Verapamil SR in Adults With Type 1 Diabetes

Study Overview
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Brief Summary
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This study has been set up within the framework of the INNODIA network. INNODIA is a global partnership between 31 academic institutions, 6 industrial partners, a small sized enterprise and 2 patient organizations, bringing their knowledge and experience together with one common goal: To fight type 1 diabetes. (www.innodia.eu) The overall aim of INNODIA is to advance in a decisive way how to predict, stage, evaluate and prevent the onset and progression of type 1 diabetes (T1D). For this, INNODIA has established a comprehensive and interdisciplinary network of clinical and basic scientists, who are leading experts in the field of T1D research in Europe and UK (United Kingdom), with complementary expertise from the areas of immunology, Beta-cell biology, biomarker research and T1D therapy, joining forces in a coordinated fashion with industry partners and two foundations, as well as with all major stakeholders in the process, including regulatory bodies and patients with T1D and their families.

Detailed Description
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The study is a multicenter, randomized, double-blind, placebo-controlled study in volunteers with newly diagnosed diabetes mellitus type 1 (within 6 weeks after diagnosis). The purpose of the clinical trial is to confirm the effect of 360mg Verapamil sustained release (SR) administered orally once daily (titrated over the first 3 months from 120 mg to 360 mg) on the preservation of beta-cell function measured as stimulated C-peptide after 12 months compared to placebo. The study has a cross-over design and a duration of approximately 24 months, consisting of 3 telephone visits and 7 visits at the trial site. The duration of the treatment phase with verapamil is 12 months, and an additional (optional) follow-up visit will be carried out 12 months after completion of the study. The study procedures are identical in all 20 clinical centres across Europe and the UK.

Official Title
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A Randomised, Double-blind, Placebo Controlled, Parallel Group, Multi-centre Trial in Adult Subjects With Newly Diagnosed Type 1 Diabetes Mellitus Investigating the Effect of Verapamil SR on Preservation of Beta-cell Function (Ver-A-T1D)

