Verapamil SR in Adults With Type 1 Diabetes

NCT04545151 | Completed Phase 2 DMC

• 3 other identifiers: Ver-A-T1D2020-000435-452023-506545-27-00
• Study Type: interventional
• Target: 136
• Locations: 6 countries
• Sites: 22

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.

Conditions

Diabetes Mellitus, Type 1

Keywords

INNODIA; Typ-1 Diabetes; Verapamil; Beta cell; C-peptide

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Area under the stimulated C-peptide response curve

  At 3, 6, 9 and 24 months

• Proinsulin, Insulin, Pro-IAPP and Proglucagon secretion

  At baseline and 3, 6, 9 and 12 months

• Fasting C-peptide

  At 12 months

• DBS C-peptide

  At baseline, week 4, week 8, and 3, 6, and 9 months

• Change in HbA1c

  Baseline, 12 and 24 months

Other Outcomes (4)

• Quality of life: DTSQs questionnaire

  At week 4 , month 6 and month 12.

• Quality of life: DTSQc questionnaire

  At month 12

• Quality of life: ADDQoL questionnaire

  At month 6 and at month 12

Study Arms (2)

Verapamil SR

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

Verapamil SR 120 mg DRUG

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

Also known as: VeraHEXAL KHK 120 mg, Isoptin retard 120 mg

Verapamil SR

Placebo DRUG

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

Also known as: Matching Placebo for Verapamil SR 120 mg

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Have given written informed consent
• Age ≥18 and \<45 at consent
• Must have a diagnosis of T1D of within 6 weeks duration at screening (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

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Graz: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (22)

Medical University of Graz, Department of Internal Medicine Division of Endocrinology and Metabolism

Graz, Styria, 8010, Austria

Location

Universitair Ziekenhuis Brussel

Brussels, Belgium

Location

Université Libre de Bruxelles/ Hôpital Erasme

Brussels, Belgium

Location

Universitair Ziekenhuis Antwerpen

Edegem, Belgium

Location

Katholieke Universiteit Leuven

Leuven, Belgium

Location

Institut National de la Santé et de la Recherche Médicale

Paris, France

Location

HKA Hannover

Hanover, Germany

Location

Universität Ulm

Ulm, Germany

Location

Università Vita-Salute San Raffaele

Milan, Italy

Location

Università degli Studi di Siena

Siena, Italy

Location

Queen Elizabeth Hospital

Birmingham, United Kingdom

Location

Southmead Hospital

Bristol, United Kingdom

Location

Addenbrokes Hospital

Cambridge, United Kingdom

Location

University Hospital of Wales

Cardiff, United Kingdom

Location

NHS Greater Glasgow and Clyde-Queen Elizabeth University Hospital, Department of Diabetes

Glasgow, United Kingdom

Location

Bart's Hospital QMUL

London, United Kingdom

Location

Guy's Hospital

London, United Kingdom

Location

Queens Medical Centre

Nottingham, United Kingdom

Location

John Radcliffe Hospital

Oxford, United Kingdom

Location

OCDEM, John Radcliffe Hospital

Oxford, United Kingdom

Location

Royal Hallamshire Hospital

Sheffield, United Kingdom

Location

Singleton Hospital

Swansea, United Kingdom

Location

Related Publications (12)

• Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014 Jan 4;383(9911):69-82. doi: 10.1016/S0140-6736(13)60591-7. Epub 2013 Jul 26.

  PMID: 23890997 BACKGROUND

• DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018 Jun 16;391(10138):2449-2462. doi: 10.1016/S0140-6736(18)31320-5.

  PMID: 29916386 BACKGROUND

• Lachin JM, McGee P, Palmer JP; DCCT/EDIC Research Group. Impact of C-peptide preservation on metabolic and clinical outcomes in the Diabetes Control and Complications Trial. Diabetes. 2014 Feb;63(2):739-48. doi: 10.2337/db13-0881. Epub 2013 Oct 2.

