia Diary 
Subjects will be provided with a Glycemia Diary, a home blood glucose meter 
and supplies for use at home during the study, and will be instructed in correct 
SMBG technique. Subjects will measure blood glucoses according to a pre-
specified schedule, presented below, and record them in their Glycemia Diary. 
 
 Except as indicated for the Post-Procedure Intensive Monitoring Phase 
(Days 0-14), all subjects will be required to test a fasting (pre-breakfast) 
and a pre-dinner blood glucose level using SMBG daily.  In addition, they 
will perform more intensive monitoring of blood glucose, 4 times per day 
(once pre-breakfast [fasting] AND once before lunch, once before dinner, 
and once before bed), on at least 3 days on the week before each clinic 
visit and each telephone visit.   
 
 On Days 0-14 following the DMR procedure (the Post-Procedure Intensive 
Monitoring Phase), subjects will be required to perform more intensive 
monitoring of blood glucose, 4 times per day (once pre-breakfast [fasting] 
AND once before lunch, once before dinner, and once before bed), every 
single day during this period. 

 
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 Subjects will be requested to monitor blood glucose levels with increased 
frequency whenever they experience any illnesses (eg, cold, flu), or have 
symptoms of hyper- or hypoglycemia. 
 
Subjects will be instructed to bring their Glycemia Diary to the clinic at every 
study visit, and to scan/fax 7-day records to the site prior to each telephone visit. 
 
While symptoms of hyper- or hypoglycemia can be variable across patients with 
diabetes, the symptoms outline below may typically be associated with abnormal 
blood glucose levels, and should prompt subjects to perform SMBG more 
frequently:  
 
Low Blood Glucose Symptoms 
 Sweating  
 Shaking  
 Sudden mood changes (irritated)  
 Hunger pangs  
 Difficulty speaking  
 Rapid heartbeat  
 Epileptic seizure  
 Loss of consciousness  
 
High Blood Glucose Symptoms 
 Frequent urination  
 Increased thirst  
 Dry mouth 
 
 
Below are some symptoms that can apply to both high and low blood glucose: 
 Fatigue  
 Dizziness  
 Headache  
 Distorted vision  
 Nausea  
 Concentration problems  
 Confusion  
 Difficulty standing and walking  
 Muscle spasms  
 Tired and/or weak feeling  
 
6.11 Management of Glycemia and Antidiabetic Medication 
While the subjects are in the study, they will continue seeing their HCPs per their 
customary schedule, or as needed, for all non-glucose related medical issues.  
The management of the subjects’ glycemic control will be carried out by the 
investigator at the study site, who will be guided by the hyperglycemia and 
hypoglycemia management guidelines as outlined in the protocol (Section 
6.11.2).  The investigator will keep the subjects’ HCPs apprised of any diabetes 
medication changes, and may seek their input if needed. At the completion of the 
study, the subjects’ HCPs will resume full management of their diabetes. 

 
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Over the course of the study, subject’s glycemia will be managed by assessing 
the following parameters: 
 Antidiabetic medication use 
 SMBG values as recorded in the Glycemia Diary  
 A1c levels 
 Occurrence of hypoglycemia 
 Symptomatic severe hyperglycemia 
 
All study Investigators and study site personnel will be instructed in the 
importance of SMBG, Glycemia Diary review, and meticulous diabetes 
management with lifestyle counseling at the study visits, especially for subjects 
whose glucose values exceed accepted thresholds (i.e., >180 mg/dL [10.0 
mmol/L]). The Investigator will be instructed to probe for factors that may 
contribute to inadequate glycemic control, such as: 
 
 Compliance with concurrent diabetes therapies 
 Compliance with diet and exercise guidelines 
 Intercurrent disease 
 
Subjects will fax/scan their Glycemia Diary results prior to the telephone 
contacts, and bring their Glycemia Diaries to every study visit. During these 
telephone and on-site visits, the SMBG levels recorded in the Glycemia Diary will 
be reviewed, and compliance with concurrent diabetes therapies and diet and 
exercise guidelines will be assessed. Additional lifestyle and nutritional 
counseling will be provided to educate subjects on the importance of diet and 
exercise in relation to blood glucose control. 
 
Antidiabetic medication regime established during the Run-In Period will be 
continued through the index procedure without change, except for SU use, until 
the Week 24 visit (Visit 12), unless subjects meet the Study Exclusion criteria as 
outlined in Section 4.1.2, at the Baseline Visit (Post Medication Run-In, Visit 2) or 
unless they meet the on-treatment rescue therapy criteria as outlined below. 
Subjects on SU medications at study entry who qualify for the DMR/Sham 
procedure will be instructed to take half their usual dose of SUs the day before 
the DMR/Sham procedure, and no SU intake the day of the procedure.  
Following the procedure, subjects on SU medications will be instructed to restart 
their medicines in an incremental fashion (step-wise increase to pre-procedure 
dose) guided by how well their dietary intake is progressing (eg, tolerability of full 
soft diet, calorie intake), by their blood glucose levels as noted during their 
intense glucose monitoring efforts and investigator clinical judgment. 
 
 Hyperglycemia Management 
If any 2 consecutive FPG values as determined by SMBG exceed the threshold 
limits outlined below, the subject will be called for an unscheduled visit as soon 
as possible.  

 
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The threshold values for rescue treatment will be defined as follows: 
 Baseline up to Week 12: FPG > 220 mg/dL (12.2 mmol/L) 
 Week 12 up to Week 24: FPG >200 mg/dL (11.1 mmol/L) or no 
improvement in A1c from Baseline  
• 
A confirmatory FPG is to be obtained by the local or central laboratory. 
If the confirmatory FPG exceeds the threshold value, the investigator 
will perform an assessment for rescue using the factors listed below: 
• 
Blood glucose absolute value compared to rescue threshold 
• 
Overall trajectory of  FPG relative to run-in and baseline 
• 
Isolated incident vs a persistent elevation in blood sugar  
• 
Presence or absence of hyperglycemic symptoms  
• 
Presence or absence of an assignable cause of high blood sugar (e.g. 
intercurrent infection) 
 
At Week 24, subjects who were in the sham-treated group and who accept the 
offer to crossover to the DMR procedure will be assessed by the investigator for 
rescue therapy based on the criteria above if they meet the threshold value.   
 
The DMR-treated subjects will be offered rescue therapy at Week 24 if they have 
an HbA1c >8% or no improvement in A1c from baseline, and subsequently will 
be offered treatment escalation at 12-week intervals if their HbA1c levels exceed 
8%. 
 
At the beginning of their study participation, randomized subjects will be on 2 or 3 
oral antidiabetic medications (OADs), one of which must be metformin. Protocol-
specified guidance on escalation of treatment based on the above glycemic 
criteria, occurring at 12-week intervals, is outlined in following Table: 
 
 
Hyperglycemia Rescue Therapy Guidelines: 
On-Study Regimen 
Dose Adequacy1 
Rescue Regimen 
Metformin + other 
OAD(s) 
Submaximal metformin 
only 
↑ metformin dose if 
tolerated 
Submaximal other OAD 
only2 
↑ other OAD dose if 
tolerated 
Submaximal both 
↑ metformin dose if 
tolerated; if not, ↑ other 
OAD dose if tolerated2 
Metformin + other 
OAD(s) 
Maximally tolerated 
Add Liraglutide 1.23 mg 
subcutaneous (sc) daily4 
Metformin, other 
OAD(s), Liraglutide 
1.2 mg 
Maximally tolerated 
OADs 
↑Liraglutide to 1.8 mg sc 
daily 
 

 
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 Refer to Appendix 3 Table 8.3 of the American Diabetes Association (ADA) Standard of 
Medical Care in Diabetes 2018 for the maximum approved daily dose of non-insulin 
glucose lowering agents. 
 
2 If a subject is on submaximal SU dose, that dose can be maintained. 
 
3 The choice of Liraglutide as a rescue agent was made to ensure homogeneity for the 
treatment population and ensure maximum efficacy for patients failing two to three 
OADs.   
 
4 Investigators are advised to follow the package insert for Liraglutide, namely to start at 
0.6mg sc daily for two weeks and then escalate to 1.2mg sc daily thereafter, if 
tolerated, to reduce the risk of GI side effects. 
 
