Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

Repurposing of Verapamil as a Beta Cell Survival Therapy in Type 1 Diabetes

The overall purpose of this trial is to assess the efficacy and safety of using oral verapamil in subjects with recent onset T1D in order to downregulate TXNIP and enhance the patients' endogenous beta cell mass and insulin production. The objectives are therefore to assess parameters of beta cell survival (including new biomarkers), insulin production and glucose control and the feasibility of this approach and thereby provide the basis for future, larger/expanded, longer-term verapamil studies and the off-label use of this approved drug for Type 1 Diabetes (T1D).

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Verapamil

Detailed Description

Loss of pancreatic beta-cell mass is a key factor in T1D, but therapies to halt this process are not available. The investigators have discovered thioredoxin-interacting protein (TXNIP), as a promising target in this regard and have now found that the commonly used anti-hypertensive drug and calcium channel-blocker, verapamil, effectively lowers beta-cell TXNIP expression in rodent beta-cells and human islets, promotes beta-cell survival and rescues mice from T1D. This makes verapamil a potentially attractive drug for T1D, but prospective clinical data are lacking. The investigators primary objective is therefore to conduct a randomized, placebo-controlled, double-blind study of the efficacy and safety of verapamil in adults with recent-onset T1D and to demonstrate that subjects on oral verapamil daily for 12 months will have improved insulin production (as an indirect measure of beta-cell mass).

Results will have major translational implications with potential immediate impact on clinical care, encourage large clinical follow-up trials, evaluate markers of beta cell health and ultimately help develop a novel therapy that enhances the patient's own beta-cell mass and function.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects must meet all of the following criteria:
• Diagnosis of Type 1a Diabetes Mellitus based on American Diabetes Association (ADA) Criteria
• Written informed consent obtained from the subject including consent for the use of research-related health information
• ≥ 18 years of age and ≤ 45 years of age
• < 3 months since T1D was diagnosed
• BMI < 30
• Baseline A1c <10%
• Detectable fasting or stimulated C-peptide level (above the lower limit of detection of the assay)
• C-peptide increase during screening mixed meal tolerance test with a minimal stimulated value of ≥ 0.2 pmol/mL
• Presence of antibodies to at least one of the following antigens: insulin, glutamic acid decarboxylase (GAD)-65, Insulinoma Antigen 2 (IA-2) and Zinc Transporter 8 (ZnT8)
• Agree to intensive management of diabetes with a HgbA1c goal of < 7.0% and willing to wear and insulin pump and Continuous Glucose Monitoring System (CGMS)
• If female, (a) surgically sterile or (b) postmenopausal or (c) if of reproductive potential, willing to use medically acceptable birth control (e.g. female hormonal contraception, barrier methods or sterilization) until 3 months after completion of any Treatment Period
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
• Currently receiving insulin therapy
• Willing to forego other forms of experimental treatment during the study

Exclusion Criteria:

• Subjects must have none of the following:
• Any medical condition that, in the opinion of the investigator, would interfere with safe completion of the trial
• Pregnant females or lactating females who intend to provide their own breast milk to the baby during the study
• Current therapy with Glucagon-like peptide (GLP)-1 receptor agonists, pramlintide, or any other agents that might be thought to potentially stimulate pancreatic beta cell regeneration or insulin secretion
• Current treatment with oral antidiabetic agents
• Uncompensated heart failure, fluid overload, myocardial infarction or evidence of ischemic heart disease or other serious cardiac disease as described in New York Heart Association (NYHA) Class III or IV criteria within the 12 weeks before randomization
• History of epilepsy, cancer, cystic fibrosis, sickle cell anemia, neuropathy, peripheral vascular disease or cerebrovascular disease
• Untreated hypothyroidism or active Graves' disease with hyperthyroidism
• Treatment with systemic glucocorticoid therapy by oral, intravenous (IV), or intramuscular (IM) route within 12 weeks before randomization; patients who are likely to require treatment with corticosteroids during the trial are also excluded
• Evidence of active infection
• Total bilirubin > 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x ULN
• A psychiatric or medical disorder that would prevent giving informed consent
• Hypersensitivity to verapamil or any component of the formulation; known left ventricular dysfunction; hypotension (systolic pressure <90 mm Hg); PR interval prolongation on EKG or any bradyarrhythmia (e.g. sick sinus syndrome, Anterior Ventral (AV) block); atrial flutter or fibrillation, and an accessory bypass tract (Wolff-Parkinson- White (WPW) syndrome, Lown-Ganong-Levine syndrome)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Verapamil; 13-26 subjects with Type 1 Diabetes meeting the inclusion criteria will be randomly assigned to receive daily oral verapamil for 12 months. The initial dose of verapamil will be 120 mg daily, and this will be advanced if tolerated to a maximum dose of 360 mg daily. The verapamil tablets will be encapsulated to match the placebo capsules	Drug: Verapamil
Placebo Comparator: Placebo; 13-26 subjects with Type 1 Diabetes meeting the inclusion criteria will be randomly assigned to receive daily oral placebo for 12 months. The initial dose of placebo will be 120 mg daily, and this will be advanced if tolerated to a maximum dose of 360 mg daily. The placebo tablets will be encapsulated to match the verapamil capsules	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Beta Cell Mass	Functional Beta Cell Mass as determined by the area under the curve (AUC) from a 2-hour Mixed Meal-Stimulated C-peptide after daily verapamil for 12 months. A greater improvement in insulin production (as an indirect measure of beta cell mass) in subjects receiving verapamil as compared to those receiving placebo would provide an indication of the efficacy of this intervention. The C-peptide AUC (0-120 min) was calculated by using the trapezoidal rule and was divided by the time of the test to obtain the mean AUC (in nmol/L).	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Exogenous Insulin Requirements	Percent change in exogenous insulin requirements over the last 7-14 consecutive days at 12 months. This will be assessed as a surrogate inverse marker of residual beta cell function.	12 months
Percent Change From Baseline in Exogenous Insulin Requirements	Percent change in exogenous insulin requirements over the last 7-14 consecutive days at 12 weeks. This will be assessed as a surrogate inverse marker of residual beta cell function.	12 weeks
HbA1C	Glycemic control, as measured by HbA1c. In addition to being an important determinant of residual beta cell function/survival, it also helps reveal a more complete picture of beta cell function.	12 months
HbA1c	Glycemic control, as measured by HbA1c. In addition to being an important determinant of residual beta cell function/survival, it also helps reveal a more complete picture of beta cell function.	12 weeks
Hypoglycemic Events	Glycemic control, as measured by hypoglycemic events.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta Cell Markers	Beta cell markers. We will collect serum at baseline and at Week 12 and Months 6, 9 and 12 for future assessment of putative beta cell markers.	12 weeks and 12 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Fernando Ovalle, MD, University of Alabama at Birmingham; Principal Investigator: Anath Shalev, MD, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: February 20, 2015
• First Submitted That Met QC Criteria: February 25, 2015
• First Posted (Estimate): February 26, 2015

Study Record Updates

• Last Update Posted (Actual): February 5, 2020
• Last Update Submitted That Met QC Criteria: January 22, 2020
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: diabetes; insulin; type 1 diabetes; verapamil; beta cells; beta cell function
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Verapamil
• Other Study ID Numbers: 3-SRA-2014-302-M-R