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

Study Overview
=================
Brief Summary
-----------------
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 48 weeks post treatment.

Official Title
-----------------
A Prospective, Randomized, Double-Blind, Sham-Controlled, Multi-Center Pivotal Study to Evaluate the Efficacy and Safety of Duodenal Mucosal Resurfacing Using the Revita® System in Subjects With Type 2 Diabetes on Insulin Therapy

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Device: Duodenal Mucosal Resurfacing (DMR)
* Device: Duodenal Mucosal Resurfacing (Sham)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male, and non-pregnant, non-lactating females 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: 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 Glycosylated hemoglobin A1c (HbA1c) of 7.5-10% (both inclusive) confirmed at the end of at least a 3-week stable run-in period Body mass index (BMI) > 24 to ≤ 40 kg/m^2 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. Able to sign an informed consent form and comply with study requirements Exclusion Criteria: FPG >270 mg/dL on Visit 1 or Visit 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 Subjects who are on any other class of antidiabetic drug agents other than permitted non-insulin baseline ADAs 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 Recurrent or severe urinary tract or genital mycotic infections or history of genitourinary infection within 4 weeks prior to informed consent ALT or AST >3 times upper limit normal values Use of an investigational drug within 1 month or 5 half-lives (whichever is longer) before the screening Diagnosed with type 1 diabetes or with a recent history of ketoacidosis Ketosis-prone T2D History of non-healing diabetic ulcers or amputations History of more than 1 severe hypoglycemia episode or hypoglycemia unawareness within past 6 months of screening 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 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 Secondary hypothyroidism or inadequately controlled primary hypothyroidism (thyroid stimulating hormone [TSH] value outside the normal range at screening) Known history of thyroid cancer or hyperthyroidism with treatment within the past 12 months or inadequately controlled hyperthyroidism An uncontrolled endocrine condition such as multiple endocrine neoplasia (except T2D) 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) 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 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 Known history of chronic pancreatitis or a recent history of acute pancreatitis within the past year 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 Symptomatic gallstones, symptomatic kidney stones, or acute cholecystitis Clinically active systemic infection 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 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) Known active coagulopathy or current upper gastro-intestinal bleeding conditions such as ulcers, gastric varices, strictures, or congenital or acquired intestinal telangiectasia Known cases of anemia, thalassemia, or conditions that affect red blood cell (RBC) turnover such as a recent blood transfusion within 90 days 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 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 Use of drugs known to affect GI motility (e.g., metoclopramide) 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 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 History of new or worsening signs or symptoms of coronary heart disease (CHD) within the last 3 months Known case of severe peripheral vascular disease Known case of symptomatic heart failure with reduced ejection fraction (NYHA Class II-IV) requiring pharmacologic therapy to control symptoms 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 Subjects who are at risk of pancreatitis, particularly those with a recent fasting triglyceride value of >600 mg/dL within the past 3 months Actively participating in a weight-loss program and currently not in the maintenance phase 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 History of any illicit alcohol or substance abuse 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 Use of dietary supplements or herbal preparations that may have unknown effects on glycemic control or risk of bleeding Participating in another ongoing clinical trial of an investigational drug or device 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 Any other mental or physical condition which, in the opinion of the investigator, makes the subject a poor candidate for clinical-trial participation Unwilling or unable to perform SMBG, complete the subject glycemia diary, or comply with study visits and other study procedures as required per protocol 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)

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Duodenal Mucosal Resurfacing (DMR)<br>Duodenal Mucosal Resurfacing (DMR) treatment will include hydrothermal ablation of the duodenal muscosa in an upper endoscopic procedure in patients with type 2 diabetes on insulin. | Device: Duodenal Mucosal Resurfacing (DMR)<br>* The Fractyl DMR Procedure utilizes the Revita® Catheter to perform hydrothermal ablation of the duodenum. The Catheter is delivered trans-orally over a guide-wire to first inject saline to lift the sub-mucosal space, followed by an ablation of the duodenal mucosa. Subjects who receive the DMR treatment are followed for 48 weeks post treatment.<br>|
| Sham Comparator: Duodenal Mucosal Resurfacing Sham (Sham)<br>Duodenal Mucosal Resurfacing Sham (Sham) treatment will include an upper endoscopic procedure similar to DMR treatment without hydrothermal ablation of the duodenal mucosa in patients with type 2 diabetes on insulin. | Device: Duodenal Mucosal Resurfacing (Sham)<br>* The Sham procedure consists of placing the Revita® Catheter as described above into the duodenum for a minimum of 30 minutes and then removing it from the patient. Subjects who receive the Sham procedure are followed for 48 weeks post treatment and are offered cross over to undergo the DMR procedure at 48 weeks and are followed for further 48 weeks post treatment. Sham subjects who choose not to cross over are discontinued from the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidences and event rates of hypoglycemic events - Primary Outcome 1 | HbA1c ≤7% without an increase in number of ADAs from baseline | Baseline to Week 24 | 
| Incidences and event rates of hypoglycemic events - Primary Outcome 2 | HbA1c reduction from baseline of ≥1% without an increase in number of ADAs from baseline | Baseline to Week 24 | 
| Incidences and event rates of hypoglycemic events - Primary Outcome 3 | HbA1c reduction from baseline of ≥0.5% without an increase in number of ADAs from baseline | Baseline to Week 24 | 
| Incidences and event rates of hypoglycemic events - Primary Outcome 4 | Any HbA1c reduction from baseline without an increase in number of ADAs from baseline | Baseline to Week 24 | 
| Incidences and event rates of hypoglycemic events - Primary Outcome 5 | Change in number of prescribed ADAs | Baseline to Week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Type 2 Diabetes, Diabetes Mellitus, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Revita System, Duodenal Mucosal Resurfacing, Insulin-Dependent Diabetes Mellitus