Prior to starting Liraglutide rescue therapy, a careful GI history should be 
obtained and the presence of nausea, vomiting or diarrhea be recorded prior to 
the initiation of liraglutide treatment. Subjects who are not felt to be candidates 
for Liraglutide therapy based on the Investigator’s judgement, or who do not 
tolerate the drug, may have an   OAD that the subject is not taking (TZD or DPP-
4 inhibitor or SGLT2 inhibitor or SU) added to their regimen, and prescribed as 
per labeled instructions.  For rescue therapy with SUs, only glipizide or 
glimepiride use is allowed.  
 
For subjects who may require more intensive diabetes management, 
investigators will be counseled to consider initiating insulin therapy if blood 
glucose is ≥300 mg/dL (16.7 mmol/L) or HbA1C is ≥10% or if the patient has 
persistent symptoms of hyperglycemia (i.e., polyuria or polydipsia). As the 
patient’s glucose toxicity resolves, the regimen may, potentially, be simplified. If 
subjects remain poorly controlled despite intensification therapy with insulin, they 
will be discontinued from the study. 
 
 Hypoglycemia Management 
Hypoglycemia is the major limiting factor in the glycemic management of both 
T1D and T2D. Subjects entering the Screening Phase of the study will be 
identified as having T2D without hypoglycemia unawareness or a history of 
severe hypoglycemia (more than 1 severe hypoglycemic event, as defined by 
need for third-party-assistance, in the last year). During study conduct, however, 
subjects may be at risk of experiencing hypoglycemia due to the combination of 
background antidiabetic medication use and procedure effects.  
 
The International Hypoglycaemia Study Group (2017) has classified  
hypoglycemia as outlined in following Table: 
 
Hypoglycemia Definition and Treatment Guidelines: 
 
Hypoglycemia Criteria 
Description 

 
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Glucose alert value ≤70 mg/dL (3.9 mmol/L) 
Sufficiently low for treatment with 
fast-acting carbohydrate 
Clinically 
significant 
hypoglycemia 
<54 mg/dL (3.0 mmol/L) 
Sufficiently low to indicate serious, 
clinically important hypoglycemia 
Severe 
hypoglycemia 
No specific glucose 
threshold 
Hypoglycemia associated with 
severe cognitive impairment, 
requiring external assistance for 
recovery 
 
During the Run-in Phase (Screening through Procedure), hypoglycemia meeting 
the criteria outlined below will be exclusionary. 
 
Hypoglycemia  Criteria 
Outcome 
 Any severe hypoglycemic event, defined as 
hypoglycemia requiring third-party 
assistance; or  
 Any clinically significant hypoglycemic 
event, defined as self-monitored or 
laboratory plasma glucose level < 54 mg/dL 
(3.0 mmol/L); or  
 ≥ 2 glucose alert values ≤70 mg/dL (3.9 
mmol/L) unless a clear correctable 
precipitating factor can be identified 
 Immediate treatment of 
hypoglycemia 
 Subject exclusion from study  
 
Hypoglycemia that occurs following randomization, whether noted with SMBG or 
due to symptoms, must be recorded in the Glycemia Diary and treated. Glucose 
(15–20 g) is the preferred treatment for the conscious individual with 
hypoglycemia at the glucose alert value of ≤70 mg/dL [3.9 mmol/L]), although 
any form of carbohydrate that contains glucose may be used. Fifteen minutes 
after treatment, if SMBG shows continued hypoglycemia, the treatment should be 
repeated. Once SMBG-obtained value returns to normal, the individual should 
consume a meal or snack to prevent recurrence of hypoglycemia. 
 
The use of glucagon is indicated for the treatment of hypoglycemia in people 
unable or unwilling to consume carbohydrates by mouth. Glucagon should be 
prescribed for all individuals at increased risk of clinically significant 
hypoglycemia, defined as blood glucose <54 mg/dL (3.0 mmol/L), such that it is 
available should it be needed.  
Patients are instructed to contact the Investigative site as soon as possible for 
review of Glycemia Diary data and to assess if a change in glycemic therapy is 
required in case one of the following occurs: 
1. any severe hypoglycemic episode 
2. 2 or more previously unreported episodes of blood glucose ≤70 mg/dl  
 

 
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If a subject has symptoms suggestive of hypoglycemia, the subject should 
perform SMBG, and treat if indicated, as discussed regarding hypoglycemia 
management above (6.11.2).  However, if it is not possible to obtain a 
confirmatory SMBG value in the setting of symptoms suggestive of 
hypoglycemia, the subject should assume the symptoms were due to 
hypoglycemia and should be treated. All glucose values ≤70 mg/dL (3.9 mmol/L), 
and all symptomatic treated episodes of hypoglycemia, with or without a SMBG 
value, should be recorded in the subject’s Glycemia Diary. Information on 
hypoglycemia will be transcribed from the diary onto the hypoglycemia eCRF 
page by the site. Because the analysis for hypoglycemia will be based on data 
recorded on the Hypoglycemia Reporting eCRF page and not the AE eCRF 
page, it is requested that the Investigator not report the hypoglycemic events on 
the AE eCRF page unless the hypoglycemia episode meets the criteria of an 
SAE. However, the Investigator is not prohibited from characterizing 
hypoglycemia as an AE. Any event of hypoglycemia reported as an AE will be 
cross-checked to ensure that the event is also reported on the Hypoglycemia 
Reporting eCRF page.  
 
In the case of symptomatic hypoglycemia or severe hypoglycemia appropriate 
adjustment of antidiabetic therapy, such as a dose reduction / discontinuation of 
ongoing rescue medication or existing background therapy can be initiated. 
Reduction or discontinuation of ongoing rescue medication should be considered 
before a reduction in the dose of existing background therapy. 
 
6.12 Concomitant Medications 
All concomitant medications will be recorded at the Screening Visit. The use of 
ongoing and any new medications will then be noted at each following study visit.  
All medication use will be captured in the source documents and on the 
appropriate eCRF page. The following information will be recorded for each 
medication: name, indication, dose, frequency, start date, end date. 
 
 
7 
Study Management 
 
7.1 Regulatory Compliance  
This clinical trial will be conducted according to 21 CFR Part 812, 21 CFR Part 
50, 21 CFR Part 56; EN ISO 14155:2011; GCP principles and the principles of 
the World Medical Association Declaration of Helsinki 1964 (including all 
amendments and Notes of Clarification, up to and including the Scotland 2000 
amendment and Tokyo 2004 Note of Clarification). The Investigator will conduct 
all aspects of this trial in accordance with all national, state, and local laws or 
regulations. 
 
7.2 Institutional Review Board (IRB) Review 
IRB approval is required for each institution participating in this clinical 
investigation. Investigators are responsible for obtaining and maintaining 

 
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approval of the study, including the subject consent forms and recruitment 
materials, by their institution’s IRB. The IRB approved Informed Consent Form 
must be retained at the investigational site and made available for inspection.  
 
The clinical site’s IRB must meet all relevant regulatory requirements. The study 
protocol and ICFs will be reviewed by the IRB, and written approval from the 
committee must be received by Fractyl prior to enrolling subjects into the study. 
The protocol must be re-approved by the IRB upon receipt of amendments and 
annually, as local regulatory requirements require. 
 
The Investigator is responsible for submitting all protocol changes and SAE 
reports to the IRB according to local procedures. At a minimum, all SAEs 
requiring an investigational device exemption safety report must be immediately 
reported. 
 
In accordance with applicable local regulatory requirements, the Investigator may 
be obligated to provide periodic safety updates on the conduct of the study at his 
or her site and notification of study closure to the IRB. Such periodic safety 
updates and notifications are the responsibility of the Investigator and not of the 
Sponsor. 
 
All relevant correspondence from the IRB will be forwarded by the respective 
study site to the Sponsor in a timely fashion. 
 
7.3 Study Records 
All information and data sent to Fractyl or their authorized representatives 
concerning subjects or their participation in this study are considered confidential. 
All data used in the analysis and reporting of this evaluation will be used in a 
manner without identifiable reference to the subject. 
 
The following records must be maintained in designated Fractyl Clinical Study 
administrative files: 
 Clinical protocol and all amendments 
 Investigator’s Brochure 
 IRB Roster 
 IRB approval letter(s) and approved informed consent(s) (including any 
revisions) 
 Approved advertisements for subject recruitment (if applicable) 
 Correspondence with the IRB  
 Signed Clinical Study Agreement 
 Site authorized personnel signature list/Delegation of Authority Log 
 Signed Non-Disclosure Agreement  
 Curriculum vitae for all investigators  
 Financial Disclosure Forms 
 Correspondence relating to this study (with Sponsor, clinical monitors, 
other Investigators, etc.) 

