Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

NCT ID: NCT02372253

Last Updated: 2020-02-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 32 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-28
• Study Completion Date: 2019-12-31

Brief Summary

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).

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.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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

Group Type: EXPERIMENTAL

Verapamil

Intervention Type: DRUG

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Verapamil

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Fernando Ovalle

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Fernando Ovalle, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Anath Shalev, MD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

3-SRA-2014-302-M-R

Identifier Type: -

Identifier Source: org_study_id