Safety & Effectiveness of Duodenal Mucosal Resurfacing (DMR) Using the Revita™ System in Treatment of Type 2 Diabetes

Study Overview
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Brief Summary
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The Revita™ System is being investigated to assess the ability to improve glycemic control in conjunction with diet and exercise in patients with Type 2 diabetes who are inadequately controlled with oral anti-diabetic medications. The purpose of this study is to demonstrate the safety and effectiveness of the Fractyl DMR Procedure using the Revita™ System compared to a sham procedure. At 24 weeks, subjects randomized to the DMR procedure be continued to be followed per protocol till 48 Weeks and the Sham treatment arm will be offered to cross over to receive the DMR treatment and will be followed per protocol for 24 weeks post treatment.

Detailed Description
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The study is a randomized, double-blind sham-controlled prospective multi-center clinical investigation of subjects with T2D sub-optimally controlled on two oral anti-diabetic medications, one of which must be metformin, comparing the Fractyl DMR procedure using the Revita™ System to a sham procedure. All subjects will participate in a 4 week oral anti-diabetic medication run-in period before the procedure to confirm inadequate blood glucose control in conjunction with medication compliance and nutritional counseling. Subjects who meet all criteria after screening are randomized 2:1 (DMR to sham), with double blinding (subject and endocrinologist/Sponsor). The endoscopist is not blinded.

Official Title
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Randomized, Double-Blind, Sham-Controlled, Prospective, Multi-Center Pilot Study to Evaluate the Safety and Effectiveness of Duodenal Mucosal Resurfacing Using the Revita™ System in the Treatment of Type 2 Diabetes