 
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 IFU 
 Device Accountability Log and device related paperwork (including 
shipping documents, invoices, device return log, etc.) 
 Normal value(s)/Range(s) for all laboratories used 
 Laboratory certification(s) for all laboratories used  
 Monitoring Letters/Report(s) and Sponsor Representative Signature Log 
 eCRF Completion Guidelines 
 Reports (including Adverse Event reports, annual reports and final reports 
from Investigator and Sponsor) 
 
The following records must be maintained for each subject enrolled in the study: 
 Signed subject consent form 
 All completed eCRFs 
 Record of any side effects, device malfunction, and treatment failures 
(with supporting documentation) 
 Procedure reports, nursing notes, and subject office files 
 Patient diaries 
 Copies of all laboratory records 
 Records of any interventions (procedure reports, nursing notes, etc.) 
 Reports of all imaging, including representative images 
 Records related to subject deaths during the investigation (including death 
records, death certificate and autopsy report, if performed). 
 
The Investigator or Investigational site will maintain in original format all essential 
study documents and source documentation that support the data collected on 
the subjects in compliance with GCP standards and all applicable federal, state, 
and local laws, rules and regulations related to the conduct of a clinical study.  
Investigator files containing all records and reports of the investigation should be 
retained for a minimum of two years or longer after approval of a marketing 
application, two years after records are no longer required to support marketing 
application, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the DMR procedure. It is Fractyl’s responsibility to inform 
the Investigator when these documents no longer need to be maintained. To 
avoid any error, the investigator should contact Fractyl before destroying any 
records and reports pertaining to the study to ensure they no longer need to be 
retained. The Investigator will take measures to ensure that these essential 
documents are not accidentally damaged or destroyed. If for any reason the 
Investigator withdraws responsibility for maintaining these essential documents, 
custody must be transferred to an individual who will assume responsibility, and 
Fractyl must receive written notification of this custodial change. Notice of 
transfer should be submitted to the FDA not later than 10 working days after the 
Sponsor has been notified of the change. 
 
7.4 Study Reports 
Investigators are required to prepare and submit the following complete, 
accurate, and timely reports as outlined in the following table. 

 
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Responsibilities for Preparing & Submitting Reports 
 
Type of Report 
Prepared by 
Investigator for 
Time of Notification 
(From Documented Event) 
Case Report Forms 
(working copy) 
Fractyl 
Ready for monitoring within 10 
working days 
Serious Adverse Event 
(device related or not) 
Fractyl, IRB 
(as required) 
Within 24 hours of knowledge 
Device Malfunction 
Fractyl 
Within 24 hours of knowledge 
Subject death during the 
investigation 
Fractyl and IRB 
Within 24 hours of knowledge 
Unanticipated Adverse 
Device Effect 
Fractyl, IRB  
(as required) 
Within 24 hours of knowledge 
Subject withdrawal 
Fractyl 
Within 7 days of knowledge 
Withdrawal of IRB/EC 
approval 
Fractyl  
Within 24 hours of knowledge 
Deviation from 
investigational protocol 
Fractyl, IRB  
(as required) 
Within 7 days of knowledge 
Informed consent not 
obtained from subject 
Fractyl and IRB 
Within 24 hours of knowledge 
Annual Progress report 
Fractyl and IRB 
Within 1 month of annual 
IRB/Approval date 
Final summary report 
Fractyl, IRB  
(as required) 
Within 3 months of study 
completion 
Other information as 
requested by Fractyl, IRB
As appropriate 
As requested 
 
Reports generated for this clinical investigation should be stored in accordance 
with section 7.3.   
 
Investigator’s Annual and Final Reports 
Each year a summary report is prepared by the Study Principal Investigator and 
Sponsor providing a synopsis of the subjects treated to date, safety profile, as 
well as other pertinent clinical information associated with the device usage. The 
report is provided to each study site Investigator to file reports as required by 
IRB, local guidelines and government regulations.   
  
Upon completion or termination of the study a final report is prepared.  This 
report contains a critical evaluation of all data collected during the course of the 
investigation at each institution.  The report must be signed by the Principal 

 
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Investigator at the site and is provided to the IRB and a copy to Fractyl.  Any 
modifications to this final report must be reviewed and approved by Fractyl.   
 
7.5 Device Accountability 
All devices received for this trial are inventoried and accounted for throughout the 
study. The devices must be stored in a secure, limited-access area. Upon 
request by the Sponsor or study completion, all unused consumable devices and 
all pieces of capital equipment are returned to Fractyl. No devices may be used 
outside this trial except by authorized investigators in accordance with the 
protocol. 
 
Devices that do not function properly during use or others that may be 
determined by the Sponsor to be needed for post use evaluation are retained by 
the site until the evaluation is complete at which time they are returned to the 
Sponsor.  
 
7.6 Protocol Deviations  
The investigator must not make changes or deviate from the protocol, except to 
protect the life and physical well-being of a subject in an emergency. The 
investigator shall notify the Sponsor and the reviewing IRB (as applicable) of any 
deviation from the investigational plan to protect the life or physical well-being of 
a subject in an emergency, and those deviations which affect the scientific 
integrity of the clinical investigations. Such notice shall be given as soon as 
possible, but no later than 24 hours after the emergency occurred, or per 
prevailing local requirements, if sooner than 24 hours.  
 
All deviations from the investigational plan must be documented and reported to 
the Sponsor using entry onto the eCRF. Sites may also be required to report 
deviations to the IRB, per local guidelines and government regulations.  
 
Deviations are reviewed and evaluated on an ongoing basis and, as necessary, 
appropriate corrective and preventive actions (including notification, center re-
training, or discontinuation) are put into place by the Sponsor. 
 
7.7 Investigational Site Termination 
Fractyl reserves the right to terminate an investigational site for any of the 
following reasons: 
 Repeated failure to complete eCRFs 
 Failure to obtain Informed Consent 
 Failure to report SAEs within 24 hours of knowledge 
 Loss of or unaccounted for device inventory 
 Repeated protocol deviations 
 Failure to enroll an adequate number of subjects 
 
7.8 Adverse Event Reporting 
 

 
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 Adverse Events (AEs) 
An AE is any untoward medical occurrence, unintended disease or injury, or any 
untoward clinical sign (including an abnormal laboratory finding) in subjects, 
users, or other persons, regardless of whether or not it is related to the 
investigational medical device. 
 This definition includes adverse events related to the medical device of 
this investigation. 
 This definition includes adverse events related to the procedures involved 
(any procedures in the clinical investigational plan) 
 For adverse events involving “users or other persons”, this definition is 
restricted to adverse events related to the medical device of this 
investigation. 
. 
Adverse events are classified and tabulated by relationship to procedure or 
device, severity, and body system. Serious Adverse Events (SAEs), deaths and 
Unanticipated Adverse Device Effects (UADEs) will be listed separately.   
 
The following should not be recorded as AEs: 
 Pre-planned procedure unless the condition for which the procedure was 
planned has worsened from the first study-related activity after the subject 
has signed the informed consent form. 
 Pre-existing conditions found as a result of screening procedures. These 
should be recorded as medical history/concomitant illness. 
 
Out-of-range laboratory values that are deemed clinically significant by the 
Investigator will be considered AEs and recorded as such on the eCRFs, 
 
Adverse Event information will be recorded in the eCRF Adverse Event Form. 
AEs, SAEs and UADEs will be coded using MedDRA.  
 
Adverse events are graded on a 3-point scale and reported as indicated on the 
eCRF. The intensity of an adverse experience is defined as follows:  
 
 Mild: Discomfort noticed, but no disruption to daily activity 
 Moderate: Discomfort sufficient to reduce or affect normal daily activity  
 Severe: Inability to work or perform normal daily activity 
 
Study Procedure and Device Relationship: the relationship of an adverse event 
to the device and to the procedure will be assessed by the investigator as 
follows: 
Definitely Related: Clear-cut temporal association and no other possible cause. 
Probably Related: Clear-cut temporal association and a potential alternative 
etiology is not apparent. 

 
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Possibly Related: 
Temporal association is less clear and other etiologies are 
also possible. 
Not Related: 
There is no temporal association and/or evidence exists that 
the event is definitely related to another etiology 
All adverse event reports are filed as required by IRB and FDA regulations. For 
all adverse events (whether device-related or not), all sections of the appropriate 
Adverse Event Form(s) must be completed. In this study, all adverse events are 
collected starting after informed consent has been signed. 
 
