Verapamil for Beta Cell Survival Therapy in Type 1 Diabetes

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.

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)