The Effect of Verapamil on Beta Cell Function in Adolescents and Adults With Cystic Fibrosis-related Dysglycemia
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Change in 30-minute C-peptide area under the curve after mixed-meal tolerance test
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 14 years and older
- •Genetically-confirmed diagnosis of cystic fibrosis
- •Clinical diagnosis of pancreatic insufficiency, defined as requiring pancreatic enzyme replacement therapy (PERT)
- •Diagnosis of AGT or CFRD within 3-months of study enrollment
- •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
- •CFRD is defined as having a fasting glucose >126 mg/dL and/or OGTT 2-hour glucose >200 mg/dL
- •Willing to attempt to maximize verapamil to the goal study dosage of 360 mg PO daily
- •If taking elexacaftor/tezacaftor/ivacaftor (ETI), willing to adjust dosing
排除标准
- •Severe lung disease indicated by forced expiratory volume in 1 second (FEV1) <50% predicted on most recent spirometry testing
- •Body mass index (BMI) <18 kg/m2
- •Weight <50 kg
- •Current or planned pregnancy within the next 6 months
- •Treatment with IV antibiotics for a CF exacerbation within 1 month
- •Systemic supraphysiologic glucocorticoid use within 1 month
- •Initiation or discontinuation of a CFTR modulator within 3 months (i.e. recent change in CFTR modulator formulation/usage)
- •Current use of insulin, a GLP-1 receptor agonist, or oral anti-diabetic agent
- •Most recent HbA1c >7%
- •Not taking a CFTR modulator due to genotype-ineligibility
- •Current use of vanzacaftor/tezacaftor/deutivcaftor
- •Known hypersensitivity to verapamil
- •Blood pressure (BP) <90/60 (adults) or <5th centile for age and gender (youth) in 2 out of 3 measurements
- •Heart rate (HR) <60 bpm (adults) or <2nd centile for age and gender (youth) in 2 out of 3 measurements
- •History of previously diagnosed vasovagal syncopal episodes related to hypotension
- •History of significant cardiac disease (e.g. severe ventricular dysfunction, hypertrophic cardiomyopathy)
- •History of certain arrhythmias (e.g. AV block, accessory pathway such as Wolff-Parkinson-White or Lown-Ganong-Levine syndromes)
- •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
- •End stage renal disease on dialysis
- •History of Duchenne's muscular dystrophy
- •Need for the use of any pertinent medications (beta blockers, carbamazepine, phenobarbital, phenytoin, HMG-CoA reductase inhibitors, lithium, theophylline, clonidine).
- •Allergy to any of the components of the MMTT standardized meal
研究组 & 干预措施
Intervention Arm
verapamil hydrochloride
干预措施: Verapamil Hydrochloride (Drug)
结局指标
主要结局
Change in 30-minute C-peptide area under the curve after mixed-meal tolerance test
时间窗: Baseline, 6 months
laboratory test, measured in ng/mL
次要结局
- Change in 180 minute C-peptide area under the curve after mixed-meal tolerance test(Baseline, 6 months)
- Change in insulin level area under the curve after mixed-meal tolerance test(Baseline, 6 months)
- Change in glucose area under the curve after mixed-meal tolerance test(Baseline, 6 months)
- Change in proinsulin area under the curve after mixed-meal tolerance test(Baseline, 6 months)
- Change in hemoglobin A1c(Baseline, 6 months)
- Change in elexacaftor/tezacaftor/ivacaftor trough levels(Baseline, 8 weeks, 6 months)
- Change in aspartate aminotransferase (AST)(Baseline, 8 weeks, 6 months)
- Change in alanine aminotransferase (ALT)(Baseline, 8 weeks, 6 months)
- Change in glucose management indicator (GMI) %(Baseline, 8 weeks, 6 months)
- Change in average glucose (AG) mg/dL(Baseline, 8 weeks, 6 months)
- Change in standard deviation (SD)(Baseline, 8 weeks, 6 months)
- Change in coefficient of variation (CV)(Baseline, 8 weeks, 6 months)
- Change in percent time <54 mg/dL(Baseline, 8 weeks, 6 months)
- Change in percent time <70 mg/dL(Baseline, 8 weeks, 6 months)
- Change in percent time >180 mg/dL(Baseline, 8 weeks, 6 months)
- Change in percent time >250 mg/dL(Baseline, 8 weeks, 6 months)
- Change in percent time 70-180 mg/dL(Baseline, 8 weeks, 6 months)
- Change in percent time 70-140 mg/dL(Baseline, 8 weeks, 6 months)
- Change in Chronic Respiratory Infection Symptom Score (CRISS)(Baseline, 8 weeks, 6 months)
- Change in Patient Assessment of Constipation (PAC) questionnaire score(Baseline, 8 weeks, 6 months)
- Change in hypoglycemia symptom questionnaire (HSQ)(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(Baseline, 8 weeks, 6 months)
- Change in Electrocardiogram (ECG)-Measured QTc Interval(Baseline, 8 weeks, 6 months)
- Change in percent predicted Forced Expiratory Volume in 1 Second (FEV1)(Baseline, 8 weeks, 6 months)
- Change in percent predicted Forced Vital Capacity (FVC)(Baseline, 8 weeks, 6 months)
- Change in blood pressure(Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months)
- Change in heart rate(Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months)
- Change in weight(Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (week 12, 16, 20), 6 months)
- Change in body mass index(Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months)
- Medication Adherence by Pill Count(Baseline, weekly telehealth visits (weeks 1-7), 8 weeks, monthly telehealth visits (weeks 12, 16, 20), 6 months)
研究者
Kevin Scully
Principle Investigator; Pediatric Endocrinologist
Rhode Island Hospital