Verapamil SR in Adults With Type 1 Diabetes

Diabetes Mellitus, Type 1 Clinical Trial

— Ver-A-T1D  

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04545151
• Other study ID #: Ver-A-T1D
• Secondary ID: 2020-000435-45
• Status: Recruiting
• Phase: Phase 2
• Start date: February 8, 2021
• Est. completion date: April 2026

Study information

• Verified date: November 2023
• Source: Medical University of Graz
• Contact: Martina Brunner, MSc
• Phone: +43 316 385
• Email: martina.brunner[@]medunigraz.at
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 138
• Est. completion date: April 2026
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

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
• 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

Locations

Country	Name	City	State
Austria	Medical University of Graz, Department of Internal Medicine Division of Endocrinology and Metabolism	Graz	Styria
Austria	Krankenhaus der Barmherzigen Brüder Linz	Linz
Austria	Klinik Hietzing Wiener Gesundheitsverbund	Vienna
Austria	Klinik Landstraße Wiener Gesundheitsverbund	Vienna
Belgium	Universitair Ziekenhuis Brussel	Brussels
Belgium	Université Libre de Bruxelles/ Hôpital Erasme	Brussels
Belgium	Universitair Ziekenhuis Antwerpen	Edegem
Belgium	Katholieke Universiteit Leuven	Leuven
France	Institut National de la Santé et de la Recherche Médicale	Paris
Germany	HKA Hannover	Hanover
Germany	Universität Ulm	Ulm
Italy	Università Vita-Salute San Raffaele	Milano
Italy	Università degli Studi di Siena	Siena
Poland	Slaski Uniwersytet Medyczny w Katowicach	Katowice
United Kingdom	Queen Elizabeth Hospital	Birmingham
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Addenbrokes Hospital	Cambridge
United Kingdom	University Hospital of Wales	Cardiff
United Kingdom	NHS Tayside - Ninewells Hospital, NRS Diabetes - Diabetes Support Unit	Dundee
United Kingdom	NHS Greater Glasgow and Clyde-Queen Elizabeth University Hospital, Department of Diabetes	Glasgow
United Kingdom	Bart's Hospital QMUL	London
United Kingdom	Guy's Hospital	London
United Kingdom	NHs-Manchester Royal Infirmary, Diabetic Medicine	Manchester
United Kingdom	Queens Medical Centre	Nottingham
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	OCDEM, John Radcliffe Hospital	Oxford
United Kingdom	Royal Hallamshire Hospital	Sheffield
United Kingdom	Singleton Hospital	Swansea

Sponsors (2)

Lead Sponsor	Collaborator
Medical University of Graz	Juvenile Diabetes Research Foundation

Countries where clinical trial is conducted

Austria,  Belgium,  France,  Germany,  Italy,  Poland,  United Kingdom, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Quality of life: DTSQs questionnaire	Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Diabetes Treatment Satisfaction Questionnaire - DTSQs	At week 4 , month 6 and month 12.
Other	Quality of life: DTSQc questionnaire	Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Diabetes Treatment Satisfaction Questionnaire - DTSQc	At month 12
Other	Quality of life: ADDQoL questionnaire	Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): · the Audit of Diabetes Dependent Quality of Life - ADDQoL	At month 6 and at month 12
Other	Quality of life: HypoFear questionnaire	Patients' quality of life will be assessed by participant-reported outcome measures (PROMS): the Hypoglycaemia Fear Survey - HFS	At week 4 , at month 6 and at month 12
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	DKA	Number of treatment emergent episodes of diabetic ketoacidosis	Baseline to 12 months
Secondary	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
Secondary	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
Secondary	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)