Verapamil Effect in Cystic Fibrosis-related Dysglycemia

The Effect of Verapamil on Beta Cell Function in Adolescents and Adults With Cystic Fibrosis-related Dysglycemia

We 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.

Study Overview

• Status: Not yet recruiting
• Conditions: Cystic Fibrosis (CF); Cystic Fibrosis Related Diabetes; Abnormal Glucose Tolerance
• Intervention / Treatment: Drug: Verapamil Hydrochloride

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.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kevin J Scully; Phone Number: 401-444-5504; Email: kevin_scully@brown.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Diabetes Research Center, Massachusetts General Hospital
      • Contact: Melissa Putman; Phone Number: 617-726-8722; Email: msputman@mgh.harvard.edu
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
      • Contact: Kevin J Scully; Phone Number: 401-444-5504; Email: kevin_scully@brown.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Arm; verapamil hydrochloride	Drug: Verapamil Hydrochloride; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 30-minute C-peptide area under the curve after mixed-meal tolerance test	laboratory test, measured in ng/mL	Baseline, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 180 minute C-peptide area under the curve after mixed-meal tolerance test	laboratory test, measured in ng/mL	Baseline, 6 months
Change in insulin level area under the curve after mixed-meal tolerance test	laboratory test, measured in microIU/mL	Baseline, 6 months
Change in proinsulin area under the curve after mixed-meal tolerance test	laboratory test, measured in pmol/L	Baseline, 6 months
Change in glucose area under the curve after mixed-meal tolerance test	laboratory test, measured in mg/dL	Baseline, 6 months
Change in hemoglobin A1c	laboratory test, measured in %	Baseline, 6 months
Change in elexacaftor/tezacaftor/ivacaftor trough levels	Laboratory test, measured in micrograms/mL	Baseline, 8 weeks, 6 months
Change in aspartate aminotransferase (AST)	Laboratory test, measured in IU/L	Baseline, 8 weeks, 6 months
Change in alanine aminotransferase (ALT)	Laboratory test, measured in IU/L	Baseline, 8 weeks, 6 months
Change in glucose management indicator (GMI) %	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in average glucose (AG) mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in standard deviation (SD)	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in coefficient of variation (CV)	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time <54 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time <70 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time >180 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time >250 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time 70-180 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in percent time 70-140 mg/dL	continuous glucose monitoring	Baseline, 8 weeks, 6 months
Change in Chronic Respiratory Infection Symptom Score (CRISS)	8-item patient-reported questionnaire scored from 0 to 100, with higher scores indicating greater symptom severity	Baseline, 8 weeks, 6 months
Change in Patient Assessment of Constipation (PAC) questionnaire score	Likert scale questionnaire with 12 items, each scored 0-4, total score ranging from 0-48 with higher scores related to worse outcomes	Baseline, 8 weeks, 6 months
Change in hypoglycemia symptom questionnaire (HSQ)	5-item patient-reported questionnaire scored from 0-16, with higher scores indicating greater symptom severity	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months
Change in Electrocardiogram (ECG)-Measured PR Interval	Cardiac conduction assessed by 12-lead electrocardiogram, measured in milliseconds	Baseline, 8 weeks, 6 months
Change in Electrocardiogram (ECG)-Measured QTc Interval	Cardiac conduction assessed by 12-lead electrocardiogram, measured in milliseconds	Baseline, 8 weeks, 6 months
Change in percent predicted Forced Expiratory Volume in 1 Second (FEV1)	Pulmonary function will be assessed using spirometry	Baseline, 8 weeks, 6 months
Change in percent predicted Forced Vital Capacity (FVC)	Pulmonary function will be assessed using spirometry	Baseline, 8 weeks, 6 months
Change in blood pressure	electronic cuff measured systolic and diastolic blood pressure, measured in mmHg	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months
Change in heart rate	Electronically measured, reported in beats per minute	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months
Change in weight	in-perrson and home-reported measurements using study provided scale, measured in kg	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months
Change in body mass index	in-person and self reported BMI, calculated using study-provided home scale and height on file at baseline	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months
Medication Adherence by Pill Count	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.	Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months

Collaborators and Investigators

• Sponsor: Rhode Island Hospital

Publications and helpful links

General Publications

• Norris AW, Ode KL, Merjaneh L, Sanda S, Yi Y, Sun X, Engelhardt JF, Hull RL. Survival in a bad neighborhood: pancreatic islets in cystic fibrosis. J Endocrinol. 2019 Apr;241(1):R35-R50. doi: 10.1530/JOE-18-0468.
• Forlenza GP, McVean J, Beck RW, Bauza C, Bailey R, Buckingham B, DiMeglio LA, Sherr JL, Clements M, Neyman A, Evans-Molina C, Sims EK, Messer LH, Ekhlaspour L, McDonough R, Van Name M, Rojas D, Beasley S, DuBose S, Kollman C, Moran A; CLVer Study Group. Effect of Verapamil on Pancreatic Beta Cell Function in Newly Diagnosed Pediatric Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2023 Mar 28;329(12):990-999. doi: 10.1001/jama.2023.2064.
• Ntimbane T, Krishnamoorthy P, Huot C, Legault L, Jacob SV, Brunet S, Levy E, Gueraud F, Lands LC, Comte B. Oxidative stress and cystic fibrosis-related diabetes: a pilot study in children. J Cyst Fibros. 2008 Sep;7(5):373-84. doi: 10.1016/j.jcf.2008.01.004. Epub 2008 Apr 16.
• Umashankar B, Eliasson L, Ooi CY, Kim KW, Shaw JAM, Waters SA. Beyond insulin: Unraveling the complex interplay of ER stress, oxidative damage, and CFTR modulation in CFRD. J Cyst Fibros. 2024 Sep;23(5):842-852. doi: 10.1016/j.jcf.2024.06.004. Epub 2024 Jun 18.
• Ode KL, Ballman M, Battezzati A, Brennan A, Chan CL, Hameed S, Ismail HM, Kelly A, Moran AM, Rabasa-Lhoret R, Saxby NA, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2022: Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes. 2022 Dec;23(8):1212-1228. doi: 10.1111/pedi.13453. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2028
• Study Completion (Estimated): August 31, 2028

Study Registration Dates

• First Submitted: June 30, 2026
• First Submitted That Met QC Criteria: June 30, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: June 30, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: cystic fibrosis; continuous glucose monitoring; verapamil; beta cell function; cystic fibrosis related diabetes; mixed meal tolerance test; abnormal glucose tolerance
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Respiratory Tract Diseases; Digestive System Diseases; Lung Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cystic Fibrosis; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Verapamil
• Other Study ID Numbers: 2390110

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No