Evaluation of the Efficacy and Safety of Duodenal Mucosal Resurfacing Using the Revita® System in Subjects With Type 2 Diabetes on Insulin Therapy

The Revita® system is being investigated to assess the efficacy of DMR versus Sham on improvement in Glycemic, Hepatic and Cardiovascular endpoints for patients with Type 2 Diabetes who are inadequately controlled with insulin therapy. The purpose of this study is to demonstrate the efficacy and safety of the Fractyl DMR Procedure using the Revita® System compared to a sham. Subjects randomized to the DMR procedure will be followed per protocol till 48 weeks post treatment. Subjects in the Sham treatment arm will be offered cross over to receive the DMR treatment at 48 weeks and will be followed per protocol for 24 weeks post treatment.

Inclusion Criteria:

1. Male; and Non-pregnant, Non-lactating Females

2. Age between 21 and 70 years (both inclusive)

3. Subjects with type 2 diabetes on stable doses of metformin (maximum tolerated dose) requiring a minimum of 20 units up to a maximum of 60 units of basal insulin; OR Subjects currently on basal insulin (20-60 units/day) who meet other inclusion criteria but are on other ADAs (including GLP-1a, DPP4, etc) are eligible following an 8-week washout period and initiating on Metformin if not already on it.

4. Glycosylated Hemoglobin A1c (HbA1c) of 7.5-9.5% (both inclusive) confirmed at the end of at least 3-week stable run in period.

5. FPG ≥180 to <270 mg/dl (measured after overnight 8 hr fasting and at least 36 hours after the last evening dose of glargine or at least 12 hours after the last dose of NPH insulin)

6. Body Mass Index (BMI) ≥ 28 and ≤ 40 kg/m2

7. Women of Child-bearing potential (WOCBP) should have negative urine beta hCG pregnancy test and must agree to use two of the established contraceptive methods throughout the study duration

8. Able to sign an informed consent form and comply with study requirements.

Exclusion Criteria:

1. HbA1c <7.5 or >9.5% and/or <180mg or FPG ≥ 270 mg/dl, confirmed by laboratory measurement, after overnight 8hr fasting (off insulin) after at least 3 weeks stable run-in period.

2. Known case of absolute insulin deficiency as indicated by clinical assessment, and a fasting plasma C-peptide of <0.6 ng/ml

3. Any drugs or concomitant medications (such as psychoactive drugs such as carbamazepine, phenobarbital, sympathomimetics, corticosteroids and sex hormones, etc.) that can interfere with glucose metabolism

4. Subjects who have a known or documented SGLT2i and/or Metformin intolerance prior to the study

5. Recurrent or severe urinary tract or genital mycotic infections or history of genitourinary infection within 4 weeks prior to informed consent

6. ALT >3 times upper limit normal values unless the findings are consistent with Gilberts disease or if associated with underlying NAFLD.

7. Use of an investigational drug within 1 month or 5 half-lives (whichever is longer) before the screening

8. Diagnosed with Type 1 Diabetes or with a recent history of ketoacidosis

9. Ketosis-prone Type 2 Diabetes

10. History of non healing diabetic ulcers or amputations

11. History of more than 1 severe hypoglycemia episode or unawareness within past 6 months of screening

12. Known intestinal autoimmune disease, as evidenced by either a positive Anti-GAD test, including Celiac disease, or pre-existing symptoms of lupus erythematosus, scleroderma or other autoimmune connective tissue disorder, which affects the small intestine

13. Secondary hypothyroidism or inadequately controlled primary hypothyroidism (TSH value outside the normal range at screening)

14. Known history of thyroid cancer or hyperthyroidism who have undergone treatment within past 12 months or inadequately controlled hyperthyroidism

15. An uncontrolled endocrine condition such as multiple endocrine neoplasia etc (except type 2 diabetes)

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, active and uncontrolled GERD (grade 3 esophagitis or greater)

17. Known history of a structural or functional disorder of the stomach, including gastric ulcer, chronic gastritis, gastric varices, (a large hiatal hernia or type II and higher paraoesophageal hernia) cancer or any other disorder of the stomach

18. Previous GI surgery that could affect the ability to treat the duodenum such as subjects who have had a Billroth 2, Roux-en-Y gastric bypass, gastric sleeve or other similar procedures or conditions

19. Known history of chronic pancreatitis or a recent history of acute pancreatitis within the past year

20. Presence of acute or chronic Hepatitis B or C (except if Hep C is cured) of Cirrhosis; or hepatic decompensation/acute liver disease during the last 6 months; or alcoholic or autoimmune chronic hepatitis.

21. Symptomatic gallstones or symptomatic kidney stones, acute cholecystitis

22. Clinically active systemic infection

23. 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) , who are on potential immunosuppressants or whose immune status makes the subject a poor candidate for clinical trial participation in the opinion of the Investigator

24. History of malignancy within the past 5 years

25. Known active coagulopathy, or current upper gastro-intestinal bleeding conditions such as ulcers, gastric varices, strictures, or congenital or acquired intestinal telangiectasia

26. Subjects with active helicobacter pylori infection (Subjects may be enrolled if they had history of h pylori infection and were successfully treated)

27. Known cases of anemia, thalassemia or conditions that affect RBC turnover such as recent blood transfusion within 90 days

28. Use of anticoagulation therapy (such as warfarin, coumadin, NOAC) or anti platelet agents (such as thienopyridine) which cannot be discontinued for 5-7 days or 2 drug half-lives before and the procedure

29. 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.

30. Use of drugs known to affect GI motility (e.g. Metoclopramide)

31. History of moderate to severe chronic kidney disease (CKD), with estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2 (estimated by Modification of Diet in Renal Disease [MDRD]) or end stage renal failure or on dialysis

32. History of Myocardial Infarction, Stroke, or major event requiring hospitalization within the last 3 months prior to screening

33. History of new or worsening signs or symptoms of CHD within the last 3 months

34. Known case of severe peripheral vascular disease

35. Known case of heart failure requiring pharmacologic therapy

36. Clinically significant ECG findings such as new clinically significant arrythmia or conduction disturbances that increases risk and requires intervention as determined by the investigator

37. Fasting triglyceride value of >600 mg/dL (increases risk of pancreatitis)

38. Participating in a weight loss program and is currently not in the maintenance phase

39. General contraindications to deep or conscious sedation or general anesthesia or high risk as determined by anesthesiologist (e.g. ASA score 4 or higher) or contraindications to upper GI Endoscopy

40. History of any illicit alcohol or substance abuse

41. Use of weight loss medication such as Meridia, Xenical, or over the counterweight loss medications or other prescribed medications used specifically for purpose of weight loss.

42. Use of Dietary supplements or herbal preparations that may have unknown effects on glycemic control, risk of bleeding

43. Participating in another ongoing clinical trial of an investigational drug or device

44. History of non-adherence to treatment in the previous 6 months, as determined by the investigator based on patient history, HbA1C value and/or drug accountability.

45. Any other mental or physical condition which, in the opinion of the investigator, makes the subject a poor candidate for clinical trial participation

46. 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.

47. Recovered from severe COVID 19 infection within 6 months or those who have persistent long COVID-19 symptoms (i.e. they have not recovered for several weeks or months since start of symptoms that were suggestive of COVID-19 irrespective if they are tested or not.

Conditions:
• Diabetes Mellitus
• Diabetes Mellitus, Type 2