Type 1 Diabetes Mellitus
Conditions
Keywords
verapamil, type 1 diabetes, diabetes, beta cells, beta cell function, insulin
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).
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.
Interventions
DRUGVerapamil
DRUGPlacebo
Sponsors
Juvenile Diabetes Research Foundation
University of Alabama at Birmingham
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional Beta Cell Mass | 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
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Exogenous Insulin Requirements | 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. |
| HbA1C | 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. |
| HbA1c | 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. |
| Hypoglycemic Events | 12 months | Glycemic control, as measured by hypoglycemic events. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Beta Cell Markers | 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. |
Countries
United States
Participant flow
Pre-assignment details
32 subjects with recent-onset Type 1 diabetes were screened for autoantibodies and MMTT-stimulated C-peptide. Five were not eligible for randomization (3 were antibody negative and 2 were C-peptide negative). One additional participant declined.
Participants by arm
| Arm | Count |
|---|---|
| Verapamil Verapamil SR 360mg Daily | 11 |
| Placebo Matching Placebo | 13 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non Compliance | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Verapamil | Placebo |
|---|---|---|---|
| Age, Continuous | 30.3 years STANDARD_DEVIATION 2.2 | 32.3 years STANDARD_DEVIATION 2.3 | 28.3 years STANDARD_DEVIATION 2.1 |
| Body Mass Index | 23.25 kg/m^2 STANDARD_DEVIATION 0.75 | 24.4 kg/m^2 STANDARD_DEVIATION 0.8 | 22.1 kg/m^2 STANDARD_DEVIATION 0.7 |
| Fasting Plasma Glucose | 6.65 mmol/L STANDARD_DEVIATION 1 | 6.4 mmol/L STANDARD_DEVIATION 1 | 6.9 mmol/L STANDARD_DEVIATION 1 |
| HbA1C | 6.7 % STANDARD_DEVIATION 0.4 | 6.6 % STANDARD_DEVIATION 0.4 | 6.8 % STANDARD_DEVIATION 0.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 23 Participants | 10 Participants | 13 Participants |
| Region of Enrollment United States | 24 participants | 11 participants | 13 participants |
| Sex: Female, Male Female | 10 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 14 Participants | 6 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 7 / 11 | 2 / 13 |
| serious Total, serious adverse events | 0 / 11 | 0 / 13 |
Outcome results
Primary
Functional Beta Cell Mass
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).
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | Functional Beta Cell Mass | 0.74 nmol/L | Standard Error 0.07 |
| Placebo | Functional Beta Cell Mass | 0.46 nmol/L | Standard Error 0.08 |
Secondary
HbA1c
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | HbA1c | 6.0 Percent | Standard Error 0.1 |
| Placebo | HbA1c | 6.6 Percent | Standard Error 0.3 |
Secondary
HbA1C
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | HbA1C | 6.4 Percent | Standard Error 0.2 |
| Placebo | HbA1C | 6.9 Percent | Standard Error 0.3 |
Secondary
Hypoglycemic Events
Glycemic control, as measured by hypoglycemic events.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | Hypoglycemic Events | 0.55 events per month | Standard Error 0.31 |
| Placebo | Hypoglycemic Events | 2.72 events per month | Standard Error 0.86 |
Secondary
Percent Change From Baseline in Exogenous Insulin Requirements
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.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | Percent Change From Baseline in Exogenous Insulin Requirements | 27.0 Percent Change | Standard Error 15.6 |
| Placebo | Percent Change From Baseline in Exogenous Insulin Requirements | 69.8 Percent Change | Standard Error 7.9 |
Secondary
Percent Change From Baseline in Exogenous Insulin Requirements
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.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Verapamil | Percent Change From Baseline in Exogenous Insulin Requirements | 5.9 Percent Change | Standard Error 11.4 |
| Placebo | Percent Change From Baseline in Exogenous Insulin Requirements | 26.0 Percent Change | Standard Error 9.5 |
Other Pre-specified
Beta Cell Markers
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.
Time frame: 12 weeks and 12 months