A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study of VX-770 to Evaluate Safety, Pharmacokinetics, and Biomarkers of CFTR Activity in Cystic Fibrosis (CF) Subjects With Genotype G551D
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 39
- 试验地点
- 15
- 主要终点
- Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
研究概览
简要总结
The purpose of this study was to evaluate the safety and tolerability of ivacaftor in patients with cystic fibrosis (CF) who were aged 18 years or older and have a G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.
详细描述
This was a double-blind, placebo-controlled, cross-over, multiple dose study of up to 28 days of dosing, in subjects with cystic fibrosis (CF) who have a G551D-CTFR gene mutation. Enrollment of 39 subjects occurred at 15 centers in the US, Canada, and Germany.
The study was conducted in 2 parts:
- Part 1 consisted of Group A and Group B. Subjects in Group A (10 subjects) were randomized to receive 25 mg of ivacaftor every 12 hours [q12h] (4 subjects), 75 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days. Subjects in Group B (10 subjects) were randomized to receive 75 mg of ivacaftor q12h (4 subjects), 150 mg of ivacaftor q12h (4 subjects), or placebo (2 subjects) for 14 days. Following a 7- to 28-day washout period, the subjects who received active study drug crossed over to the alternate dose strength of ivacaftor for an additional 14 days. Placebo subjects continued to receive placebo for an additional 14 days.
- Part 2 consisted of Group C; these subjects did not participate in Part 1. Subjects were randomized to receive 150 mg of ivacaftor q12h (7 subjects), 250 mg of ivacaftor q12h (7 subjects), or placebo (4 subjects) for a total of 28 days. Ivacaftor doses studied in Part 2 were selected following an interim pharmacokinetic/pharmacodynamic (PK/PD) and statistical analyses of data from Part 1. The 2 doses selected for Part 2 were anticipated to enable better definition of the optimal therapeutic dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Weighing at least 40 kg
- •Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele
- •Forced expiratory volume in 1 second (FEV1) of at least 40% of predicted normal for age, gender, and height
- •Willing to remain on stable medication regimen for the duration of study participation
- •No significant clinical laboratory abnormalities, not pregnant, and willing to use at least 2 highly effective birth control methods during Part 1 and 1 highly effective birth control method during Part 2 of the study
- •No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator
排除标准
- •History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject
- •Ongoing acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 14 days of Day 1 of the study
- •History of alcohol, medication or illicit drug abuse within one year prior to Day 1
- •Abnormal liver function ≥ 3x the upper limit of normal
- •History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation)
- •History of solid organ or hematological transplantation
- •Pregnant or breast-feeding (for women)
- •Ongoing participation in another therapeutic clinical trial, or prior participation in an investigational drug study without appropriate washout
- •Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP3A4)
研究组 & 干预措施
Ivacaftor Group A
Subjects in Part 1 who first received 25 mg or 75 mg of ivacaftor every 12 hours (q12h) for 14 days, then crossed over to receive the alternate dose for another 14 days.
干预措施: Ivacaftor 25 mg/75 mg (Drug)
Ivacaftor Group B
Subjects in Part 1 who first received 75 mg or 150 mg of ivacaftor q12h for 14 days then crossed over to receive the alternate dose for another 14 days.
干预措施: Ivacaftor 75 mg/150 mg (Drug)
Ivacaftor Group C
Subjects in Part 2 who received 150 mg or 250 mg of ivacaftor q12h for 28 days.
干预措施: Ivacaftor 150 mg or 250 mg (Drug)
Placebo
Subjects who received placebo in Part 1 and subjects who received placebo in Part 2.
干预措施: Placebo (Drug)
结局指标
主要结局
Number of Subjects With Adverse Events (Combined Part 1 and Part 2)
时间窗: Baseline to Follow-up
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
Number of Adverse Events (Combined Part 1 and Part 2)
时间窗: Baseline to Follow-up
Adverse event data were collected up to the follow-up visit (5 to 9 days after last dose of study drug). Serious adverse events that were ongoing at the follow-up visit were followed until the event resolved, returned to baseline, or was determined to be a stable or chronic condition.
次要结局
- Change From Baseline in Nasal Potential Difference (Combined Part 1 and Part 2)(14 days and 28 days)
- Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second [FEV1] (Combined Part 1 and Part 2)(14 days and 28 days)
- Change From Baseline in the Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score (Part 2 Only)(Respiratory Domain Score)(14 days and 28 days)
- Change From Baseline in Maximum Sweat Chloride Concentration (Combined Part 1 and Part 2)(14 days and 28 days)