Ver-A-T1D: Verapamil SR in Adults With Type 1 Diabetes

Sponsor

Medical University of Graz (Other)

Overall Status

Recruiting

CT.gov ID

NCT04545151

Collaborator

Juvenile Diabetes Research Foundation (Other)

138

Enrollment

Locations

Arms

35.7

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Verapamil SR 120 mg Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

138 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Masking Description:

Trial participants and research teams will be blinded to the treatment group for the duration of the trial. The double blinding will be achieved by providing verapamil SR identical placebo tablets.

Primary Purpose:

Treatment

Official Title:

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)

Actual Study Start Date :

Feb 8, 2021

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Verapamil SR 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 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 Other Names: VeraHEXAL KHK 120 mg Isoptin retard 120 mg
Placebo Comparator: Placebo 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 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 Other Names: Matching Placebo for Verapamil SR 120 mg

Arm

Intervention/Treatment

Experimental: Verapamil SR

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

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

Other Names:

VeraHEXAL KHK 120 mg

Isoptin retard 120 mg

Placebo Comparator: Placebo

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

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

Other Names:

Matching Placebo for Verapamil SR 120 mg

Outcome Measures

Primary Outcome Measures

Area under the stimulated C-peptide response curve [At 12 months]
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.

Secondary Outcome Measures

Area under the stimulated C-peptide response curve [At 3, 6, 9 and 24 months]
The area under the stimulated C-peptide response curve over the first two hours of a mixed meal tolerance test (MMTT)
Proinsulin, Insulin, Pro-IAPP and Proglucagon secretion [At baseline and 3, 6, 9 and 12 months]
Proinsulin, Insulin, Pro-IAPP and Proglucagon during the first two hours of a mixed meal tolerance test (MMTT)
Fasting C-peptide [At 12 months]
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.
DBS C-peptide [At baseline, week 4, week 8, and 3, 6, and 9 months]
The DBS (Dried blood spot) C-peptide measurements at all observation times
Change in HbA1c [Baseline, 12 and 24 months]
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.
Severe hypoglycaemic episodes [Baseline to 12 months]
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)
DKA [Baseline to 12 months]
Number of treatment emergent episodes of diabetic ketoacidosis
Change in insulin requirements [Baseline, 12 and 24 months]
Change in insulin requirements, baseline to 12 months as the daily total dose (three days average) in units per kg body weight (BW)
Change in T1D associated autoantibodies [Baseline to 12 months]
Change in T1D associated autoantibodies (GADA, IAA, IA-2A and ZnT8A) from baseline to 12 months
Continous glucose monitoring (CGM) [At Baseline and every 2 weeks prior to each visit (week 4, week 8, and 3, 6, and 9 months)]
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)

Other Outcome Measures

Quality of life: DTSQs questionnaire [At week 4 , month 6 and month 12.]
Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Diabetes Treatment Satisfaction Questionnaire - DTSQs
Quality of life: DTSQc questionnaire [At month 12]
Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Diabetes Treatment Satisfaction Questionnaire - DTSQc
Quality of life: ADDQoL questionnaire [At month 6 and at month 12]
Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): · the Audit of Diabetes Dependent Quality of Life - ADDQoL
Quality of life: HypoFear questionnaire [At week 4 , at month 6 and at month 12]
Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Hypoglycaemia Fear Survey - HFS

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of Graz, Department of Internal Medicine Division of Endocrinology and Metabolism	Graz	Styria	Austria	8010
2	Universitair Ziekenhuis Brussel	Brussels		Belgium
3	Université Libre de Bruxelles/ Hôpital Erasme	Brussels		Belgium
4	Universitair Ziekenhuis Antwerpen	Edegem		Belgium
5	Katholieke Universiteit Leuven	Leuven		Belgium
6	Institut National de la Santé et de la Recherche Médicale	Paris		France
7	HKA Hannover	Hanover		Germany
8	Universität Ulm	Ulm		Germany
9	Università Vita-Salute San Raffaele	Milano		Italy
10	Università degli Studi di Siena	Siena		Italy
11	Slaski Uniwersytet Medyczny w Katowicach	Katowice		Poland
12	Lunds Universität	Lund		Sweden
13	Queen Elizabeth Hospital	Birmingham		United Kingdom
14	Southmead Hospital	Bristol		United Kingdom
15	Addenbrokes Hospital	Cambridge		United Kingdom
16	University Hospital of Wales	Cardiff		United Kingdom
17	Bart's Hospital QMUL	London		United Kingdom
18	Guy's Hospital	London		United Kingdom
19	Queens Medical Centre	Nottingham		United Kingdom
20	John Radcliffe Hospital	Oxford		United Kingdom
21	OCDEM, John Radcliffe Hospital	Oxford		United Kingdom
22	Royal Hallamshire Hospital	Sheffield		United Kingdom
23	Singleton Hospital	Swansea		United Kingdom