Clinical trial NCT04545151: Verapamil SR in Adults With Type 1 Diabetes
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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Diabetes Mellitus, Type 1
Keywords: INNODIA
Typ-1 Diabetes
Verapamil
Beta cell
C-peptide
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2020-09-10
Enrollment: 138
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: Inclusion Criteria:

* 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

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

Primary outcomes:
measure: Area under the stimulated C-peptide response curve
timeFrame: At 12 months
Secondary outcomes:
measure: Area under the stimulated C-peptide response curve
timeFrame: At 3, 6, 9 and 24 months
measure: Proinsulin, Insulin, Pro-IAPP and Proglucagon secretion
timeFrame: At baseline and 3, 6, 9 and 12 months
measure: Fasting C-peptide
timeFrame: At 12 months
measure: DBS C-peptide
timeFrame: At baseline, week 4, week 8, and 3, 6, and 9 months
measure: Change in HbA1c
timeFrame: Baseline, 12 and 24 months
measure: Severe hypoglycaemic episodes
timeFrame: Baseline to 12 months
measure: DKA
timeFrame: Baseline to 12 months
measure: Change in insulin requirements
timeFrame: Baseline, 12 and 24 months
measure: Change in T1D associated autoantibodies
timeFrame: Baseline to 12 months
measure: Continous glucose monitoring (CGM)
timeFrame: At Baseline and every 2 weeks prior to each visit (week 4, week 8, and 3, 6, and 9 months)
Other outcomes:
measure: Quality of life: DTSQs questionnaire
timeFrame: At week 4 , month 6 and month 12.
measure: Quality of life: DTSQc questionnaire
timeFrame: At month 12
measure: Quality of life: ADDQoL questionnaire
timeFrame: At month 6 and at month 12
measure: Quality of life: HypoFear questionnaire
timeFrame: At week 4 , at month 6 and at month 12
Locations:
city: Graz
country: Austria
facility: Medical University of Graz, Department of Internal Medicine Division of Endocrinology and Metabolism
state: Styria
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Brussels
country: Belgium
facility: Université Libre de Bruxelles/ Hôpital Erasme
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Leuven
country: Belgium
facility: Katholieke Universiteit Leuven
city: Paris
country: France
facility: Institut National de la Santé et de la Recherche Médicale
city: Hanover
country: Germany
facility: HKA Hannover
city: Ulm
country: Germany
facility: Universität Ulm
city: Milano
country: Italy
facility: Università Vita-Salute San Raffaele
city: Siena
country: Italy
facility: Università degli Studi di Siena
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Addenbrokes Hospital
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow and Clyde-Queen Elizabeth University Hospital, Department of Diabetes
city: London
country: United Kingdom
facility: Bart's Hospital QMUL
city: London
country: United Kingdom
facility: Guy's Hospital
city: Nottingham
country: United Kingdom
facility: Queens Medical Centre
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Oxford
country: United Kingdom
facility: OCDEM, John Radcliffe Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Swansea
country: United Kingdom
facility: Singleton Hospital
Study officials:
affiliation: Medical University of Graz
name: Thomas R. Pieber, MD, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Cardiff University
name: Dayan Colin, MD, Prof
role: PRINCIPAL_INVESTIGATOR
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