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

Inclusion Criteria:

1. Male, and non-pregnant, non-lactating females
2. Age between 21 and 70 years (both inclusive)

Subjects with type 2 diabetes on stable doses of 20-100 units (both inclusive) of total daily insulin dose of basal insulin or basal insulin combined with short-acting insulin and up to 3 permitted non-insulin antidiabetic agents (ADAs). Permitted non-insulin ADAs include:

1. Metformin,
2. Glucagon-like peptide-1 receptor agonist (GLP-1 RA) including dual peptide agonists and related molecules (e.g., glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RA),
3. Dipeptidyl peptidase 4 inhibitor (DPP-4i),
4. Thiazolidinediones (TZD),
5. Sodium-glucose cotransporter 2 inhibitors (SGLT2i),
6. Sulfonylureas (SU),
7. Meglitinides
8. Glycosylated hemoglobin A1c (HbA1c) of 7.5-10% (both inclusive) confirmed at the end of at least a 3-week stable run-in period
9. Body mass index (BMI) > 24 to ≤ 40 kg/m^2
10. Women of childbearing potential (WOCBP) should have a negative urine beta human chorionic gonadotrophin (hCG) pregnancy test and must agree to use two established contraceptive methods throughout the study duration.
11. Able to sign an informed consent form and comply with study requirements

Exclusion Criteria:

1. FPG >270 mg/dL on Visit 1 or Visit 2
2. Known case of absolute insulin deficiency as indicated by clinical assessment, a history of type 1 diabetes, and a fasting plasma C-peptide of <0.6 ng/ml
3. Subjects who are on any other class of antidiabetic drug agents other than permitted non-insulin baseline ADAs
4. Any drugs or concomitant medications (e.g., psychoactive drugs such as carbamazepine, phenobarbital, sympathomimetics such as ephedrine, corticosteroids, anabolic steroids, and male sex hormones such as testosterone) that can interfere with glucose metabolism
5. Recurrent or severe urinary tract or genital mycotic infections or history of genitourinary infection within 4 weeks prior to informed consent
6. ALT or AST >3 times upper limit normal values
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 T2D
10. History of non-healing diabetic ulcers or amputations
11. History of more than 1 severe hypoglycemia episode or hypoglycemia unawareness within past 6 months of screening
12. In case of 2 or more glucose alert values of ≤70 mg/dL (3.9 mmol/L) unless a clear correctable precipitating factor can be identified / clinically significant hypoglycemia with self-monitored or laboratory plasma glucose level <54 mg/dL (3.0 mmol/L) /severe hypoglycemic episode requiring third party assistance occurring during run-in period
13. Known intestinal autoimmune disease, including celiac disease, ulcerative colitis, Crohn's disease, lupus erythematosus, scleroderma, or other autoimmune connective tissue disorder, which affects the small intestine
14. Secondary hypothyroidism or inadequately controlled primary hypothyroidism (thyroid stimulating hormone [TSH] value outside the normal range at screening)
15. Known history of thyroid cancer or hyperthyroidism with treatment within the past 12 months or inadequately controlled hyperthyroidism
16. An uncontrolled endocrine condition such as multiple endocrine neoplasia (except T2D)
17. 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 gastroesophageal reflux disease (GERD) (grade 3 esophagitis or greater)
18. Known history of a structural or functional disorder of the stomach including gastric ulcer, chronic gastritis, gastric varices, hiatal hernia (a large hiatal hernia or type II and higher paraoesophageal hernia), cancer, or any other disorder of the stomach
19. 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
20. Known history of chronic pancreatitis or a recent history of acute pancreatitis within the past year
21. Presence of acute or chronic active hepatitis B or C (except if hepatitis C is cured) or cirrhosis; hepatic decompensation/acute liver disease during the last 6 months; or alcoholic or autoimmune chronic hepatitis
22. Symptomatic gallstones, symptomatic kidney stones, or acute cholecystitis
23. Clinically active systemic infection
24. Known immunocompromised status including but not limited to individuals who have undergone organ transplantation, chemotherapy, or radiotherapy within the past 12 months; have clinically significant leukopenia; are positive for the human immunodeficiency virus (HIV); are on potential immunosuppressants; or individuals whose immune status makes the subject a poor candidate for clinical trial participation in the opinion of the Investigator
25. History of active malignancy or partial remission from clinically significant malignancy within the past 5 years (except basal or squamous cell skin cancer, carcinoma in situ, those who received curative treatment and are in complete remission for 5 years, or if the subject is confirmed as cancer free)
26. Known active coagulopathy or current upper gastro-intestinal bleeding conditions such as ulcers, gastric varices, strictures, or congenital or acquired intestinal telangiectasia
27. Known cases of anemia, thalassemia, or conditions that affect red blood cell (RBC) turnover such as a recent blood transfusion within 90 days
28. Use of anticoagulation therapy (e.g., warfarin, coumadin, or novel oral anticoagulants such as NOAC) or anti-platelet agents (e.g., thienopyridine) which cannot be discontinued for 5-7 days or 2 drug half-lives before the procedure
29. Use of systemic glucocorticoids (excluding topical or ophthalmic applications 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 an estimated glomerular filtration rate (eGFR) of <45 mL/min/1.73m2 (estimated by Modification of Diet in Renal Disease [MDRD]), end-stage renal failure, or on dialysis
32. History of myocardial infarction, stroke, TIA, coronary artery intervention, CHF exacerbation, or a major event requiring hospitalization within the last 6 months prior to screening
33. History of new or worsening signs or symptoms of coronary heart disease (CHD) within the last 3 months
34. Known case of severe peripheral vascular disease
35. Known case of symptomatic heart failure with reduced ejection fraction (NYHA Class II-IV) requiring pharmacologic therapy to control symptoms
36. Clinically significant electrocardiogram (ECG) findings such as new clinically significant arrhythmia or conduction disturbances that increase risk and require intervention as determined by the investigator
37. Subjects who are at risk of pancreatitis, particularly those with a recent fasting triglyceride value of >600 mg/dL within the past 3 months
38. Actively participating in a weight-loss program and currently not in the maintenance phase
39. General contraindications to deep or conscious sedation, general anesthesia, 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, over-the-counter weight-loss medications, or other prescribed medications used specifically for the purpose of weight loss
42. Use of dietary supplements or herbal preparations that may have unknown effects on glycemic control or 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, 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 SMBG, complete the subject glycemia diary, or comply with study visits and other study procedures as required per protocol
47. Recovered from severe COVID-19 infection (requiring hospitalization) but with persistent long COVID-19 symptoms (i.e., the individual has not recovered for several weeks or months since the start of symptoms that were suggestive of COVID-19, irrespective if the individual is tested or not)