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

The Revita™ System is being investigated to assess the ability to improve glycemic control in conjunction with diet and exercise in patients with Type 2 diabetes who are inadequately controlled with oral anti-diabetic medications. The purpose of this study is to demonstrate the safety and effectiveness of the Fractyl DMR Procedure using the Revita™ System compared to a sham procedure. At 24 weeks, subjects randomized to the DMR procedure be continued to be followed per protocol till 48 Weeks and the Sham treatment arm will be offered to cross over to receive the DMR treatment and will be followed per protocol for 24 weeks post treatment.

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.

Eligibility Criteria:
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