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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Double-blind Sham-controlled Trial to Evaluate Efficacy+Safety of Revita Duodenal Mucosal Resurfacing (DMR) Treatment Paradigm+Retreatment in Patients With Type 2 Diabetes Using Non-insulin Glucose Lowering Medications (REMIND)

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Device: Revita® DMR Treatment
* Other: Sham procedure


Participation Criteria
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Eligibility Criteria
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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%). 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: 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Crossover Assignment
Interventional Model Description: The study is a single-center, randomized, double-blind, sham-controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: DMR procedure<br>Patients receive Revita® DMR Treatment Paradigm 1. After unblinding at 24 weeks, they receive retreatment. | Device: Revita® DMR Treatment<br>* The Revita® System is an endoscopic treatment consisting of a single catheter and console designed to lift the duodenal mucosa with saline followed by controlled circumferential hydrothermal ablation of the mucosa. For this study Revita® DMR procedure will be conducted as follows: DMR Treatment Paradigm 1- After initial 2 Lift and Ablate step, remaining Lift: Ablate steps will be conducted in 1:1 manner.<br>* Other names: Revita Duodenal Mucosal Resurfacing;|
| Sham Comparator: Sham procedure<br>Patients receive a sham procedure. After unblinding takes place at 24 weeks, patients receive a Revita® DMR Treatment Paradigm 1. 48 weeks after initial sham (= 24 weeks after first DMR) patients may receive retreatment, if they want to. | Other: Sham procedure<br>* The sham control for the Revita DMR procedure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety endpoint | Safety endpoint is evaluated 12 weeks post DMR and 12 weeks post retreatment with DMR - Number (percentage) of patients experienced device and procedure-related Serious Adverse Events (SAEs), Unanticipated Device Effects (UADEs), Serious Adverse Device Effects (SADEs), Suspected Unexpected Serious Adverse Reaction (SUSARs) | 12 weeks post DMR and 12 weeks post retreatment with DMR | 
| Feasibility endpoint 1 | Feasibility endpoint is evaluated during and after the procedure: - Number of ablations, whether a DMR was successful (>3 ablations) | During procedure | 
| Feasibility endpoint 2 | Feasibility endpoint is evaluated during and after the procedure: - Procedure time, defined as time between catheter in and catheter out. | During procedure | 
| Efficacy endpoint 1 | Efficacy is evaluated at 24 weeks compared to baseline and sham: - Mean change in Fasting Plasma Glucose (FPG)/Flash Glucose Monitoring (FGM) | 24 weeks post DMR/sham | 
| Efficacy endpoint 2 | Efficacy is evaluated at 24 weeks compared to baseline and sham: - Change in HbA1c | 24 weeks post DMR/sham | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary safety endpoint | Secondary safety endpoint is evaluated during follow-up and compared to baseline and sham at week 24 and compared to baseline and 12 weeks after (re)-DMR for all patients: incidences and event rates of hypoglycemic events during complete study period | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 1: mean change in HbA1c | Efficacy endpoint 1: mean change in HbA1c | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 2: mean Change in Fasting Glucose | Efficacy endpoint 2: mean Change in Fasting Glucose | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 2: mean Change in Time in Range (TIR) | Efficacy endpoint 2: mean Change in Time in Range | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 3: In patients with baseline abnormal Alanine Transaminase (ALT), Aspartate Aminotransferase (AST), and Gamma Glutamyl Transferase (GGT) values, change in ALT, AST, GGT | Efficacy endpoint 3: In patients with baseline abnormal ALT, AST and GGT values, change in ALT, AST, GGT | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 4: Change in body weight | Efficacy endpoint 4: Change in body weight | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 5: Change in Fasting C-peptide | Efficacy endpoint 5: Change in Fasting C-peptide | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 6: Change in FPG | Efficacy endpoint 6: Change in FPG | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 7: Change in homeostasis model assessment for insulin resistance (HOMA-IR) | Efficacy endpoint 7: Change in HOMA-IR | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 8: Change in Framingham Risk Score-Cardiovascular risk score (FRS-CVD) | Efficacy endpoint 8: Change in Framingham Risk Score-Cardiovascular risk score (FRS-CVD) | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 9: Change in MRI-proton density fat fraction (MRI-PDFF) | Efficacy endpoint 9: Change in MRI-PDFF | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 10: Achievement of HbA1c ≤ 53 mmol/mol (7.0%) | Efficacy endpoint 10: Achievement of HbA1c ≤ 53 mmol/mol (7.0%) | Through study completion, an average of 1 or 1,5 years | 
| Efficacy endpoint 11: Change in food intake (amount of calories, fat, carbohydrates, proteins etc.) based on intake registration data | Efficacy endpoint 11: Change in food intake (amount of calories, fat, carbohydrates, proteins etc.) based on intake registration data | Through study completion, an average of 1 or 1,5 years | 
| Mechanistic: Change in resection tissue findings in morphological features | Mechanistic: Change in morphological features | Week 12 after (re)DMR | 
| Mechanistic: Change in resection tissue findings in functional level changes | Mechanistic: Change in functional level changes | Week 12 after (re)DMR | 
| Mechanistic: Change in resection tissue findings in cellular level changes | Mechanistic: Change in cellular level changes | Week 12 after (re)DMR | 
| Mechanistic: Mean Changes in small intestinal biopsy gene expression | Mechanistic: Mean Changes in small intestinal biopsy gene expression | Week 12 after (re)DMR | 
| Mechanistic: Mean Changes in small intestinal biopsy metabolomics/proteomics | Mechanistic: Mean Changes in small intestinal biopsy metabolomics /proteomics | Week 12 after (re)DMR | 
| Mechanistic: Change in Plasma Citrulline | Mechanistic: Change in Plasma Citrulline | Through study completion, an average of 1 or 1,5 years | 
| Mechanistic: Change in Cystatin Value | Mechanistic: Change in Cystatin Value | Through study completion, an average of 1 or 1,5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 2 Diabetes, Duodenal ablation, Endoscopy, Duodenal Mucosal Resurfacing