AEs that may result from the DMR System include those commonly associated 
with gastrointestinal endoscopy procedures, as well as device-related AEs: 
potential acute and chronic adverse consequences of the device-induced 
duodenal ablation treatment, or those resulting from device malfunction, device 
user error, selected materials, device design or device construction.  Some AEs 
may be associated with both the procedure and the device. In addition, device 
malfunctions may occur which may or may not result in a device-related AE. 
 
 
Potential AEs associated with the endoscopic procedure and sedation include 
the following: 
 
 Abdominal cramps, discomfort, or pain  
 Allergic or adverse reaction to sedation or anesthesia 
 Abdominal bloating 
 Cardiac or respiratory arrest 
 Death 
 Delayed gastric emptying  
 Dental injury 
 Difficulty swallowing 
 Digestive tract injury or perforation 
 Fever 
 Gastrointestinal bleeding 
 Headache 
 Hyperglycemia 
 Hypoglycemia 
 Hypotension 
 Hypoxia 
 Impaired judgment or reactions 
 Indigestion 
 Infection 
 Injury to esophagus 
 Laryngospasm 
 Mucosal injury to GI tract  
 Nausea  
 Pancreatitis 

 
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 Perforation 
 Pneumoperitoneum 
 Pulmonary aspiration 
 Sore or irritated throat  
 Vomiting 
 
Potential AEs associated with the device include the following: 
 Abcess formation  
 Abdominal cramps, discomfort, or pain 
 Allergic reaction to the device materials or methylene blue  
 Death 
 Delayed gastric emptying  
 Diarrhea 
 Digestive tract injury 
 Duodenal stenosis 
 Fever 
 Gastric dumping syndrome 
 Gastritis 
 Gastrointestinal bleeding 
 Hyperglycemia 
 Hypoglycemia 
 Infection 
 Mucosal injury to GI tract  
 Nausea  
 Nutritional malabsorption 
 Pancreatitis 
 Perforation 
 Stomach or duodenal obstruction  
 Stricture  
 Structural damage to the GI tract 
 Thermal damage to the duodenum wall or surrounding structures 
 Ulcer 
 Vomiting 
 
Device malfunctions that lead to device-related AEs include: 
 
 Console delivers incorrect ablation time and temperature profile resulting 
in GI tract injury or perforation 
 Hole in hot fluid catheter balloon resulting in leakage of hot fluid that 
results in GI tract injury or perforation  
 Lost catheter component in the GI tract or wall that results in GI tract injury 
or perforation 
 
Device malfunctions that may or may not result in device-related AEs include: 

 
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 Component degradation  
 Device breakage  
 Device disarticulation  
 
Any procedural or device-related adverse events are to be followed until there is 
evidence of resolution or permanent change. 
 
The determination of whether an adverse event is classified as a SAE or UADE 
is based on the definitions contained in sections 7.8.2 and 7.8.3, taking into 
account the clinical judgment of the investigator. 
 
 Serious Adverse Events (SAEs) 
A SAE is any untoward medical occurrence that:  
 Results in death,  
 Is immediately life-threatening,  
 Results in disability or permanent damage, 
 Requires intervention to prevent permanent impairment or damage, 
 Requires participant hospitalization or prolongation of existing 
hospitalization,  
 Is a congenital anomaly/birth defect, or 
 Is any other serious or important medical event 
 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
This definition includes device deficiencies that might have led to a SAE if a) 
suitable action had not been taken or b) intervention had not been made or c) if 
circumstances had been less fortunate. These are handled under the SAE 
reporting system. 
 
Planned hospitalization for a pre-existing condition, or a procedure required by 
the protocol, without serious deterioration in health, is not considered a SAE. 
 
 
A SAE may or may not be considered related to the device. 
 
 Unanticipated Adverse Device Effect (UADE) 
An UADE is defined as any serious adverse effect on health or safety or any life 
threatening problem or death caused by, or associated with, the device if that 
effect, problem or death was not previously identified in nature, severity or 
degree of incidence in the investigational plan; or any other unanticipated serious 
problem associated with the device that relates to the rights, safety or welfare of 
subjects.  
 

 
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  Adverse Events of Special Interest 
Adverse Events of Special Interest are characterized as: 
 Specific events that may be related to the mechanism of action of the 
DMR procedure (eg, hypoglycemia)  
 Potential adverse consequences of the procedure (eg, GI adverse events)  
 Rare events that may or may not be related to the DMR procedure/device, 
but are of interest to the Sponsor (eg, unexplained fever) 
 
Irrespective of whether an AE is serious or non-serious, the following events are 
defined as ‘protocol-specified adverse events of special interest’ and have 
additional reporting requirements. 
 
Events of Special Interest are: 
 Hypoglycemia 
 Diarrhea 
 Abdominal pain 
 Nausea 
 Vomiting 
 Gastrointestinal bleeding 
 Unexplained fever 
 
As stated in Section 6.11.2, hypoglycemia, unless the hypoglycemia episode 
meets the criteria of an SAE, will not be recorded as an adverse event, but will be 
captured on the Hypoglycemia Reporting eCRF page. However, the Investigator 
is not prohibited from characterizing hypoglycemia as an AE. Any event of 
hypoglycemia reported as an AE will be cross-checked to ensure that the event 
is also reported on the Hypoglycemia Reporting eCRF page.   
 
Prior to starting Liraglutide rescue therapy, a careful GI history should be 
obtained and the presence of nausea, vomiting or diarrhea be recorded prior to 
the initiation of liraglutide treatment. For episodes of diarrhea, time from the DMR 
(or Sham) procedure, as well as duration of episode, will be recorded. 
Characteristics of diarrhea (bloody, steatorrhea), and other clinical symptoms 
associated with diarrhea (eg, fever, abdominal pain) will also be recorded.  
 
All episodes of abdominal pain, or nausea, or vomiting will be reported as 
separate AEs.  If a subject experiences combined symptoms of pain, nausea and 
vomiting, each will be reported as a separate AE unless a clear medical 
diagnosis is determined, eg, viral gastroenteritis, and time from the DMR (or 
Sham) procedure, as well as duration of episode, will be recorded. The 
Investigator needs to assess the clinical state of the subject to ensure that 
potential obstruction or stenosis/stricture of the GI tract is not present. Three 
SAEs of duodenal stricture were reported early in the DMR clinical program, but 
there have been no occurrences after procedural and device  modifications were 
implemented. Nevertheless, if symptoms persist (e.g. two weeks for mild 
symptoms, three days for moderate symptoms and 48 hours for severe 

 
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symptoms) or progress, an endoscopic evaluation is recommended but left to the 
discretion of the investigator. 
 
For any episodes of gastrointestinal bleeding, time from the DMR (or Sham) 
procedure, as well as duration of episode, will be recorded. All episodes will be 
followed carefully to resolution. Additional laboratory tests or diagnostic tests 
should be done according to medical judgment depending on the clinical course. 
 
If a subject experiences a fever (> 38° C) that occurs within 2 weeks of the 
DMR/Sham procedure, and persists for several days, efforts should be made to 
identify a cause for the fever, if possible. All additional symptoms associated with 
the fever (eg, rigors, abdominal pain, diarrhea) should be recorded.  
 
 SAE & UADE Reporting 
AEs observed during the course of this trial, regardless of severity or relationship 
to the trial procedure or investigational medical device will be recorded on the 
appropriate Adverse Event Form and reported to the Sponsor. 
 
For US sites and reporting to FDA, the procedures for handling and 
reporting/notification of SAEs shall be carried out in accordance with the 
applicable sections of 21 CFR Part 812 and local IRB requirements. 
 
Investigator Safety Reporting Requirements  
SAEs will be recorded in the Adverse Event Form and the event is to be reported 
to the Sponsor within 24 hours of knowledge of the event. Information not 
available at the time of the initial report must be documented in the Adverse 
Event Form within 24 hours of receipt of the new information. Substantiating data 
such as relevant hospital or medical records and diagnostic test reports should 
also be submitted by scan/fax to the Sponsor.   
 
An Investigator shall submit to the Sponsor and to the reviewing IRB a report of 
any UADE occurring during an investigation as soon as possible, but in no event 
later than 10 working days after the investigator first learns of the effect.    
 
The Investigator must adhere to all reporting requirement for his IRB and national 
authorities. 
 
Sponsor Safety Reporting Requirements  
SAEs and UADEs will be reported to the FDA, in accordance with 21 CFR Part 
812. 
 