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Verapamil SR 120 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have given written informed consent Age ≥18 and <45 years at consent Must have a diagnosis of T1D of within 6 weeks duration at screening (from date of the first insulin injection) Must have at least one or more diabetes-related autoantibodies present at screening: GADA, IA-2A and/or ZnT8A Must have fasting C-peptide levels ≥100 pmol/L measured at screening Be willing to comply with intensive diabetes management Exclusion Criteria: Be immunodeficient or have clinically significant chronic lymphopenia: Leukopenia (< 3,000 leukocytes /µL), neutropenia (<1,500 neutrophils/µL), lymphopenia (<800 lymphocytes/µL), or thrombocytopenia (<100,000 platelets/µL) Have active signs or symptoms of acute infection at the time of screening Be currently pregnant or lactating, or anticipate getting pregnant during the 12 months study period Require use of immunosuppressive agents including chronic use of systemic steroids Have evidence of current or past human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection Have any complicating medical issues or abnormal clinical laboratory results that may interfere with study conduct, or cause increased risk to include pre-existing cardiac disease, chronic obstructive pulmonary disease (COPD), sickle cell disease, neurological, or blood count abnormalities as judged by the investigator Have a history of malignancies other than skin History of liver insufficiency or laboratory evidence of liver dysfunction with aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 3 times the upper limits of normal History of renal insufficiency or evidence of renal dysfunction with creatinine greater than 1.5 times the upper limit of normal Current or ongoing use of non-insulin pharmaceuticals that affect glycaemic control within prior 7 days of screening Use of any other investigational drug in the previous 30 days and/or intent on using any investigational drug for the duration of the trial Current use of Verapamil or other calcium channel blockers Known hypersensitivity to Verapamil or to any of its excipients Concomitant medication known for significantly inducing or inhibiting CYP3A4 and/or glycoprotein-P metabolism Intake of grapefruit juice, licorice, St.John's Wort, cannabidiol, ginkgo biloba Substrate intake of CYP3A4 and/or glycoprotein-P metabolism, as judged by the investigator Hypotension (of less than 100mmHg systolic), sick sinus syndrome (except patients with a functioning artificial pacemaker), uncompensated heart failure or severe left ventricular dysfunction; marked bradycardia (less than 50 beats/minute), atrial flutter or atrial fibrillation in the presence of an accessory bypass tract (e.g. Wolff-Parkinson-White syndrome), hypertrophic cardiomyopathy, acute myocardial infarction, attenuated neuromuscular transmission (e.g. by myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy) ECG second or third degree atrioventricular block; Incomplete branch block Any condition that in the investigator's opinion may adversely affect study participation or may compromise the study results Current use of ß-blockers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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 |
| --- | --- |
| Experimental: Verapamil SR<br>Eligible participants will be randomised into the Verapamil SR arm and receive instructions on frequency of administration (daily intake). 80 participants on the experimental arm are expected to complete the trial. | Drug: Verapamil SR 120 mg<br>* For use as a test product in this blinded study, the IMP will be modified by re-packaging. The film-coated tablets will be squeezed from their blisters and filled into HDPE Twist-Off bottles. Each bottle will be labeled as required per country requirement. Labels will be blinded. Drug administration: from Day 0 to Week 4: 120 mg once daily from Week 4 to Week 8: 240 mg once daily from Week 8 to Month 12: 360 mg once daily<br>* Other names: Isoptin retard 120 mg;|
| Placebo Comparator: Placebo<br>Eligible participants will be randomised into the placebo arm and receive instructions on frequency of administration (daily intake). 40 participants on the control arm are expected to complete the trial. | Drug: Placebo<br>* The matching placebo will be filled into HDPE Twist-Off bottles, in the same way as the verum. Each bottle will be labeled as required per country requirement. Labels will be blinded. Drug administration: from Day 0 to Week 4: 120 mg once daily from Week 4 to Week 8: 240 mg once daily from Week 8 to Month 12: 360 mg once daily<br>* Other names: Matching Placebo for Verapamil SR 120 mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the stimulated C-peptide response curve | The primary objective is to determine the changes in stimulated C-peptide response during the first two hours of a mixed meal tolerance test (MMTT) at baseline and after 12 months for 360mg Verapamil SR administered orally once daily versus placebo. | At 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the stimulated C-peptide response curve | The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT) | At 3, 6, 9 and 24 months | 
| Proinsulin, Insulin, Pro-IAPP and Proglucagon secretion | Proinsulin, Insulin, Pro-IAPP and Proglucagon during the first two hours of a mixed meal tolerance test (MMTT) | At baseline and 3, 6, 9 and 12 months | 
| Fasting C-peptide | To determine the effects of 360mg Verapamil SR administered orally once daily on fasting C-peptide and Dried Blood Spot (DBS) C-peptide measurements over time. | At 12 months | 
| DBS C-peptide | The DBS (Dried blood spot) C-peptide measurements at all observation times | At baseline, week 4, week 8, and 3, 6, and 9 months | 
| Change in HbA1c | To determine the effects of 360mg Verapamil SR administered orally once daily on HbA1c daily total insulin dose and continous glucose monitoring (CGM) time in range. | Baseline, 12 and 24 months | 
| Severe hypoglycaemic episodes | Number of treatment emergent severe hypoglycaemic episodes. Severe hypoglycaemia denotes severe cognitive impairment requiring external assistance for recovery according to the American Diabetes Association (ADA) | Baseline to 12 months | 
| DKA | Number of treatment emergent episodes of diabetic ketoacidosis | Baseline to 12 months | 
| Change in insulin requirements | Change in insulin requirements, baseline to 12 months as the daily total dose (three days average) in units per kg body weight (BW) | Baseline, 12 and 24 months | 
| Change in T1D associated autoantibodies | Change in T1D associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) from baseline to 12 months | Baseline to 12 months | 
| Continous glucose monitoring (CGM) | Continous glucose monitoring (CGM) time in range (70-140 mg/dL, 3.9-7.8 mmol/L) and (70-180 mg/dL, 3.9-10.0 mmol/L), time above range (>180 mg/dL, >10.0 mmol/L), time below range (<70 mg/dL, < 3.9 mmol/L) | At Baseline and every 2 weeks prior to each visit (week 4, week 8, and 3, 6, and 9 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INNODIA, Typ-1 Diabetes, Verapamil, Beta cell, C-peptide