Evaluation of Verapamil Hydrochloride on Beta-Cell Function Preservation in Adults with Newly Diagnosed Type 1 Diabetes Mellitus
- Trial ID
- 2023-506545-27-01
- Protocol
- Ver-A-T1D
- Sponsor
- Medical University Of Graz
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate 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 in adult subjects with newly diagnosed type 1 diabetes mellitus. This is clinically relevant as it assesses the preservation of beta-cell function, which is crucial for maintaining endogenous insulin production and potentially reducing the need for exogenous insulin therapy.
Secondary objectives include:
- Determining the effects of 360mg Verapamil SR on fasting C-peptide and Dried Blood Spot (DBS) C-peptide measurements over time.
- Evaluating the impact on HbA1c, daily total insulin dose, and continuous glucose monitoring (CGM) time in range.
- Assessing the effects on other biomarkers related to immunological changes and beta-cell death and survival.
- Evaluating the safety profile, including vital signs and ECG, of 360mg Verapamil SR administered orally once daily.
Participants
The clinical trial involves a total of **56 participants** diagnosed with **Type 1 Diabetes Mellitus**. The study population includes both male and female subjects, aged between 18 and 44 years, who are generally in good health aside from their recent diagnosis of Type 1 Diabetes. Participants were selected based on specific criteria, including a diagnosis of Type 1 Diabetes within six weeks of screening and the presence of at least one diabetes-related autoantibody. Additionally, participants must have fasting C-peptide levels of at least 100 pmol/L and be willing to adhere to intensive diabetes management. The trial does not include any vulnerable populations. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria, but participants are expected to comply with the study's management protocols.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, parallel-group, multi-center study** aimed at evaluating the effect of Verapamil SR on the preservation of beta-cell function in adult subjects with newly diagnosed **Type 1 diabetes mellitus**. The primary objective is to assess changes in stimulated C-peptide response during the first two hours of a mixed meal tolerance test (MMTT) at baseline and after 12 months of treatment with 360 mg Verapamil SR administered orally once daily compared to placebo. The trial is expected to last until April 2026, with an estimated recruitment start date in February 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, recent diagnosis of Type 1 diabetes, presence of diabetes-related autoantibodies, and fasting C-peptide levels. Following successful screening, participants will be randomized to receive either Verapamil SR or placebo. Study visits will occur at baseline and at 3, 6, 9, and 12 months to monitor primary and secondary endpoints, including C-peptide response, proinsulin, insulin, and other metabolic markers. The end-of-study visit will coincide with the 12-month assessment, where final evaluations will be conducted.
The expected length of participant involvement is 12 months, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that necessitate discontinuation. The trial will adhere to rigorous methodological standards to ensure the validity and reliability of the findings, contributing valuable insights into the management of Type 1 diabetes.
Treatment
The clinical trial involves the administration of **VeraHEXAL KHK 120 mg retard Retardtabletten**, which contains the active substance **verapamil hydrochloride**. This medication is formulated as a **prolonged-release tablet** and is intended for **oral use**. The dosage regimen for the trial specifies a maximum daily dose of 360 mg, administered once daily. The treatment period is set for a maximum of 12 months. The medication is provided by HEXAL AG and is used as a test product in this double-blind study. To maintain the study's blinding, the investigational medicinal product (IMP) will be modified by re-packaging.
The study also includes a **placebo** control, which is designed to match the **VeraHEXAL KHK 120 mg retard Retardtabletten** in appearance and administration. The placebo is used to ensure the study's double-blind design, allowing for an unbiased comparison of the effects of the active treatment versus no active treatment. The placebo is administered in the same manner as the active medication, with a once-daily oral dosage, and is also provided for a maximum treatment period of 12 months. The use of a placebo control is critical in assessing the true efficacy of the active treatment by providing a baseline for comparison.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the changes in **stimulated C-peptide** response during the first two hours of a mixed meal tolerance test (MMTT). The primary endpoint is the area under the stimulated C-peptide response curve after 12 months of therapy with 360 mg Verapamil SR administered orally once daily, compared to placebo. Secondary endpoints include the area under the stimulated C-peptide response curve at 3, 6, and 9 months, as well as other parameters such as proinsulin, insulin, Pro-IAPP, and proglucagon secretion during the first two hours of the MMTT at baseline and at 3, 6, 9, and 12 months.
Additional secondary endpoints include fasting C-peptide levels after 12 months, DBS C-peptide measurements at all observation times, and changes in HbA1c from baseline to 12 months. The trial will also monitor the number of treatment-emergent severe hypoglycemic episodes and episodes of diabetic ketoacidosis (DKA), changes in insulin requirements from baseline to 12 months, and changes in type 1 diabetes-associated autoantibodies. Continuous glucose monitoring (CGM) metrics such as time in range, time above range, and time below range will also be evaluated. The efficacy assessments will be conducted at specified time points throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on beta-cell function preservation in adult subjects with newly diagnosed type 1 diabetes mellitus.
Inclusion and Exclusion Criteria
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 of the following 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 persistent 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 08 Feb 2021 | 22 |
 Belgium | Not Recruiting | 08 Feb 2021 | 12 |
 France | Not Recruiting | 08 Feb 2021 | 6 |
 Germany | Not Recruiting | 08 Feb 2021 | 12 |
 Italy | Not Recruiting | 08 Feb 2021 | 12 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VeraHEXAL KHK 120 mg retard Retardtabletten | Test | RETARDTABLETTEN | ORAL USE | 360 | 12 | PRD828130 |
Placebo to VeraHEXAL KHK 120 mg retard Retardtabletten | Placebo | N/A | — | — | — | N/A |