Safety & Effectiveness of Duodenal Mucosal Resurfacing (DMR) Using the Revita™ System in Treatment of Type 2 Diabetes

The study is a randomized, double-blind sham-controlled prospective multi-center clinical
investigation of subjects with T2D sub-optimally controlled on two oral anti-diabetic
medications, one of which must be metformin, comparing the Fractyl DMR procedure using the
Revita™ System to a sham procedure. All subjects will participate in a 4 week oral
anti-diabetic medication run-in period before the procedure to confirm inadequate blood
glucose control in conjunction with medication compliance and nutritional counseling.
Subjects who meet all criteria after screening are randomized 2:1 (DMR to sham), with double
blinding (subject and endocrinologist/Sponsor). The endoscopist is not blinded.

Inclusion Criteria:

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.

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

Exclusion Criteria:

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

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

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

Additional exclusion criteria to be confirmed during the screening process:

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

6. Active and uncontrolled GERD defined as grade III esophagitis or greater

7. Abnormalities of the GI tract preventing endoscopic access to the duodenum

8. Anatomic abnormalities in the duodenum that would preclude the completion of the DMR
procedure, including tortuous anatomy

9. Malignancy newly diagnosed by endoscopy

10. Upper gastrointestinal conditions such as ulcers, polyps, varices, strictures,
congenital or acquired intestinal telangiectasia