Conditions
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Type 2 Diabetes

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and non-pregnant women 28-65 years of age Diagnosed with T2D for at least 3 years A1C of 7.5 - 9.5% (59-80 mmol/mol) BMI ≥ 28 and ≤ 40 kg/m2 On two to three oral OADs (metformin plus one to two additional OADs) with two (see note below) at least at half maximum labeled dose (or highest tolerated) with no changes in medication in the 12 weeks prior to the Screening Visit (Visit 1) (Refer to ADA Standard of Medical Care in Diabetes 2018, Table 8.3 for the maximum approved daily dose of non-insulin glucose lowering agents) (43). Note: For subjects on sulfonylurea (SU) glucose-lowering drugs for diabetes, the only SUs permitted in the study will be glipizide or glimepiride, and their doses below half maximum labeled dosing will not be an exclusion for study entry. Patients unwilling to reduce the dose of SU at the time of the DMR procedure as described by protocol will be excluded. Agree to use an additional glucose-lowering treatment (eg, liraglutide, other OAD with the exception of glyburide) if recommended by the study investigator in case of persistent hyperglycemia. Agree not to donate blood during their participation in the study Able to comply with study requirements and understand and sign the Informed Consent Form Women of childbearing potential (WOCBP) must be using two acceptable methods of contraception throughout the study Women must not be breastfeeding Exclusion Criteria: Diagnosed with Type 1 Diabetes (T1D) History of diabetic ketoacidosis or hyperosmolar nonketotic coma Probable insulin production failure, defined as fasting C Peptide serum <1 ng/mL (333pmol/l) Previous use of any types of insulin for >1 month (at any time, except for treatment of gestational diabetes) Current use of injectable medications for diabetes (insulin, GLP-1RA) Current use of glyburide, a sulfonylurea (SU) glucose-lowering drug for diabetes Hypoglycemia unawareness or a history of severe hypoglycemia (more than 1 severe hypoglycemic event, as defined by need for third-party-assistance, in the last year) Known autoimmune disease, including but not limited to celiac disease, or pre-existing symptoms of systemic lupus erythematosus, scleroderma or other autoimmune connective tissue disorder Previous GI surgery that could limit treatment of the duodenum such as Bilroth 2, Roux-en-Y gastric bypass, or other similar procedures or conditions History of chronic or acute pancreatitis History of diabetic gastroparesis Known active hepatitis or active liver disease Acute gastrointestinal illness in the previous 7 days Known history irritable bowel syndrome, radiation enteritis or other inflammatory bowel disease, such as Crohn's disease Known history of a structural or functional disorder of the esophagus that may impede passage of the device through the gastrointestinal tract or increase risk of esophageal damage during an endoscopic procedure, including Barrett's esophagus, esophagitis, dysphagia, achalasia, stricture/stenosis, esophageal varices, esophageal diverticula, esophageal perforation, or any other disorder of the esophagus 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 Known history of a structural or functional disorder of the stomach including gastroparesis, gastric ulcer, chronic gastritis, gastric varices, hiatal hernia (> 2 cm), cancer or any other disorder of the stomach Known history of chronic symptoms suggestive of a structural or functional disorder of the stomach, including any symptoms of chronic upper abdominal pain, chronic nausea, chronic vomiting, chronic dyspepsia or symptoms suggestive of gastroparesis, including post-prandial fullness or pain, post-prandial nausea or vomiting or early satiety Known history of duodenal ulcer, intestinal diverticula (diverticulitis), intestinal varices, intestinal stricture/stenosis, small bowel obstruction, or any other obstructive disorder of the GI tract Currently have ongoing symptoms suggestive of intermittent small bowel obstruction, such as recurrent bouts of post-prandial abdominal pain, nausea or vomiting Active H. pylori infection (Subjects with active H. pylori may continue with the screening process if they are treated with an appropriate antibiotic regimen) History of coagulopathy, upper gastrointestinal bleeding conditions such as ulcers, gastric varices, strictures, congenital or acquired intestinal telangiectasia Current use of anticoagulation therapy (such as warfarin) which cannot be discontinued for 7 days before and 14 days after the procedure Current use of P2Y12 inhibitors (clopidogrel, pasugrel, ticagrelor) which cannot be discontinued for 14 days before and 14 days after the procedure. Unable to discontinue non-steroidal anti-inflammatory drugs (NSAIDs) during treatment through 4 weeks following the procedure. Use of low dose aspirin is allowed. Current use of serotonergic medications (SSRI) Use of systemic glucocorticoids (excluding topical or ophthalmic application 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) Receiving weight loss medications such as Meridia, Xenical, or over the counter weight loss medications Untreated/inadequately treated hypothyroidism, defined as an elevated Thyroid-Stimulating Hormone (TSH) level at Screening; if on thyroid hormone replacement therapy, must be on stable dose for at least 6 weeks prior to Screening Persistent Anemia, defined as Hemoglobin <10 g/dL Subjects who have donated blood or received a transfusion in the prior 3 months Subjects with conditions that alter red blood cell turnover Subjects with prosthetic joints Significant cardiovascular disease including known history of valvular disease, or myocardial infarction, heart failure, transient ischemic attack or stroke within the last 6 months Moderate or severe chronic kidney disease (CKD), with estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2 (estimated by MDRD) Known immunocompromised status, including but not limited to individuals who have undergone organ transplantation, chemotherapy or radiotherapy within the past 12 months, who have clinically-significant leukopenia, who are positive for the human immunodeficiency virus (HIV) or whose immune status makes the subject a poor candidate for clinical trial participation in the opinion of the Investigator Active systemic infection Active malignancy within the last 5 years (with the exception of treated basal cell or treated squamous cell carcinoma) Subjects with a personal or family history of medullary thyroid carcinoma Subjects with Multiple Endocrine Neoplasia syndrome type 2 Not a candidate for surgery or general anesthesia Active illicit substance abuse or alcoholism Current smoker Participating in another ongoing clinical trial of an investigational drug or device 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 patient diary, or comply with study visits and other study procedures as required per protocol Additional exclusion criteria to be confirmed during the screening process: A1c post Run-In Phase < 7.5% (59 mmol/mol) or > 9.5% (86 mmol/mol) Any severe hypoglycemic event, defined as hypoglycemia requiring third-party assistance; or any clinically significant hypoglycemic event, defined as self-monitored or laboratory plasma glucose level < 54 mg/dL (3.0 mmol/L); or ≥ 2 glucose alert values ≤70 mg/dL (3.9 mmol/L), unless a clear correctable precipitating factor can be identified, since the screening visit (Visit 1) Uncontrolled hyperglycemia with a glucose level >270 mg/dl (>15 mmol/L) after an overnight fast or >360 mg/dl (>20 mmol/l) in a randomly performed measurement during Medication Run-In Period and confirmed by a second measurement (not on the same day) Mean of 3 separate blood pressure measurements >180 mmHg (systolic) or >100 mmHg (diastolic) WOCBP with a positive urine pregnancy test at Baseline Visit Active and uncontrolled GERD defined as grade III esophagitis or greater Abnormalities of the GI tract preventing endoscopic access to the duodenum Anatomic abnormalities in the duodenum that would preclude the completion of the DMR procedure, including tortuous anatomy Malignancy newly diagnosed by endoscopy Upper gastrointestinal conditions such as ulcers, polyps, varices, strictures, congenital or acquired intestinal telangiectasia

Ages Eligible for Study
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Minimum Age: 28 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


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 mucosa in an upper endoscopic procedure in patients with type 2 diabetes. | 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 DRM treatment are followed for 48 weeks while Sham subjects who cross over and undergo the DMR procedure at 24 weeks are followed for further 24 weeks post treatment. Sham subjects who choose not to cross over are discontinued from the study.<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. | Device: Duodenal Mucosal Resurfacing Sham (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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Hemoglobin A1c (HbA1c) | Change in HbA1c from baseline in DMR vs Sham groups | 24 weeks post procedure | 

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