In the event of a UADE, Sponsor will immediately conduct an evaluation of a 
UADE, and report the results of such evaluation to FDA and to all reviewing 
IRB’s and participating investigators within 10 working days after the Sponsor 
first receives notice of the effect. Thereafter the Sponsor shall submit such 
additional reports concerning the effect as FDA requests. 

 
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All possibly and probably device and procedure related AEs (including 
SAEs/UADEs/AESIs) reported during 24 weeks follow up will be followed until 
resolution. This will also also include resolution of all AEs (signs and symptoms) 
reported upto 24 weeks for which there is not yet a definitive diagnosis and/or 
attribution of cause by the 24 weeks follow up visit. 
 
 
7.9 Data Monitoring Committee (DMC) 
A DMC will be convened for the study and assembled prior to subject enrollment. 
The group will be multidisciplinary and membership will include individuals not 
participating in the clinical study. The DMC members will act independently from 
both the Sponsor and the study investigators. The group will consist of an 
endoscopist, endocrinologist and a biostatistician. Full DMC details including 
structure, roles and responsibilities are included in the DMC Charter. 
 
General responsibilities of the DMC include: 
 Review and finalization of the DMC Charter 
 Review of data during the trial regarding safety and regarding quality of 
trial conduct, including participant risk versus benefit, and other factors 
potentially affecting patient safety 
 Monitoring of the quality of the treatment provided at individual sites by 
reviewing the occurrence of peri-procedural complications and major 
protocol violations 
 Providing recommendations to the Sponsor about modifications in the 
protocol and/or continuation of the trial necessary to maintain the safety of 
the subjects 
 
To maintain continuous blinding and study integrity, the safety analysis will be 
conducted by an independent statistician, and measures will be taken to ensure 
the validity of the data and integrity of the study’s conduct. As part of the DMC 
Charter, the DMC will agree upon a set of stopping rules for the study, consistent 
with principles outlined in Section 7.9.1. A fundamental responsibility of a DMC is 
to make recommendations to the Sponsor concerning the continuation of the 
study: whether to continue the study as designed; other recommendations that 
might be made include study termination, study continuation with major or minor 
modifications, or temporary suspension of enrollment and/or study intervention 
until some uncertainty is resolved. The DMC will document its recommendations, 
and the rationale for such recommendations, in a form that can be reviewed by 
the Sponsor and then circulated, if and as appropriate, to IRBs, FDA, and/or 
other interested parties. In almost all cases, a DMC is advisory to the Sponsor; 
the Sponsor decides whether to accept recommendations to discontinue a trial.  
 
 Stopping Rules 
 

 
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The DMC may recommend termination or suspension of the study if any of the 
following predefined conditions are met: 
 The DMC may terminate or suspend the study if an SAE resulting in death is 
possibly, probably, or definitely related to the investigational device and/or 
procedure 
 The DMC may recommend termination of the study if an SAE that is probably 
or definitely related to the investigational device or the investigational 
procedure occurs at a true rate as determined by the lower 95% confidence 
bound of SAEs resulting in serious injury, permanent impairment of a body 
function or permanent damage to a body structure that is greater than 1% 
 In addition, termination or suspension may be recommended for any other 
perceived safety concern based on clinical judgment, including but not limited 
to a higher than anticipated rate for device failures resulting in adverse 
events, or unexpected SAEs 
 Treatment of the subjects will be paused if 6 subjects require escalation of 
their baseline antidiabetic medications or addition of another antidiabetic 
medication at any time following DMR treatment or sham procedure, while the 
DMC evaluates the data to consider whether treatments should continue   
 
7.10 Clinical Events Committee (Adjudication Committee) 
A clinical events committee (CEC) will be established to review important safety 
adverse events reported by trial investigators to determine whether the 
adjudication of severity and relatedness meets protocol-specified criteria.  
 
The CEC will be composed of members covering necessary medical specialties 
(eg, gastroenterology, endocrinology) and device clinical trial experts. CEC 
members must disclose any potential conflicts of interest and must be 
independent of the Sponsor. 
 
Information reviewed on each death, SAE, UADE, or AE of Special Interest may 
include laboratory, pathology and/or imaging data, autopsy reports, physical 
descriptions, and any other data deemed relevant. The CEC will be masked to 
the assigned study arm when performing their assessments. The importance of 
the CEC is in assessing Investigator attribution of causality to the randomized 
treatment (DMR or Sham) in instances when severity or causality assessments 
may be deemed subjective and/or require the application of a complex definition.  
 
In their assessments, the CEC will be guided by the adverse events depicted in 
Section 7.8.1 as potential adverse events associated with sedation, endoscopy 
or the DMR  procedure, or device-related adverse events associated with the 
DMR catheter and console, including device-related adverse events from the 
materials selected, device design or construction.  While the CEC will use their 
judgment in adjudicating causality, general guidelines can be stated: 
 

 
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 If the adverse event is associated with sedation, it should be ascribed to 
the procedure 
 If the adverse event is one that has been described with endoscopic 
procedures, it should be ascribed to both the device and the procedure  
 If the adverse event is one that is rarely, if at all, associated with non-
invasive endoscopic procedures, it should be ascribed to the device 
 If the adverse event is one that has been identified in the protocol as a 
potential device-related adverse event, it should be ascribed to the device 
 
The relationship of an adverse event to the device and to the procedure is to be  
assessed by the Investigator utilizing the criteria outlined in Section 7.8.1, Study 
Procedure and Device Relationship. The CEC will review each causality 
assessment to ensure that the causality meets these protocol-specified criteria. 
 
Only events that have been adjudicated will be used in the DMC safety 
assessments to guide the DMC decision regarding study continuation. The CEC 
will work in accordance with written guidelines included in the CEC Charter 
describing in details the composition, tasks, responsibilities and work processes 
of the Committee. 
 
The CEC will not share responsibility with DMC for evaluating interim 
comparisons; however, their assessments (performed at frequent intervals 
throughout the trial with results incorporated into the database in a timely 
manner) will help to ensure that the data reviewed by DMC are as accurate and 
free of bias as possible. 
 
 
8 Data Management and Statistical Considerations 
 
8.1     Data Collection and Quality Control 
          8.1.1 Site Training 
The training of investigational site personnel on proper data collection, 
documentation practices, and eCRF completion is the responsibility of Fractyl. To 
ensure uniform data collection and protocol compliance, Fractyl-appointed 
clinical monitors will review the clinical protocol, techniques for the identification 
of eligible subjects, and instructions on in-hospital/office visit data collection with 
the study site research coordinators. This will be completed before or in 
conjunction with site initiation. 
 
           8.1.2 Electronic Case Report Forms (eCRFs) 
Subject data are recorded in a limited access secure electronic data capture 
(EDC) system. All changes made to the clinical data will be captured in an 
electronic audit trail and available for review by Fractyl or its representative. The 
associated software and database are designed to meet regulatory compliance 
for deployment as part of a validated system compliant with laws and regulations 

 
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applicable to the conduct of clinical studies pertaining to the use of electronic 
records and signatures.  
 
The Investigator will provide his/her electronic signature on the appropriate 
eCRFs in compliance with local regulations. A written signature on printed 
eCRFs will also be provided if required by local regulation. Changes to data 
previously submitted to the Sponsor require a new electronic signature by the 
Investigator acknowledging and approving the changes. 
 
eCRFs must be completed fully for each subject by the site staff, e-signed by the 
Investigator, and available for review by regulatory authorities, Fractyl and/or its 
designees. 
 
           8.1.3 Data Reporting 
The investigator, or an individual designated by him/her, is responsible for 
recording all study data on the eCRFs supplied by Fractyl. The required study 
data will also be documented in the subject’s medical record.  
 
All patient related medical data in the study will be handled confidentially and as 
per applicable data protection laws and local regulations and will not be released 
without the written consent of the subject (or the subject’s guardian). The data 
will be handled and stored in an anonymous format. 
 
          8.1.4 Data Monitoring  
Completed eCRFs will be verified by a Fractyl appointed monitor at the site at 
regular intervals throughout the study. To this end, the investigator must permit 
inspection of the study files, subject eCRFs, and subject medical records by 
Fractyl-appointed monitors and authorized government agencies, as indicated.    
 
The study will be monitored according to applicable provisions of Fractyl or 
designee’s Monitoring Procedures, and in conformance with Good Clinical 
Practices. Study monitors must be qualified by training and experience. 
 
