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Trial record 1 of 10 for:    verapamil and diabetes
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Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

This study is currently recruiting participants.
Verified November 2017 by Fernando Ovalle, University of Alabama at Birmingham
Sponsor:
ClinicalTrials.gov Identifier:
NCT02372253
First Posted: February 26, 2015
Last Update Posted: November 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Fernando Ovalle, University of Alabama at Birmingham
  Purpose
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 Intervention Phase
Type 1 Diabetes Mellitus Drug: Verapamil Drug: Placebo Phase 2

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Fernando Ovalle, University of Alabama at Birmingham:

Primary Outcome Measures:
  • Functional Beta Cell Mass [ Time Frame: 12 months ]
    Functional Beta Cell Mass as determined by the change in 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:
  • Exogenous insulin requirements [ Time Frame: 12 months ]
    Exogenous insulin requirements as assessed by mean daily insulin use over 7 consecutive days is a surrogate inverse marker of residual beta cell function.

  • Exogenous insulin requirements [ Time Frame: 12 weeks ]
    Exogenous insulin requirements as assessed by mean daily insulin use over 7 consecutive days is a surrogate inverse marker of residual beta cell function.

  • Glycemic control [ Time Frame: 12 months ]
    Glycemic control, as measured by HbA1c and subject-reported hypoglycemic events, and hypoglycemic and hyperglycemic excursions. 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.

  • Glycemic control [ Time Frame: 12 weeks ]
    Glycemic control, as measured by HbA1c and subject-reported hypoglycemic events, and hypoglycemic and hyperglycemic excursions. 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:
  • TXNIP expression in peripheral blood monocytes (PBMCs) [ Time Frame: 12 weeks and 12 months ]
    TXNIP expression in peripheral blood monocytes (PBMCs). Since TXNIP is ubiquitously expressed and we already have observed that verapamil is capable of downregulating TXNIP in non-pancreatic tissues we will use this measurement as a marker of the verapamil effects

  • 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 assessment of putative beta cell markers, e.g. proinsulin/C-peptide ratio, demethylated insulin DNA 45, and microRNAs, e.g. miR-204 (46 and our unpublished ongoing work).

  • Cytokines [ Time Frame: 12 weeks and 12 months ]

    Cytokines. TXNIP has been shown to promote inflammasome activation 47 and as such the production of IL-1β. We will therefore primarily analyze the serum levels of IL-1β representing a potential additional measure of TXNIP function and an important factor involved in T1D.

    Cytokines. TXNIP has been shown to promote inflammasome activation 47 and as such the production of IL-1β. We will therefore primarily analyze the serum levels of IL-1β representing a potential additional measure of TXNIP function and an important factor involved in T1D.


  • Glucose during MMTT [ Time Frame: 12 weeks and 12 months ]
    Glucose during MMTT. In addition to C-peptide measurements during MMTTs, we will also calculate the AUC for the associated glucose levels. Together with the C-peptide this will provide an indication for any potential effects on insulin sensitivity and glucose control

  • Glycemic Variability [ Time Frame: 12 weeks and 12 months ]
    Glycemic Variability. We will determine this by calculating the MAGE (mean amplitude glycemic excursions) calculated by 7-point self-measured blood glucose and by CGMS. These data will provide additional information about the effects of verapamil on glucose excursions and a detailed assessment of glucose homeostasis in addition to the more crude measurement by HbA1C

  • Hypoglycemic event rate [ Time Frame: 12 weeks and 12 months ]
    Hypoglycemic event rate. We will determine this by collecting subject diaries and analyzing CGMS data


Estimated Enrollment: 52
Study Start Date: February 2015
Estimated Study Completion Date: July 2019
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Verapamil
26 subjects fulfilling 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
26 subjects fulfilling 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

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

Information from the National Library of Medicine

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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, 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)
  Contacts and Locations
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


Contacts
Contact: Tiffany H Grimes, RN 205-934-4112 tdgrimes1@uabmc.edu
Contact: Kentress Davison 205-934-4112 kdavison@uab.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35233
Contact: Tiffany H Grimes, RN    205-934-4112    tdgrimes1@uabmc.edu   
Contact: Kentress Davison    205-934-4112    kdavison@uab.edu   
Principal Investigator: Anath Shalev, MD         
Principal Investigator: Fernando Ovalle, MD         
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
  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 Submitted: February 20, 2015
First Posted: February 26, 2015
Last Update Posted: November 30, 2017
Last Verified: November 2017

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