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Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

Information source: University of Alabama at Birmingham
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Type 1 Diabetes Mellitus

Intervention: Verapamil (Drug); Placebo (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: University of Alabama at Birmingham

Official(s) and/or principal investigator(s):
Fernando Ovalle, MD, Principal Investigator, Affiliation: University of Alabama at Birmingham
Anath Shalev, MD, Principal Investigator, Affiliation: University of Alabama at Birmingham

Overall contact:
Tiffany H Grimes, RN, Phone: 205-934-4112, Email: tdgrimes@uab.edu

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 T1D.

Clinical Details

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

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Functional Beta Cell Mass

Secondary outcome:

Exogenous insulin requirements

Exogenous insulin requirements

Glycemic control

Glycemic control

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). The investigators preliminary specific aims include: #1 Assessment of remaining endogenous beta-cell mass/insulin production as measured by the change from baseline in mixed meal-stimulated C peptide, and by exogenous insulin requirements in verapamil and placebo treated subjects at Week 12 and Month 12. #2 Assessment of glycemic control as measured by mean amplitude glycemic excursions and hypoglycemic event rate (CGMS and subject-reported) and HbA1c at Week 12 and Month 12. #3 Evaluation of non-invasive markers for therapeutic follow-up and beta-cell mass, i. e. TXNIP expression in peripheral blood monocytes at baseline, Week 12 and Month 12, and collection of serum for future assessment of potential beta-cell markers (proinsulin/C-peptide ratio, demethylated insulin DNA, and microRNAs). 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.

Eligibility

Minimum age: 19 Years. Maximum age: 45 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Subjects must meet all of the following criteria:

- Diagnosis of Type 1a Diabetes Mellitus based on ADA Criteria

- Written informed consent obtained from the subject including consent for the use of

research-related health information

- ≥ 19 years of age and ≤ 45 years of age

- < 3 months since T1DM 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, GAD-65, or

IA-2

- Agree to intensive management of diabetes with a HgbA1c goal of < 7. 0% and willing to

wear and insulin pump and 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

- If male and of reproductive potential, willing to use medically acceptable birth

control until 3 months after completion of any Treatment Period, unless the female partner is postmenopausal or surgically sterile

- 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 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, AV block); atrial flutter or fibrillation, and an accessory bypass tract (Wolff-Parkinson- White [WPW] syndrome, Lown-Ganong-Levine syndrome)

Locations and Contacts

Tiffany H Grimes, RN, Phone: 205-934-4112, Email: tdgrimes@uab.edu

University of Alabama at Birmingham, Birmingham, Alabama 35233, United States; Recruiting
Tiffany H Grimes, RN, Phone: 205-934-4112, Email: tdgrimes@uab.edu
Kentress Davison, Phone: 205-934-4112, Email: kdavison@uab.edu
Anath Shalev, MD, Principal Investigator
Fernando Ovalle, MD, Principal Investigator
Additional Information

Starting date: January 2015
Last updated: March 6, 2015

Page last updated: August 23, 2015

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