  PMID: 24089509 BACKGROUND

• Sorensen JS, Johannesen J, Pociot F, Kristensen K, Thomsen J, Hertel NT, Kjaersgaard P, Brorsson C, Birkebaek NH; Danish Society for Diabetes in Childhood and Adolescence. Residual beta-Cell function 3-6 years after onset of type 1 diabetes reduces risk of severe hypoglycemia in children and adolescents. Diabetes Care. 2013 Nov;36(11):3454-9. doi: 10.2337/dc13-0418. Epub 2013 Aug 29.

  PMID: 23990516 BACKGROUND

• Ovalle F, Grimes T, Xu G, Patel AJ, Grayson TB, Thielen LA, Li P, Shalev A. Verapamil and beta cell function in adults with recent-onset type 1 diabetes. Nat Med. 2018 Aug;24(8):1108-1112. doi: 10.1038/s41591-018-0089-4. Epub 2018 Jul 9.

  PMID: 29988125 BACKGROUND

• Yin T, Kuo SC, Chang YY, Chen YT, Wang KK. Verapamil Use Is Associated With Reduction of Newly Diagnosed Diabetes Mellitus. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2604-2610. doi: 10.1210/jc.2016-3778.

  PMID: 28368479 BACKGROUND

• Cooper-Dehoff R, Cohen JD, Bakris GL, Messerli FH, Erdine S, Hewkin AC, Kupfer S, Pepine CJ; INVEST Investigators. Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]). Am J Cardiol. 2006 Oct 1;98(7):890-4. doi: 10.1016/j.amjcard.2006.04.030. Epub 2006 Aug 7.

  PMID: 16996868 BACKGROUND

• Chen J, Saxena G, Mungrue IN, Lusis AJ, Shalev A. Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes. 2008 Apr;57(4):938-44. doi: 10.2337/db07-0715. Epub 2008 Jan 2.

  PMID: 18171713 BACKGROUND

• Xu G, Chen J, Jing G, Shalev A. Preventing beta-cell loss and diabetes with calcium channel blockers. Diabetes. 2012 Apr;61(4):848-56. doi: 10.2337/db11-0955.

  PMID: 22442301 BACKGROUND

• Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013 May;36(5):1384-95. doi: 10.2337/dc12-2480. Epub 2013 Apr 15.

  PMID: 23589542 BACKGROUND

• Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. doi: 10.2337/diacare.28.5.1245. No abstract available.

  PMID: 15855602 BACKGROUND

• Wych J, Brunner M, Stenson R, Chmura PJ, Danne T, Mander AP, Mathieu C, Dayan C, Pieber TR. Investigating the effect of verapamil on preservation of beta-cell function in adults with newly diagnosed type 1 diabetes mellitus (Ver-A-T1D): protocol for a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. BMJ Open. 2024 Nov 28;14(11):e091597. doi: 10.1136/bmjopen-2024-091597.

  PMID: 39613428 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Verapamil

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phenethylamines; Ethylamines; Amines; Organic Chemicals

Study Officials

• Thomas R. Pieber, MD, Prof

  Medical University of Graz

  PRINCIPAL INVESTIGATOR

• Dayan Colin, MD, Prof

  Cardiff University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 21, 2020
• First Posted: September 10, 2020
• Study Start: February 8, 2021
• Primary Completion: April 23, 2025
• Study Completion: April 17, 2026
• Last Updated: May 20, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Beginning after publication of the primary results papers reporting the prespecified endpoints described in the Statistical analysis plan. (no end date)
• Access Criteria: Researchers who provide a methodologically sound proposal - and if needed an ethics approval for the project will be able to access the IPD and supporting information. Access will be provided for research projects to achieve aims in the approved proposal at the level of individual data including for meta-analyses. Proposals should be directed to the Chief-Investigator (who may consult with other members of the trial team).To gain access, data requestors will need to sign a data access agreement. Data will be made available directly to the person requesting the data.

Locations

AU (1); BE (4); GB (12); FR (1); IT (2); DE (2)