Trial to Evaluate Efficacy+Safety of Revita DMR Treatment Paradigm 1 and Retreatment in Type 2 Diabetes Patients

The objective of this study is to evaluate feasibility, safety, and efficacy of endoscopic DMR Treatment Paradigm 1 (compared to sham) and to evaluate feasibility, safety, and efficacy of re-treatment with DMR at 24 weeks (compared to baseline and a single DMR procedure) in patients with type 2 diabetes with non-insulin glucose lowering medications.

The objective of this study is to evaluate feasibility, safety, and efficacy of endoscopic DMR Treatment Paradigm 1 (compared to sham) and to evaluate feasibility, safety, and efficacy of re-treatment with DMR at 24 weeks (compared to baseline and a single DMR procedure) in patients with type 2 diabetes with non-insulin glucose lowering medications.

The aimed effect is an adequate or improved glucose regulation and a decrease of HbA1c. Secondary effects include improved cardiovascular, hepatic, and metabolic parameters.

Eligibility Criteria:
Inclusion Criteria:

1. Diagnosed with Type 2 Diabetes. 2. Age ≥ 18 to ≤ 75 years. 3. Insulin naïve patients who are on stable dose (maximally approved or tolerated dose) of 2 or more glucose lowering drugs, including metformin, sulphonylurea (SU), (sodium-glucose cotransporter-2) inhibitors (SGLT-2i), Glucagon-like peptide-1 receptor agonists (GLP-1RA) or dipeptidyl peptidase 4 inhibitor (DPP-4i) and/or, thiazolidinedionderivaten (TZD) for at least 12 weeks.

4. BMI ≥ 24 and ≤ 40 kg/m2 5. HbA1c of ≥ 58 mmol/mol (7.5%) and ≤ 86 mmol/mol (10.0%).

1. In case of prestudy SU use, an HbA1c of ≥ 53 mmol/mol (7.0%). 6. Signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation.

   Exclusion Criteria:
   1. Uncontrolled hyperglycemia with a glucose level \>270 mg/dl (\>15.0 mmol/L) after an overnight 8-hour fasting at the end of run-in and confirmed by a second measurement on the consecutive day.
   2. Subjects on SUs who are either unable or unwilling to discontinue SUs during study period, or subjects who are using insulin. 3. Known case of absolute insulin deficiency as indicated by a fasting plasma C-peptide value of \<0.6 ng/ml.

   4. Diagnosis of autoimmune diabetes/Type 1 diabetes mellitus, monogenic (neonatal or maturity onset diabetes of the young (MODY)) diabetes or Type 1 diabetes in adults/latent autoimmune diabetes of adults (LADA).

   5. History of more than 1 severe hypoglycemia episode or unawareness within past 6 months in which third party assistance was needed.

   6. Clinically significant valvular heart disease or severe aortic stenosis. 7. Acute coronary syndrome (non-ST wave elevated myocardial infarction (STEMI), STEMI and unstable angina pectoris), stroke or transient ischemic attack within the past 3 months.

   8. Indication of acute liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN).

   9. Presence of acute or chronic active hepatitis B or C (except if hepatitis C is cured) or cirrhosis; or hepatic decompensation during the last 6 months; or alcoholic or autoimmune chronic hepatitis.

   10. Impaired renal function, defined as estimated Glomerular Filtration rate (eGFR) \< 45 ml/min/1.73m2 or end stage renal failure or on dialysis.

   11. Diagnosed with esophageal motility disorder or Glomerular Filtration rate (GERD) gr 3 or diagnosed during screening endoscopy.

   12. Known history of a structural or functional disorder of the stomach, e.g. active gastric ulcer, chronic gastritis, gastric varices, hiatal hernia, stomach cancer or any other disorder of the stomach.

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

   14. Known intestinal autoimmune disease, including Celiac disease, or pre-existing symptoms of lupus erythematosus, scleroderma, or other autoimmune connective tissue disorder, which affects the small intestine. 15. Patients with active helicobacter pylori infection. Patients may be enrolled if they had history of h-pylori infection and were successfully treated.

   16. History of active malignancy or partial remission from clinically significant malignancy within the past 5 years. With the exception of basal or squamous cell skin cancer or carcinoma in situ or those received curative treatment and in complete remission for 5 years or if subject confirmed as cancer free.

   17. Blood dyscrasias or any disorders causing hemolysis or unstable Red Blood Cells (sickle cell trait is allowed).

   18. Known case of severe peripheral vascular disease. 19. Clinically active systemic infection. 20. Known immunocompromised status, including individuals who have undergone organ transplantation, chemotherapy, or radiotherapy within the past 12 months, clinically significant leukopenia or positive for the human immunodeficiency virus (HIV), on potential immunosuppressants.

   21. Current treatment with systemic steroids or change in dosage of thyroid hormones within 6 weeks prior to consent or any other uncontrolled endocrine disorder.

   22. Use of anticoagulation therapy (such as warfarin, coumadin, Novel Oral AntiCoagulants (NOAC) or anti-platelet agents (such as thienopyridine) which cannot be discontinued for 5-7 days or 2 drug half-lives before the procedure; Acetylsalicylic acid does not need to be discontinued.

   23. Actively participating in weight loss program or using medications for weight loss 3 months prior to randomization.

   24. General contraindications to deep or conscious sedation or general anesthesia or high risk (e.g., American Society of Anesthesiologists Classification (ASA) 4 or higher) or contraindications to upper GI Endoscopy.

   25. Nursing or Pregnant women or women of child bearing potential who are unwilling to practice acceptable method of birth control.

   26. History of alcohol, legal or illegal drug and substance abuse. 27. Intake of an investigational drug in another trial within 30 days prior to consent or active participation in another clinical trial of an investigational drug or device.

   28. Any other clinical or mental condition which would jeopardize subject's safety or makes subject a poor candidate for clinical trial participation.