Long-term Verapamil Hydrochloride Therapy in Type 1 Diabetes Mellitus: A Multi-Center Study on Beta-Cell Function Preservation

The primary objective of this study is to evaluate the change in **beta-cell function** in patients with type 1 diabetes mellitus, as measured by the C-peptide response to a mixed-meal tolerance test (MMTT) at baseline and after 24 months of treatment with 360 mg of Verapamil SR administered orally once daily. This assessment is crucial for understanding the potential of Verapamil SR in preserving beta-cell function, which is vital for insulin production and glucose regulation in type 1 diabetes patients.

Secondary objectives include:

• Determining changes in beta-cell function measured by C-peptide response to MMTT at baseline and after 6, 12, and 18 months.
• Assessing changes in HbA1c levels at baseline and after 6, 12, 18, and 24 months.
• Evaluating changes in insulin requirements, measured as the total daily insulin dose in units per kg body weight, at baseline and after 6, 12, 18, and 24 months.
• Determining the number of severe hypoglycemic and ketoacidosis episodes in adults with type 1 diabetes.
• Assessing the safety of short-term (weekly) titration of Verapamil SR from 120 mg to 360 mg over the first 3 weeks.
• Evaluating safety parameters, including vital signs and ECG, over 24 months in adults with type 1 diabetes receiving 360 mg of Verapamil SR daily.

The clinical trial involves a total of **21 participants** diagnosed with **Type 1 diabetes mellitus (T1D)**. The study population includes both male and female subjects, aged **18 years and older**, who are not considered part of a vulnerable population. Participants were selected based on their eligibility for Visit 6 of the Ver-A-T1D trial, either on active treatment with Placebo or Verapamil SR, or having completed Visit 5 of the Ver-A-T1D study with plans to continue to Visit 6. All participants have provided written informed consent and have fasting C-peptide levels of at least 50 pmol/L. The trial does not specify any particular lifestyle considerations such as diet or physical activity for the participants.

The clinical trial is designed as an open-label, multi-centre study to evaluate the long-term effects of **verapamil hydrochloride** on beta-cell function in adults diagnosed with Type 1 diabetes mellitus. The trial follows a **randomized, controlled** methodology, with participants receiving 360 mg of verapamil SR orally once daily. The primary objective is to assess changes in beta-cell function, measured by C-peptide response to a mixed-meal tolerance test (MMTT) at baseline and after 24 months of therapy. Secondary endpoints include changes in blood glucose control, insulin requirements, and the incidence of severe hypoglycemic episodes and diabetic ketoacidosis.

The trial is expected to last approximately 24 months, with participant involvement beginning at the screening visit and concluding at the end-of-study visit. The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits at 6, 12, 18, and 24 months. These visits are designed to monitor the primary and secondary endpoints, as well as to ensure participant safety through assessments of adverse events, vital signs, ECG, and laboratory safety parameters.

Participants are expected to be involved in the study for the full 24-month duration unless conditions arise that necessitate early termination. Such conditions may include significant adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of verapamil SR in preserving beta-cell function in Type 1 diabetes patients, contributing valuable insights into long-term diabetes management strategies.

The clinical trial involves the administration of **Verapamil Hydrochloride** in various pharmaceutical forms, primarily focusing on its effects in patients with Type 1 diabetes mellitus. The experimental medication, **Vera-Til SR 120mg Tablets**, is a **modified-release tablet** containing **verapamil hydrochloride** as the active substance. It is administered orally with a maximum daily dose of 360 mg, and the treatment period extends up to 24 months. The tablets are produced by Tillomed Laboratories Ltd and are not formulated for pediatric use.

Another experimental medication used in the trial is **ISOPTINE L.P. 240 mg**, a **prolonged-release tablet** also containing **verapamil hydrochloride**. This formulation is administered orally with the same maximum daily dose of 360 mg over a 24-month period. The product is manufactured by Viatris Medical and is similarly not intended for pediatric patients.

The trial also includes **Verapamil 120 ret - 1A-Pharma 120 mg Retardtabletten**, a **prolonged-release tablet** form of **verapamil hydrochloride**. This medication is administered orally, with a maximum daily dose of 360 mg, and the treatment duration is up to 24 months. It is produced by 1 A Pharma GmbH.

**VeraHEXAL® KHK 120 mg retard, Retardtabletten** is another **prolonged-release tablet** containing **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg for up to 24 months. This product is manufactured by HEXAL AG.

**Isoptin® retard 120 mg - Filmtabletten** is a **film-coated tablet** containing **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg over a 24-month period. The product is manufactured by Viatris Austria GmbH.

**LODIXAL 240 mg, Tabletten met verlengde afgifte** is a **prolonged-release tablet** form of **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg, and the treatment period is up to 24 months. This product is manufactured by Viatris Healthcare.

**VERAPAMIL DOC Generici 120 mg capsule rigide a rilascio prolungato** is a **prolonged-release capsule, hard**, containing **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg for up to 24 months. The product is manufactured by DOC Generici S.R.L.

**VERAPAMIL HEXAL 120 mg compresse a rilascio prolungato** is a **prolonged-release tablet** containing **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg over a 24-month period. This product is manufactured by Sandoz S.P.A.

**Isoptin® KHK retard 120 mg, Retardtabletten** is another **prolonged-release tablet** form of **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg, and the treatment duration is up to 24 months. The product is manufactured by Viatris Healthcare GmbH.

**Half Securon SR** is a **modified-release tablet** containing **verapamil hydrochloride Ph. Eur.**. It is administered orally with a maximum daily dose of 360 mg for up to 24 months. This product is manufactured by Mylan Products Limited.

**Verapamil Hennig 120 mg retard Retardtabletten** is a **prolonged-release tablet** containing **verapamil hydrochloride**. It is administered orally with a maximum daily dose of 360 mg over a 24-month period. The product is manufactured by Hennig Arzneimittel GmbH & Co. KG.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen. The trial does not include any non-experimental treatments such as placebo or comparator treatments. The primary objective is to assess the change in beta-cell function in patients with Type 1 diabetes mellitus, as measured by C-peptide response to a mixed-meal tolerance test at baseline and after 24 months of treatment.

Efficacy in this clinical trial will be assessed by evaluating the change in **C-peptide** levels, which serve as a marker of **beta-cell** function in patients with Type 1 diabetes mellitus. The primary endpoint is the change over time in the C-peptide area under the curve (C-pep AUC % change) in adults receiving 360 mg of oral Verapamil daily. This will be measured using a mixed-meal tolerance test (MMTT) at baseline (V-1) and after 24 months of therapy (V8).

Secondary endpoints include changes in C-peptide AUC % at 6, 12, and 18 months (V5 to V7), changes in blood glucose control as assessed by HbA1C at baseline and at 6, 12, 18, and 24 months (V5 to V8), and changes in insulin requirements measured as the total daily insulin dose in units per kg body weight at the same time points. Additionally, the number of treatment-emergent severe hypoglycemic episodes and episodes of diabetic ketoacidosis (DKA) will be recorded. Safety assessments will include adverse events, vital signs, ECG, and laboratory safety parameters, evaluated at baseline and at 6, 12, 18, and 24 months of therapy.