Monitoring will include pre-study site qualification, site initiation visit, on-going site 
study monitoring and study closure monitoring as described in the study 
monitoring plan. The major function of the clinical monitor is to observe and 
assess the quality of the clinical study. In addition, the study will be monitored to 
ensure that potential adverse trends are quickly identified allowing immediate 
corrective action. The monitor’s duties will include: on-site visits, observation of 
treatment with the study devices and review of study documents and results.   
 
The study monitor will review/verify IRB approvals, Informed Consent 
documents, source documents and eCRFs. Visual and/or electronic data review 
will be performed by the study monitor to identify possible data discrepancies.  
The study monitor(s) will verify the data entered into the eCRFs against hospital 
records, medical history, or other source documents to ensure accuracy and 

 
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completeness of the data. Manually generated and/or automatic queries will be 
created in the EDC system and issued to the site for appropriate response. Site 
staff will be responsible for resolving all queries in the database. 
 
8.2 Statistical Considerations 
Prior to locking the database, all data editing will be completed and decisions 
regarding the evaluability of all subject data for inclusion in the statistical analysis 
will be made. The rationale for excluding any data from the statistical analyses will 
be prospectively defined, and classification of all or part of a subjects’ data as 
non-evaluable will be completed and documented before the entire database is 
locked.   
 
Additional details on the analysis as well as any changes from the analysis plans 
presented in the protocol are provided in the Statistical Analysis Plan (SAP).   
 
           8.2.1 General Considerations 
While this protocol does specify primary and safety endpoints, these are not 
meant to define subject and study success. Instead, the results of this evaluation 
will be used to establish the safety and efficacy profile of the DMR procedure and 
to evaluate the effect size for powering future clinical investigations.  
 
Nominal and ordinal variables for each time period will be presented using 
frequencies and percent of patients in each category. Interval and ratio 
continuous variables for each time period will be presented using means and 
standard deviations, median, quartiles, and minimum and maximum. For 
variables collected at multiple follow-up time periods, tables which include 
change from baseline (where baseline is defined as last measurement prior to 
attempted treatment with DMR) will be presented at each follow-up visit. 
 
Distributions of each continuous variable will be assessed prior to analysis and 
examined for normality. Data with interval or ratio scales to be analyzed that are 
not normally distributed will be analyzed using non-parametric statistics. 
Statistical tests will be performed using two-sided significance levels of 5% 
unless otherwise specified. 
 
The primary analysis phase is the first 24 weeks of the randomized treatment 
phase. Descriptive statistics on variables collected during the Medication Run-In 
phase will also be presented for completeness. 
 
           8.2.2 Determination of Sample Size 
Up to 6 study sites will randomize a maximum of 9 subjects in a 2:1 
randomization scheme (DMR:Sham). Sample size determination is based on the 
nature of this pilot study and not statistical considerations. The study is not 
powered to show statisticial significance. 
 
           8.2.3 Analysis Populations  

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 85 of 96 
Study Population: The study population includes all subjects consented at the 
site. Within this population there are Screened, Medication Run In, Intent-to-
Treat, As-Treated and Safety populations. 
 
Intent-to-Treat (ITT): The ITT population includes all subjects who were 
randomized after the Medication Run-In phase. This is the secondary analysis 
population for efficacy (no imputation will be made for missing data, given the 
nature of the study; i.e., analysis on this population will be performed using only 
available data). Subjects will be analyzed under the treatment to which they were 
randomized. 
 
As-Treated (AT): The subset of ITT subjects who received at least one ablation 
or undergo the randomized sham procedure. This is the primary population for 
efficacy.  No imputation will be made for missing data. Subjects will be analyzed 
under the treatment received. 
 
 
Week 24 Per Protocol Population: The PP population includes all subjects in 
the AT population who did not have any major protocol deviations that could 
affect the assessment of efficacy and had their Week 24 study visit within the 
protocol-specified window. Subjects will be analyzed under the treatment 
received.  
 
 
Safety: This population includes all subjects in whom sham or DMR was 
attempted. Subjects will be analyzed according to the treatment received. 
 
           8.2.4Demographic and Baseline Characteristics  
Demographic and baseline data will be summarized using summary statistics of 
sample size, mean, standard deviation, median, quartiles, min and max for 
continuous variables and proportions and frequency of patients for categorical 
values. Demographics will be presented for the following analysis populations: 
3. The Medication Run-In 
4. ITT overall and by-randomized treatment group 
5. AT overall and by-actual treatment group  
 
           8.2.5 Safety Analysis 
All safety data will be displayed and analysed using descriptive statistical 
methods. No formal inferential analysis is planned for safety comparisons. The 
primary safety endpoint is proportion of subjects experiencing device or 
procedure related SAEs or UADEs through 24 Weeks following start of DMR or 
sham treatment. These will be presented overall and by system organ class and 
preferred term (PT). This will be conducted on the Safety analysis set overall and 
by actual treatment group. Subjects who experience more than one event in a 
given System Organ Class (SOC) and PT will be counted once within that SOC 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 86 of 96 
and PT. The total number of events and the number and percentage of subjects 
with each event will be reported.  
 
The remaining safety analyses discussed below will be carried out for the 
following sets within the Safety analysis population: 
 
1. Safety population through 24 weeks post-randomization, by treatment 
group received at start of study (DMR or sham, depending on the 
treatment the patient actually received) and overall. 
2. Safety population through 24 weeks post-DMR combined populations; 
this will include the first 24 weeks of the study for patients receiving 
DMR from the start of the study, and weeks 24-48 post crossover for 
patients switching from sham-to-DMR. Results will be presented 
separately for patients originally receiving DMR, for patients originally 
receiving Sham and receiving DMR at week 24, and for all patients 
combined receiving DMR at start of the study or at Week 24. 
 
Clinical Laboratory Tests and Vital Signs: Descriptive statistics (sample size, 
mean, standard deviation, median, quartiles, minimum and maximum) of 
observed measurement at each visit and of the change from baseline (baseline is 
defined as the last measurement prior to DMR procedure) to each visit will be 
presented for each vital sign and laboratory variable. Listings of abnormal and/or 
clinically significant findings/values will be presented for each laboratory and vital 
sign variable. 
 
Duodenal biopsy sample assessment of histological evidence of mucosal 
regrowth, inflammation and fibrosis will be summarized descriptively. Occurrence 
of  severe fibrosis or inflammation from ablated area duodenal biopsy will be 
compared to non-ablated control sample. 
 
Adverse Events: AEs, SAEs and UADEs will be coded using MedDRA.  
Treatment Emergent AEs, SAEs and UADEs are defined as events starting or 
worsening after start of DMR (or sham, if applicable). The number and percent of 
patients with Treatment Emergent AEs, SAEs and UADEs will be summarized 
overall and by primary SOC and preferred term (PT). Subjects who experience 
more than one event in a given SOC and PT will be counted once within that 
SOC and PT. Detailed listings of subjects that experience AEs and SAEs will be 
provided.  
 
The number and percent of subjects with treatment emergent AEs, UADEs and 
SAEs will be further presented by severity and by relationship to the device or 
procedure. In tabulating the severity of AEs on a per subject basis, the greatest 
severity will be assigned to a subject should there be more than one occurrence 
of the same AE with different reported severities. Relationship will be categorized 
as unrelated, possibly, probably and definitely related. The highest level of 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 87 of 96 
association will be  reported for subjects with different relationships for the same 
AE. 
 
The Hypoglycemia Reporting eCRF page will collect time of event, blood glucose 
value, symptoms if present, treatment, and duration. The incidence and event 
rates of hypoglycemia will be assessed based on the severity of the 
hypoglycemia: severe hypoglycemic event, defined as hypoglycemia requiring 
third-party assistance; or any clinically significant hypoglycemic event, defined as 
self-monitored or laboratory plasma glucose level < 54 mg/dL (3.0 mmol/L); or  
glucose alert values ≤70 mg/dL (3.9 mmol/L). 
 
Episodes of diarrhea will be recorded both as events, and as incidence.   
 
           8.2.6 Effectiveness Analysis 
 
Primary Efficacy Endpoint:   
The primary efficacy endpoint is change in A1c at 24 Weeks. The analyses will 
be carried out on the AT analysis population (primary) ,the ITT analysis 
population, and the Week 24 PP (per-protocol) population. Descriptive statistics 
(mean, standard deviation, median, quartiles, minimum and maximum, and two-
sided 95% confidence interval of the mean) of change in A1c will be presented 
by randomized treatment group (DMR vs. sham) for the ITT population and by 
actual treatment group for the AT and PP populations. Significance testing and 
statistical modeling will be omitted due to the small sample size.   
 
