Safety, Tolerability, and Effectiveness of Duodenal Mucosal RF Vapor Ablation for Insulin Elimination in Type-2 Diabetes

Inclusion Criteria:

1. Adults ≥18 years old but ≤ 65 years old. (Women of childbearing potential must beusing one acceptable methods of contraception throughout the study.)

2. Diagnosed with type 2 diabetes mellitus for ≥1 year but ≤ 8 years duration.

3. Glycated haemoglobin ≤ 8.0% (64 mmol/mol).

4. Fasting serum C-peptide ≥ 0.6 ng/mL.

5. Body mass index ≥ 27.5 and ≤ 42.5 kg/m2.

6. On a daily insulin (basal or combined with short-acting) for at least three months,with a dose ≤ 0.6 U/kg, with a stable dose (≤ 20%) over the last month.

7. Able to comply with study requirements and understand and sign the informed consentform.

Exclusion Criteria:

1. Diagnosis of Type 1 diabetes mellitus

2. Any history of diabetic ketoacidosis or hyperosmolar nonketotic coma

3. Current use of insulin pump.

4. Current, or within the last 3 months, use of a GLP-1 analogue.

5. Current use of a long-acting sulphonylureas (e.g. glibenclamide, chlorpropamide,glimepiride, glyburide)

6. History of severe hypoglycemia (more than 1 severe hypoglycemic event, as defined byneed for third-party assistance, in the last year).

7. Known autoimmune disease, including but not limited to celiac disease, duodenalCrohn disease or pre-existing symptoms of systemic lupus erythematosus, sclerodermaor other systemic autoimmune connective tissue disorder.

8. Previous gastrointestinal surgery that could limit treatment of the duodenum such asBillroth 2, Roux-en-Y gastric bypass, or other similar procedures or conditions. (Prior laparoscopic sleeve gastrectomy (LSG) will not be an exclusion).

9. History of pancreatitis (acute or chronic).

10. Known diabetic gastroparesis.

11. Persistent anaemia, defined as haemoglobin ≤ 9 g/dL

12. Known active hepatitis or active liver disease.

13. Acute gastrointestinal illness in the previous 7 days.

14. Known history of severe irritable bowel syndrome, radiation enteritis or otherinflammatory bowel disease, such as Crohn's disease.

15. Known history of a structural or functional disorder of the esophagus that mayimpede passage of the device through the gastrointestinal tract or increase risk ofesophageal damage during an endoscopic procedure, including moderate-severe (Grade Cor D) esophagitis, dysphagia due to achalasia or stricture/stenosis, esophagealvarices, esophageal perforation, or any other disorder of the esophagus.

16. Upper gastrointestinal conditions such as active ulcers, polyps, varices,strictures, congenital or acquired duodenal telangiectasia.

17. Current use of anticoagulation therapy (e.g. warfarin) or direct-acting oralanticoagulants (e.g. rivaroxaban, apixaban, edoxaban and dabigatran) that cannot bediscontinued for 3-5 days before and 7 days after the procedure.

18. Current use of P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor) that cannot bediscontinued for 5 days before and 7 days after the procedure.

19. Unable to discontinue non-steroidal anti-inflammatory drugs (NSAIDs) duringtreatment through 4 weeks following the procedure. Use of acetaminophen and low doseaspirin is allowed.

20. Use of systemic glucocorticoids (excluding topical or ophthalmic application orinhaled forms) for more than 10 consecutive days within 12 weeks prior to thebaseline visit.

21. Use of drugs known to affect gastrointestinal motility (e.g. Metoclopramide)

22. Use of weight loss medications such as Sibutramine (e.g. Meridia), Orlistat (e.g.Xenical), Phentermine or over-the-counter weight loss medications (prescriptionmedication)

23. Significant cardiovascular disease, including known history of valvular disease, ormyocardial infarction, heart failure, transient ischemic attack, or stroke within 6months prior to the Screening Visit.

24. Personal or family history of medullary thyroid carcinoma or multiple endocrineneoplasia syndrome type 2.

25. Uncontrolled thyroid disease

26. Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or >100 mmHg (diastolic).

27. Estimated glomerular filtration rate (eGFR) ≤ 45 ml/min/1.73m2 (estimated by MDRD).

28. Known immunocompromised status, including but not limited to individuals who haveundergone organ transplantation, chemotherapy, or radiotherapy within the past 12months, who have clinically significant leukopenia, who are positive for the humanimmunodeficiency virus (HIV) or whose immune status makes the participant a poorcandidate for clinical trial participation in the opinion of the investigator.

29. Active illicit substance abuse or alcoholism (>2 drinks/day regularly)

30. Active malignancy within the last 5 years (excluding non-melanoma skin cancers)

31. Active systemic infection

32. Women who are currently breastfeeding.

33. Pregnancy or wish to get pregnant in the next year.

34. Participating in another ongoing clinical trial of an investigational drug ordevice.

35. Any other mental or physical condition which, in the opinion of the studyinvestigator, makes the participant a poor candidate for clinical trialparticipation.

36. Critically ill or has a life expectancy < 3 years.

37. Use of heart pacemaker or other electronic device implants

38. General contraindications to deep or conscious sedation, general anesthesia, highrisk as determined by anesthesiologist (e.g., ASA score 4 or higher), orcontraindications to upper GI endoscopy.