Verapamil In Preclinical Type 1 Diabetes

Condition(s) studied

Investigational drug(s) / intervention(s)

Verapamil 120 Mg/24 Hours Oral Capsule, Extended Release: The experimental group will start taking an extended-release formulation of verapamil (once a day). The escalation protocol will be adapted as follows: * 30-34 kg: 120 mg/day up to 48 weeks * 35-49 kg: 120 mg/day for 4 weeks, then 240 mg/day up to 48 weeks. * ≥50 kg: 240 mg/day for 4 weeks, then 360 mg/day up to 48 weeks. The dosing regimen adopted in this protocol has been previously reported in a larger study including people in the same age group with new onset clinical T1D. The dose escalation will be based on safety assessment planned at 4 weeks. The commercial medicine (European speciality) will undergo a change in its labelling and secondary packaging so that the active treatment and placebo units are indistinguishable. The primary packaging will remain unchanged.

Placebo: The placebo in the form of white tablets in blister packs of 10 tablets. The external packaging of the drug and placebo will be similar, and the labelling will include an alphanumeric identifier generated during the randomization process.

blood sampling: OGTT with plasma glucose, insulin, C-peptide, and dry blood spot C-peptide, Chromogranin A, proinsulin, incretin secretion, aspartate aminotransferase(AST), aspartate aminotransferase (ALT), hematocrit, creatinine, complete blood count (CBC), betaHCG (human chorionic gonadotropin) for women of childbearing age. Blood collection for immunophenotyping analysis

EKG and cardiological evaluation: For safety assesment, EKG and cardiological evaluation will be completed to quantify safety endpoints (heart-rate, blood pressure and conduction period (PR interval).

Continuous Glucose Monitoring (CGM): In an exploratory analysis, theorical minimal model (OMM) equations will be integrated to calculate insulin sensitivity, as a function of the beta-cell responsivity to glucose and area under CGM signal.

Urine collection: C-peptide and creatinine concentrations

Study summary

Type 1 diabetes (T1D) is preceded by a presymptomatic phase featured by the presence of islet autoantibodies (aAbs) without (Stage 1) or with (Stage 2) dysglycemia. Clinical investigations targeting Stage 1 or Stage 2 disease have been using the time to clinical disease progression (Stage 3) as primary outcome, with a consequent need for relative high numerosity and prolonged follow-up.

Additional hurdles limit the feasibility of disease modifying therapy (DMT) trials for preclinical T1D, including the need for an established screening program able to identify those who might be eligible and the enrolment of relatively large cohorts followed until clinical onset. To overcome these major limitations, our group recently explored the use of mathematical metabolic modelling of beta cell function in the early disease stages of T1D and its ability to quantify the response to treatment. We gathered, for the current proposal, sites with an established screening program for family members of people with T1D. The evidence obtained in our previous experience led to the design of this trial aimed to test the effect of a calcium channel blocker - verapamil - on beta cell function, as quantified through mathematical modelling, in Stage 1 disease. While this drug was previously tested in children and adolescents in the early clinical phases of the disease (Stage 3), it has never been used in Stage 1 disease. Verapamil inhibits beta cell apoptosis in animal models and has been shown to increase C-peptide secretion in adults with recent onset T1D and in youths. We hypothesize that an earlier treatment with verapamil targeting people with Stage 1 disease, whose residual beta cell function is greater than those with Stage 3 disease, may result in prolonged preservation of beta cell functional mass - and, consequently, in delayed clinical progression.

Eligibility

Primary outcome measure(s)

• Beta-cell function index — 48 weeks
  Beta-cell function - measured by disposition index during OGTT - after 48 weeks of treatment.

Trial sites (1)

More Assistance Publique - Hôpitaux de Paris trials in France

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