Secondary Efficacy Endpoints:  
(i) 
A1c change from baseline to Week 24 by visit over time, DMR vs. Sham 
(ii) Fasting plasma glucose (FPG) change from baseline to Week 24, DMR vs. 
Sham 
(iii) FPG change from baseline to Week 24 by visit over time, DMR vs. Sham 
(iv) Urine Albumin Creatinine Ratio (UACR) change from baseline to Week 24, 
DMR vs. Sham 
(v) Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) 
change from baseline to Week 24, DMR vs. Sham  
 
The above secondary endpoints will be analyzed on the same analysis 
populations and the same manner as the primary efficacy endpoint.  
 
 
Additional Endpoints of Interest: 
The following are the additional endpoints of interest. They will be analyzed for 
(a) the ITT, AT, and PP subjects randomized to receiving DMR; (b) for the ITT, 
AT, and PP subjects switching from Sham to DMR at Week 24; and for (c) ITT, 
AT, amd PP subjects in (a) and (b) combined. Baseline is defined as the last 
measurement taken prior to the DMR procedure. 
 
(i) 
A1c change from Week 24 (pre-DMR) in Sham cross-over group to Week 48   

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 88 of 96 
(ii) FPG change from Week 24 (pre-DMR) in Sham cross-over group to Week 
48   
(iii) Short Form (36) Health Survey Version 2 (SF-36) change from baseline at 
Week 24 (pre- assessments and endoscopy) vs Sham 
(iv) Patient-Reported Outcomes Measurement Information System (PROMIS®) 
change from baseline at Week 24 (pre- assessments and endoscopy) vs 
Sham 
 
For each endpoint, descriptive statistics (mean, standard deviation, median, 
quartiles, minimum and maximum, and two-sided 95% confidence interval of the 
mean) will be presented.  
 
         8.2.7 Handling of Missing Data 
Missing data within this subject cohort is expected to occur at a low rate. All 
efforts will be made to prevent the occurrence of missing data. Site training and 
regular monitoring will help to minimize missing data. Due to the sample size and 
nature of this pilot study, there will be no imputation of missing data. In other 
words, analyses will be based only on available data. 
 
In the clinical study report, the number and proportion of ITT subjects who were 
in compliance through Week 24 at each follow-up visit will be presented. The 
number and percent of ITT subjects who prematurely withdraw from the study will 
be tabulated overall and by reason for withdrawal. This will be performed by 
randomized treatment group and overall. 
   
           8.2.8 Analyses on Medication Run In Phase 
The number and percent of patients with adverse events occurring during the 
Run-In phase will be presented overall and by SOC and PT. Descriptive statistics 
of end-of-run-in-phase A1c for all Medication Run-In subjects will be presented. 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 89 of 96 
9       References 
 
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International Diabetes Atlas (6th ed., pp30) 
2. CDC diabetes fact sheet 
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3. Fonseca V. Defining and characterizing the progression of Type 2 diabetes. 
Diabetes Care 2009; 32(S2):151-6. 
4. Kashyap SR, Defronzo R. The insulin resistance syndrome: physiological 
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5. Kasuga M. Insulin resistance and pancreatic beta cell failure. J Clin Invest 
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6. Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just 
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7. Jacobs PG, Konrad-Martin D, Mcmillan GP, McDermott D, Fausti SA. 
Influence of acute hyperglycemia on otoacoustic emissions and the medial 
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8. Diabetes Prevention Program Research Group. Reduction in the incidence of 
type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 
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9. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes 
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Study. Lancet 2009 Nov;374:1677-86. 
10. Look AHEAD Research Group. Reduction in weight and cardiovascular 
disease risk factors in individuals with type 2 diabetes: one-year results of the 
Look AHEAD trial. Diab Care 2007;30(6):1374-83. 
11. Look AHEAD Research Group, Wing RR. Long-Term Effects of a lifestyle 
intervention on weight and cardiovascular risk factors in individuals with type 
2 diabetes mellitus: four year results of the Look AHEAD Trial. Arch Intern 
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12. American Diabetes Association.  Standards of medical care in diabetes – 
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13. Bae JP, Lage MJ, Mo D, Nelson DR, Hoogwerf BJ.  Obesity and glycemic 
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14. Ali MK, Bullard KM, Saaddine JB, Cowie CC, Imperatore G, Gregg EW. 
Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J 
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15. Heller SR, Choudhary P, Davies C, et al.; UK Hypoglycaemia Study Group. 
Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment 
modalities and their duration. Diabetologia 2007;50:1140–1147 

 
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16. Donnelly LA, Morris AD, FrierBM, et al.; DARTS/MEMOCollaboration. 
Frequency and predictors of hypoglycaemia in Type 1 and insulin-treated 
Type 2 diabetes: a population-based study. Diabet Med 2005;22:749–755. 
17. Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes 2008;57:3169–
3176. 
18. Cryer PE. Death during intensive glyce- mic therapy of diabetes: mechanisms 
and implications. Am J Med 2011;124:993–996. 
19. Schwartz SS, Jellinger PS, Herman ME. Obviating Much of the Need for 
Insulin Therapy in Type 2 Diabetes Mellitus: A Re-Assessment of Insulin 
Therapy’s Safety Profile, Postgraduate Medicine 2016. 
20. Tang et al. Effects of Insulin Glargine and Liraglutide Therapy on Liver Fat as 
Measured by Magnetic Resonance in Patients With Type 2 Diabetes: A 
Randomized Trial. Diabetes Care 2015 Jul; 38(7):1339-46. 
21. Juurinen L et al. Effects of insulin therapy on liver fat content and hepatic 
insulin sensitivity in patients with type 2 diabetes. Am J Physiol Endocrinol 
Metab 2007;292:E829 –35. 
22. Kawamori R, Kadowaki T, Onji M, Seino Y, Akanuma Y. Hepatic safety profile 
and glycemic control of pioglitazone in more than 20,000 patients with type 2 
diabetes mellitus: Postmarketing surveillance study in Japan. Diabetes Res 
Clin Pract 2007;76(2):229–35. 
23. Liao et al. Pioglitazone and cardiovascular outcomes in patients with insulin 
resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-
analysis. BMJ Open 2017;7(1):e013927. 
24. Kernan et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack, 
N Engl J Med 2016 Apr 7. 
25. Cusi et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic 
Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus. Ann Intern Med. 
2016 Sep 6;165(5):305-15. 
26. Aroda et al. Metabolic and hormonal changes induced by pioglitazone in 
polycystic ovary syndrome: a randomized, placebo-controlled clinical trial. J 
Clin Endocrinol Metab 2009;94:469–76. 
27. Cummings DE. Metabolic surgery for type 2 diabetes. Nat Med 
2012;18(5):656-8. 
28. Cummings DE, Bloom SR, Rubino F. At the heart of the benefits of bariatric 
surgery. Nat Med 2012;18(3):358-9. 
29. Kashyap SR, Bhatt DL, Wolski K et al. Metabolic effects of bariatric surgery in 
patients with moderate obesity and type 2 diabetes: analysis of a randomized 
control trial comparing surgery with intensive medical treatment. Diabetes 
Care 2013;36(8):2175-82. 
30. Mingrone G et al.  Bariatric–metabolic surgery versus conventional medical 
treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-
label, single-centre, randomised controlled trial. The Lancet;386(9997):964-
973.  
31. O’Connor PJ. Improving medication adherence: Challenges for physicians, 
payers, and policy makers. Arch Intern Med 2006;166(17):1802-4. 

