Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

• ClinicalTrials.gov Identifier: NCT02372253
• Recruitment Status: Active, not recruiting
• First Posted: February 26, 2015
• Results First Posted: January 30, 2019
• Last Update Posted: January 30, 2019
• Sponsor: University of Alabama at Birmingham
• Collaborator: Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): Fernando Ovalle, University of Alabama at Birmingham

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Verapamil; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Repurposing of Verapamil as a Beta Cell Survival Therapy in Type 1 Diabetes
• Study Start Date: February 2015
• Actual Primary Completion Date: December 2017
• Estimated Study Completion Date: December 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Functional Beta Cell Mass [ Time Frame: 12 months ]
   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).

Secondary Outcome Measures :

1. Percent Change From Baseline in Exogenous Insulin Requirements [ Time Frame: 12 months ]
   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.
2. Percent Change From Baseline in Exogenous Insulin Requirements [ Time Frame: 12 weeks ]
   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.
3. HbA1C [ Time Frame: 12 months ]
   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.
4. HbA1c [ Time Frame: 12 weeks ]
   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.
5. Hypoglycemic Events [ Time Frame: 12 months ]
   Glycemic control, as measured by hypoglycemic events.

Other Outcome Measures:

1. Beta Cell Markers [ Time Frame: 12 weeks and 12 months ]
   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.

Eligibility Criteria

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

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)

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham

Birmingham, Alabama, United States, 35233

Sponsors and Collaborators

University of Alabama at Birmingham

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 Documents (Full-Text)

Documents provided by Fernando Ovalle, University of Alabama at Birmingham:

Study Protocol and Statistical Analysis Plan  [PDF] November 26, 2018

More Information

• Responsible Party: Fernando Ovalle, Principal Investigator, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT02372253 History of Changes
• Other Study ID Numbers: 3-SRA-2014-302-M-R
• First Posted: February 26, 2015
• Results First Posted: January 30, 2019
• Last Update Posted: January 30, 2019
• Last Verified: January 2019

Keywords provided by Fernando Ovalle, University of Alabama at Birmingham:

verapamil; type 1 diabetes; diabetes; beta cells; beta cell function; insulin

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Verapamil; Anti-Arrhythmia Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents