Abnormal Glucose Tolerance, Cystic Fibrosis (CF), Cystic Fibrosis Related Diabetes
Conditions
Keywords
cystic fibrosis related diabetes, mixed meal tolerance test, verapamil, beta cell function, continuous glucose monitoring, abnormal glucose tolerance, cystic fibrosis
Brief summary
The investigators are conducting a pilot open-label pre/post interventional trial in adolescents and adults with cystic fibrosis (CF) and abnormal glucose tolerance or early CF-related diabetes mellitus (CFRD) to assess the safety and efficacy of verapamil on beta cell function and dysglycemia.
Detailed description
Cystic fibrosis-related diabetes (CFRD) is one of the most common non-pulmonary complications of cystic fibrosis (CF) and is associated with reduced pulmonary function, worse nutritional status, earlier mortality, and impaired quality of life. Dysglycemia in CF typically begins with abnormal glucose tolerance (AGT), characterized by impaired first-phase insulin secretion and postprandial hyperglycemia, and may progress over time to CFRD. Insulin therapy is currently the only recommended treatment for CFRD; however, it adds substantial treatment burden to an already medically complex population. At present, there are no approved therapies targeting beta cell dysfunction or aimed at preventing progression from AGT to CFRD in people with CF. The pathophysiology of CFRD is increasingly recognized as being driven primarily by beta cell dysfunction rather than complete beta cell destruction. Although insulin secretion is impaired in CF, beta cell mass is relatively preserved compared with type 1 diabetes mellitus (T1D), and residual endogenous insulin production often persists for many years after CFRD diagnosis. Mechanisms contributing to beta cell dysfunction in CF are believed to include oxidative stress, inflammation, endoplasmic reticulum stress, impaired antioxidant defenses, and islet immune dysregulation. Thioredoxin-interacting protein (TXNIP), a key cellular regulator of oxidative stress, has been implicated in beta cell dysfunction and apoptosis in other forms of diabetes mellitus. Verapamil, a calcium channel blocker commonly used for hypertension and arrhythmias, has been shown to reduce TXNIP expression, decrease inflammatory signaling, and promote beta cell survival. Given the known role of oxidative stress in the CF pancreas and the preservation of residual beta cell function in CFRD, verapamil represents a promising candidate therapy for modifying beta cell dysfunction and improving dysglycemia in CF. However, the effects of verapamil on beta cell function and glucose regulation in people with CF have not previously been studied. This study is a pilot open-label, pre/post interventional trial designed to evaluate the safety, tolerability, and preliminary efficacy of verapamil in adolescents and adults with CF and AGT or early CFRD not currently treated with insulin therapy. Thirty participants aged 14 years and older with genetically confirmed CF, pancreatic insufficiency, and AGT or early CFRD will be enrolled. Following screening and confirmation of glycemic status by oral glucose tolerance testing (OGTT), participants will complete a two-week blinded continuous glucose monitoring (CGM) run-in period to establish baseline glycemia. Participants will then undergo a baseline mixed meal tolerance test (MMTT) to assess beta cell function. Verapamil extended release (ER) therapy will be initiated at 120 mg daily and titrated over approximately six weeks to a target dose of 360 mg daily as tolerated. Participants will continue treatment for six months, after which CGM and MMTT assessments will be repeated. The primary efficacy endpoint is the change from baseline in MMTT-stimulated incremental C-peptide area under the curve (AUC) during the first 30 minutes following mixed meal ingestion, a validated measure of first-phase insulin secretion and beta cell function in CF. Secondary efficacy endpoints include changes in additional MMTT-derived measures of insulin secretion and glucose metabolism, hemoglobin A1c, and CGM-derived measures of dysglycemia including time spent in hyperglycemic and hypoglycemic ranges, average glucose, glucose variability, and coefficient of variation. Safety and tolerability assessments will include monitoring of liver function tests, blood pressure, heart rate, electrocardiograms, pulmonary function tests, weight, hypoglycemia, gastrointestinal symptoms, CFTR modulator levels, adverse events, and medication adherence. The results of this pilot study will provide important preliminary data regarding the feasibility, safety, and potential efficacy of verapamil as a novel therapeutic strategy targeting beta cell dysfunction in CF-related dysglycemia and will help inform the design of future larger randomized clinical trials.
Interventions
Verapamil extended release (ER) will be initiated at a dose of 120mg daily and up-titrated over six weeks to target dose of 360mg daily as tolerated.
Sponsors
Rhode Island Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Pre/post interventional trial
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age 14 years and older 2. Genetically-confirmed diagnosis of cystic fibrosis 3. Clinical diagnosis of pancreatic insufficiency, defined as requiring pancreatic enzyme replacement therapy (PERT) 4. Diagnosis of AGT or CFRD within 3-months of study enrollment 1. AGT is defined as having either a OGTT 2-hour glucose \>140 mg/dL and \<200 mg/dL or OGTT 1-hour glucose \>200 mg/dL 2. CFRD is defined as having a fasting glucose \>126 mg/dL and/or OGTT 2-hour glucose \>200 mg/dL 5. Willing to attempt to maximize verapamil to the goal study dosage of 360 mg PO daily 6. If taking elexacaftor/tezacaftor/ivacaftor (ETI), willing to adjust dosing
Exclusion criteria
1. Severe lung disease indicated by forced expiratory volume in 1 second (FEV1) \<50% predicted on most recent spirometry testing 2. Body mass index (BMI) \<18 kg/m2 3. Weight \<50 kg 4. Current or planned pregnancy within the next 6 months 5. Treatment with IV antibiotics for a CF exacerbation within 1 month 6. Systemic supraphysiologic glucocorticoid use within 1 month 7. Initiation or discontinuation of a CFTR modulator within 3 months (i.e. recent change in CFTR modulator formulation/usage) 8. Current use of insulin, a GLP-1 receptor agonist, or oral anti-diabetic agent 9. Most recent HbA1c \>7% 10. Not taking a CFTR modulator due to genotype-ineligibility 11. Current use of vanzacaftor/tezacaftor/deutivcaftor 12. Known hypersensitivity to verapamil 13. Blood pressure (BP) \<90/60 (adults) or \<5th centile for age and gender (youth) in 2 out of 3 measurements 14. Heart rate (HR) \<60 bpm (adults) or \<2nd centile for age and gender (youth) in 2 out of 3 measurements 15. History of previously diagnosed vasovagal syncopal episodes related to hypotension 16. History of significant cardiac disease (e.g. severe ventricular dysfunction, hypertrophic cardiomyopathy) 17. History of certain arrhythmias (e.g. AV block, accessory pathway such as Wolff-Parkinson-White or Lown-Ganong-Levine syndromes) 18. Abnormal liver function tests defined as AST or ALT \>1.5 upper limit of normal \[ULN\] at the time of screening, or end stage cirrhosis 19. End stage renal disease on dialysis 20. History of Duchenne's muscular dystrophy 21. Need for the use of any pertinent medications (beta blockers, carbamazepine, phenobarbital, phenytoin, HMG-CoA reductase inhibitors, lithium, theophylline, clonidine). 22. Allergy to any of the components of the MMTT standardized meal
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 30-minute C-peptide area under the curve after mixed-meal tolerance test | Baseline, 6 months | laboratory test, measured in ng/mL |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 180 minute C-peptide area under the curve after mixed-meal tolerance test | Baseline, 6 months | laboratory test, measured in ng/mL |
| Change in insulin level area under the curve after mixed-meal tolerance test | Baseline, 6 months | laboratory test, measured in microIU/mL |
| Change in proinsulin area under the curve after mixed-meal tolerance test | Baseline, 6 months | laboratory test, measured in pmol/L |
| Change in glucose area under the curve after mixed-meal tolerance test | Baseline, 6 months | laboratory test, measured in mg/dL |
| Change in hemoglobin A1c | Baseline, 6 months | laboratory test, measured in % |
| Change in elexacaftor/tezacaftor/ivacaftor trough levels | Baseline, 8 weeks, 6 months | Laboratory test, measured in micrograms/mL |
| Change in aspartate aminotransferase (AST) | Baseline, 8 weeks, 6 months | Laboratory test, measured in IU/L |
| Change in alanine aminotransferase (ALT) | Baseline, 8 weeks, 6 months | Laboratory test, measured in IU/L |
| Change in glucose management indicator (GMI) % | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in average glucose (AG) mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in standard deviation (SD) | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in coefficient of variation (CV) | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time <54 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time <70 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time >180 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time >250 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time 70-180 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in percent time 70-140 mg/dL | Baseline, 8 weeks, 6 months | continuous glucose monitoring |
| Change in Chronic Respiratory Infection Symptom Score (CRISS) | Baseline, 8 weeks, 6 months | 8-item patient-reported questionnaire scored from 0 to 100, with higher scores indicating greater symptom severity |
| Change in Patient Assessment of Constipation (PAC) questionnaire score | Baseline, 8 weeks, 6 months | Likert scale questionnaire with 12 items, each scored 0-4, total score ranging from 0-48 with higher scores related to worse outcomes |
| Change in hypoglycemia symptom questionnaire (HSQ) | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months | 5-item patient-reported questionnaire scored from 0-16, with higher scores indicating greater symptom severity |
| Change in Electrocardiogram (ECG)-Measured PR Interval | Baseline, 8 weeks, 6 months | Cardiac conduction assessed by 12-lead electrocardiogram, measured in milliseconds |
| Change in Electrocardiogram (ECG)-Measured QTc Interval | Baseline, 8 weeks, 6 months | Cardiac conduction assessed by 12-lead electrocardiogram, measured in milliseconds |
| Change in percent predicted Forced Expiratory Volume in 1 Second (FEV1) | Baseline, 8 weeks, 6 months | Pulmonary function will be assessed using spirometry |
| Change in percent predicted Forced Vital Capacity (FVC) | Baseline, 8 weeks, 6 months | Pulmonary function will be assessed using spirometry |
| Change in blood pressure | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months | electronic cuff measured systolic and diastolic blood pressure, measured in mmHg |
| Change in heart rate | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months | Electronically measured, reported in beats per minute |
| Change in weight | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months | in-perrson and home-reported measurements using study provided scale, measured in kg |
| Change in body mass index | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months | in-person and self reported BMI, calculated using study-provided home scale and height on file at baseline |
| Medication Adherence by Pill Count | Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months | Adherence to study medication will be assessed by pill count at study visits. Adherence will be reported as the percentage of prescribed doses taken during the study period. |
Countries
United States
Contacts
CONTACTKevin J Scully
Outcome results
None listed