 
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32. Nathan DM. Clinical practice: initial management of glycemia in type 2 
diabetes mellitus. N Engl J Med 2002;347:1342-9. 
33. Schauer, P. R. et al. Bariatric surgery versus intensive medical therapy for 
diabetes — 5-year outcomes. N. Engl. J. Med. 376, 641–651 (2017). 
34. Rubino and Panagiotopoulos  “Metabolic surgery: the cutting edge of diabetes 
care” Nat Rev Gastroenterol Hepatol. 2017 Apr 21. 
35. Cook MN, Girman CJ, Stein PP, Alexander CM, Holman RR. Glycemic 
control continues to deteriorate after sulfonylureas are added to metformin 
among patients with type 2 diabetes.  Diabetes Care 2005;28(5):995-1000. 
36. O’Connor PJ. Improving medication adherence: Challenges for physicians, 
payers, and policy makers. Arch Intern Med 2006;166(17):1802-4. 
37. Phillips LS, Branch WT, Cook CB et al. Clinical inertia. Ann Intern Med 
2001;135(9):825-34. 
38. Nicolucci A, Kovacs Burns K, Holt RI et al. Diabetes Attitudes, Wishes and 
Needs second study (DAWN2™): Cross-national benchmarking of diabetes-
related psychosocial outcomes for people with diabetes. Diabetic Medicine 
2013;30(7):767-77. 
39. Dunkin BJ, Martinez J, Bejaro PA, et al. Thin-layer ablation of human 
esophageal epithelium using a bipolar radiofrequency balloon device. Surg 
Endosc 2006;20:125-30. 
40. Odze RD, Lauwers GY. Histopathology of Barrett's esophagus after ablation 
and endoscopic mucosal resection therapy. Endoscopy 2008 
Dec;40(12):1008-15.  
41. Alster et. al. “Comparison of four carbon dioxide resurfacing lasers. A clinical 
and histopathologic evaluation” Dermatol Surg. 1999 Mar;25(3):153-8. 
42. Rajagopalan H, Cherrington AD, Thompson CC et al. Endoscopic Duodenal 
Mucosal Resurfacing for the Treatment of Type 2 Diabetes: 6-Month Interim 
Analysis From the First-in-Human Proof-of-Concept Study. Diabetes Care 
2016;39(12):2254-2261. 
43. American Diabetes Association Standards of Medical Care in Diabetes – 
2018. Diabetes Care 2018; 41 Supplement 1: S1-S172. 
44. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus 
Report by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD). Diabetes Care 2018 
Dec; 41(12): 2669-2701 
 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 92 of 96 
Appendix 1: Schedule of Assessments – DMR Cases 
 
Visit 
# 
Visit 
Visit Window / 
Intervention 
Informed 
Consent 
History & 
Full PE 
Body Weight & 
Targeted PE 
Pregnancy Test 
(if applicable) 
Blood Analysis 
H.pylori Test 
ECG 
Renal Function 
MRE 
Endoscopic 
Evaluation 
Subject  
Randomization & 
Enrollment 
DMR Procedure 
Biopsy 
Blinding 
Assessment 
Lifestyle 
Counseling 
SF‐36 
Questionnaire 
PROMIS® Patient 
Reported Outcome 
Self‐Monitoring 
Blood Glucose/ 
Glycemia Diary 
Adverse Events 
Medication Use@ 
1 
Screening 
(Pre Run‐In) 
  
X 
X& 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
* 
X 
X 
2 
Baseline 
(Post Run‐In) 
Visit to 
occur 4‐6 
weeks after 
Screening 
 
 
X& 
X 
X 
 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X@ 
3 
Procedure  
(DMR) 
Max is 21 
days from 
Baseline 
Visit 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
¥ 
 
 
 
X 
X@ 
4 
Day 7 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X@ 
5 
Day 14 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X@ 
6 
Week 4 
(28 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
7 
Week 8 Call 
(56 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
8 
Week 12 
(84 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
9 
Week 15 Call 
(105 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
10 
Week 18 
(126 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
11 
Week 21 Call 
(147 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
12 
Week 24 
(168 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
X 
X 
 
X# 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
& for the purpose of eligibility, Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or >100 mmHg (diastolic), for other Blood Pressure 
assessments it will be measured in a sitting position in duplicate (in same arm) after 15 min of rest  
*Provide diary & glucose meter to the subject 
 
@Patients using SU will be asked to adjust their SU intake based on section 5.3.1 
 
#A follow up endoscopic evaluation to visually examine the treatment site and adjacent tissues will be conducted after unblinding and within 7 days of visit 12 / week 
24 
 
¥The 14-day post procedure diet reviewed with the subject  

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 93 of 96 
 
**Lifestyle Counseling discussions during phone calls at Day 7 & 14are conducted by the study coordinator in the form of reminders for the subjects and do not need 
to be conducted by a member of the nutrition staff 
 
 
Note: Subjects randomized to DMR who do not receive any ablations during the DMR procedure will be followed for safety through the Week 4 visit and then 
discontinued from the study. 
 
 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 94 of 96 
Appendix 2: Schedule of Assessments – Sham Cases 
Visit 
# 
Visit 
Visit Window / 
Intervention 
Informed 
Consent 
History & 
Full PE 
Body Weight & 
Targeted PE 
Pregnancy Test 
(if applicable) 
Blood Analysis 
H.pylori Test 
ECG 
Renal Function 
MRE 
Endoscopic 
Evaluation 
Subject  
Randomization & 
Enrollment 
Sham / Crossover 
DMR Procedure 
Biopsy 
Blinding 
Assessment 
Lifestyle 
Counseling 
SF‐36 Quality of 
Life Questionnaire 
PROMIS® Patient 
Reported Outcome 
Self‐Monitoring 
Blood Glucose/ 
Glycemia Diary 
Adverse Events 
Medication Use@ 
1 
Screening 
(Pre Run‐In) 
  
X 
X& 
 
 
X 
X 
X 
 
 
 
 
 
 
 
X 
 
 
* 
X 
X 
2 
Baseline 
(Post Run‐In) 
Visit to 
occur 4‐6 
weeks after 
Screening 
 
 
X& 
X 
X 
 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X@ 
3 
Procedure  
(DMR) 
Max is 21 
days from 
Baseline 
Visit 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
¥ 
 
 
 
X 
X@ 
4 
Day 7 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X@ 
5 
14 Day Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X@ 
6 
Week 4 
(28 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
7 
 Week 8 Call 
(56 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
8 
Week 12 
(84 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
9 
Week 15 Call 
(105 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
10 
Week 18 
(126 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
11 
Week 21 Call 
(147 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
12 
Week 24 
(168 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
3C 
Crossover to 
DMR 
Within 21 
days from 
Week 24 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
¥ 
 
 
 
X 
X 
4C 
Crossover 
Day 7 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X 
5C 
Crossover 
Day 14 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
** 
 
 
X 
X 
X 
6C 
Crossover 
Week 4 
(28 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
7C 
Crossover 
Week 8 Call 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 95 of 96 
Visit 
# 
Visit 
Visit Window / 
Intervention 
Informed 
Consent 
History & 
Full PE 
Body Weight & 
Targeted PE 
Pregnancy Test 
(if applicable) 
Blood Analysis 
H.pylori Test 
ECG 
Renal Function 
MRE 
Endoscopic 
Evaluation 
Subject  
Randomization & 
Enrollment 
Sham / Crossover 
DMR Procedure 
Biopsy 
Blinding 
Assessment 
Lifestyle 
Counseling 
SF‐36 Quality of 
Life Questionnaire 
PROMIS® Patient 
Reported Outcome 
Self‐Monitoring 
Blood Glucose/ 
Glycemia Diary 
Adverse Events 
Medication Use@ 
(56 Day) 
8C 
Crossover 
Week 12 
(84 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
9C 
Crossover 
Week 15 Call 
(105 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
10C 
Crossover 
Week 18 
(126 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
11C 
Crossover  
Week 21 Call 
(147 Day) 
+/‐ 2 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 
X 
12C 
Crossover 
Week 24 
(168 Day) 
+/‐ 7 days 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
& for the purpose of eligibility, Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or >100 mmHg (diastolic), for other Blood Pressure 
assessments it will be measured in a sitting position in duplicate (in same arm) after 15 min of rest  
*Provide diary & glucose meter to the subject 
 
@Patients using SU will be asked to adjust their SU intake based on section 5.3.1 
 
¥The 14-day post procedure diet reviewed with the subject  
 
**Lifestyle Intervention discussionsduring phone calls at Day 7 & 14 are conducted by the study coordinator in the form of reminders for the subjects and do not need 
to be conducted by a member of the nutrition staff 
 
 
Note: Subjects randomized to Sham who crossover to DMR but do not receive any ablations during the DMR procedure will be followed through the 4 week post 
crossover visit and then discontinued from the study. 
 
Note: Subjects that choose not to crossover from sham to DMR will be discontinued from the study and the End of Study CRFs will be completed.   

 
Protocol # C-40000 Version 3.0 
Revision Date: 9 July, 2020 
 
Page 96 of 96 
Appendix 3: Maximum Approved Daily Dose of Non-Insulin Glucose 
Lowering Agents 
ADA Standards of Medical Care in Diabetes 201843