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Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

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ClinicalTrials.gov Identifier: NCT02372253
Recruitment Status : Active, not recruiting
First Posted : February 26, 2015
Last Update Posted : February 5, 2018
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Fernando Ovalle, University of Alabama at Birmingham

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 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 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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

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



Primary Outcome Measures :
  1. Functional Beta Cell Mass [ Time Frame: 12 months ]
    Functional Beta Cell Mass as determined by the 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.


Secondary Outcome Measures :
  1. Exogenous insulin requirements [ Time Frame: 12 months ]
    Exogenous insulin requirements as assessed by mean daily insulin use over 7-14 consecutive days. The percent change from baseline will be assessed as a surrogate inverse marker of residual beta cell function.

  2. Exogenous insulin requirements [ Time Frame: 12 weeks ]
    Exogenous insulin requirements as assessed by mean daily insulin use over 7-14 consecutive days. The percent change from baseline will be assessed as a surrogate inverse marker of residual beta cell function.

  3. Glycemic control [ Time Frame: 12 months ]
    Glycemic control, as measured by HbA1c and hypoglycemic events. 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. Glycemic control [ Time Frame: 12 weeks ]
    Glycemic control, as measured by HbA1c and hypoglycemic events. 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.


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.



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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 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 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, IA-2 and ZnT8
  • 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
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02372253


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

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    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018

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
Verapamil
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents