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

Open to people ages 21-70

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 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:
   • Metformin,
   • 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),
   • Dipeptidyl peptidase 4 inhibitor (DPP-4i),
   • Thiazolidinediones (TZD),
   • Sodium-glucose cotransporter 2 inhibitors (SGLT2i),
   • Sulfonylureas (SU),
   • Meglitinides
4. Glycosylated hemoglobin A1c (HbA1c) of 7.5-10% (both inclusive)
5. Body mass index (BMI) > 24 to ≤ 40 kg/m²
6. 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.
7. Able to sign an informed consent form and comply with study requirements

1. FPG >270 mg/dL
2. Known case of absolute insulin deficiency as indicated by clinical assessment a fasting plasma C-peptide of <0.6 ng/ml
3. Subjects on any other class of glucose-lowering agents other than GLAs listed in inclusion criteria
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. Known diabetes related non-healing diabetic ulcers or amputations 11. History of more than 1 severe hypoglycemia episode or hypoglycemia unawareness within

   past 6 months

   12. Clinically significant hypoglycemia occurring during the run-in period, defined as a)

   2 or more glucose alert values of ≤70 mg/dL (3.9 mmol/L) unless a clear correctable precipitating factor can be identified; b) clinically significant hypoglycemia with self-monitored or laboratory plasma glucose level <54 mg/dL (3.0 mmol/L); c) severe hypoglycemic episode requiring third party assistance

   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, drug-refractory esophageal reflux symptoms, or active and uncontrolled gastroesophageal reflux disease (GERD) (grade 3 esophagitis or greater)

   18. Known 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. Known 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 non-GLA drugs known to affect GI motility (e.g., metoclopramide) 31. Known 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, transient ischemic attack, 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, disease, defined as AMA Criteria

   Class 1 or greater

   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, ST segment changes, or other conduction disturbances that increase risk of heart disease 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 substance use disorder based on the DSM-5 criteria within the last 12

   months.

   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)