Diabetes Mellitus, Type 2
Conditions
Keywords
Type 2 Diabetes, Duodenal ablation, Endoscopy, Duodenal Mucosal Resurfacing
Brief summary
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
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.
Interventions
DEVICERevita® DMR Treatment
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.
OTHERSham procedure
The sham control for the Revita DMR procedure.
Sponsors
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Fractyl Health Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
In this study, both the study team and the study subjects are blinded to the treatment through the 24 week follow-up visit. While the endoscopist is not blinded to individual treatments, he is blinded to cohort level data and is not responsible for patient follow-up. At the 24 week visit, the subject and study team are unblinded. The subjects who received the sham treatment undergo DMR treatment.
Intervention model description
The study is a single-center, randomized, double-blind, sham-controlled trial
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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 ≥ 54 mmol/mol (7.5%) and ≤ 86 mmol/mol (10.0%). 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 who are using insuline. 3. Known case of absolute insulin deficiency as indicated by a fasting plasma C-peptide value of \<0.6 ng/ml (\<0,2 nmol/L). 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety endpoint | 12 weeks post DMR and 12 weeks post retreatment with DMR | 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) |
| Feasibility endpoint 1 | During procedure | Feasibility endpoint is evaluated during and after the procedure: \- Number of ablations, whether a DMR was successful (\>3 ablations) |
| Feasibility endpoint 2 | During procedure | Feasibility endpoint is evaluated during and after the procedure: \- Procedure time, defined as time between catheter in and catheter out. |
| Efficacy endpoint 1 | 24 weeks post DMR/sham | Efficacy is evaluated at 24 weeks compared to baseline and sham: \- Mean change in Fasting Plasma Glucose (FPG)/Flash Glucose Monitoring (FGM) |
| Efficacy endpoint 2 | 24 weeks post DMR/sham | Efficacy is evaluated at 24 weeks compared to baseline and sham: \- Change in HbA1c |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary safety endpoint | Through study completion, an average of 1 or 1,5 years | 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 |
| Efficacy endpoint 1: mean change in HbA1c | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 1: mean change in HbA1c |
| 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 Fasting Glucose |
| Efficacy endpoint 2: mean Change in Time in Range (TIR) | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 2: mean Change in Time in Range |
| 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 | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 3: In patients with baseline abnormal ALT, AST and GGT values, change in ALT, AST, GGT |
| Efficacy endpoint 4: Change in body weight | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 4: Change in body weight |
| Efficacy endpoint 5: Change in Fasting C-peptide | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 5: Change in Fasting C-peptide |
| Efficacy endpoint 6: Change in FPG | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 6: Change in FPG |
| Efficacy endpoint 7: Change in homeostasis model assessment for insulin resistance (HOMA-IR) | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 7: Change in HOMA-IR |
| 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 8: Change in Framingham Risk Score-Cardiovascular risk score (FRS-CVD) |
| Efficacy endpoint 9: Change in MRI-proton density fat fraction (MRI-PDFF) | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 9: Change in MRI-PDFF |
| Efficacy endpoint 10: Achievement of HbA1c ≤ 53 mmol/mol (7.0%) | Through study completion, an average of 1 or 1,5 years | Efficacy endpoint 10: Achievement of HbA1c ≤ 53 mmol/mol (7.0%) |
| 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 | Efficacy endpoint 11: Change in food intake (amount of calories, fat, carbohydrates, proteins etc.) based on intake registration data |
| Mechanistic: Change in resection tissue findings in morphological features | Week 12 after (re)DMR | Mechanistic: Change in morphological features |
| Mechanistic: Change in resection tissue findings in functional level changes | Week 12 after (re)DMR | Mechanistic: Change in functional level changes |
| Mechanistic: Change in resection tissue findings in cellular level changes | Week 12 after (re)DMR | Mechanistic: Change in cellular level changes |
| Mechanistic: Mean Changes in small intestinal biopsy gene expression | Week 12 after (re)DMR | Mechanistic: Mean Changes in small intestinal biopsy gene expression |
| Mechanistic: Mean Changes in small intestinal biopsy metabolomics/proteomics | Week 12 after (re)DMR | Mechanistic: Mean Changes in small intestinal biopsy metabolomics /proteomics |
| Mechanistic: Change in Plasma Citrulline | Through study completion, an average of 1 or 1,5 years | Mechanistic: Change in Plasma Citrulline |
| Mechanistic: Change in Cystatin Value | Through study completion, an average of 1 or 1,5 years | Mechanistic: Change in Cystatin Value |
Countries
Netherlands
Contacts
PRINCIPAL_INVESTIGATORJacques JG Bergman, MD, PhD
Amsterdam UMC
Outcome results
None listed