A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 74
- 试验地点
- 40
- 主要终点
- Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
研究概览
简要总结
This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
- •To prevent pregnancy, female participants of childbearing potential and their male partners will be required to use pre-specified, highly effective methods of non-hormonal contraception. Male participants with female partners of childbearing potential will be required to use a condom.
- •Body weight ≥35 kg.
- •Sweat chloride value ≥60 mmol/L from test results obtained during screening.
- •Subjects must have an eligible CFTR genotype:
- •Heterozygous for F508del and a minimal function (MF) mutation known or predicted not to be responsive to TEZ and/or IVA.
- •Homozygous for F508del
- •Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at the Screening Visit
- •Stable CF disease as judged by the investigator.
- •Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow up Visit.
排除标准
- •History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject.
- •History of cirrhosis with portal hypertension.
- •Risk factors for Torsade de Pointes
- •History of hemolysis.
- •Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening.
- •Clinically significant abnormal laboratory values at screening
- •An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before the first dose of study drug.
- •Lung infection with organisms associated with a more rapid decline in pulmonary status
- •An acute illness not related to CF within 14 days before the first dose of study drug
- •A standard digital ECG demonstrating QTc >450 msec at screening.
- •History of solid organ or hematological transplantation.
- •History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period.
- •History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator.
- •Ongoing or prior participation in an investigational drug study, with certain exceptions. (e.g., ongoing participation in NCT02565914)
- •Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (applies only to the Heterozygous F508del/MF cohorts; does not apply to the Homozygous F508del/F508del Cohort).
- •Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
研究组 & 干预措施
Part 1: Placebo - Cohort 1A and 1B Combined
Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks.
干预措施: Matched Placebo (Drug)
Part 1 Cohort 1A: Triple Combination (TC)
Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: TEZ (Drug)
Part 1 Cohort 1A: Triple Combination (TC)
Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: IVA (Drug)
Part 1 Cohort 1A: Triple Combination (TC)
Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: VX-440 (Drug)
Part 1 Cohort 1B: TC Low Dose
Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: TEZ (Drug)
Part 1 Cohort 1B: TC Low Dose
Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: IVA (Drug)
Part 1 Cohort 1B: TC Low Dose
Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.
干预措施: VX-440 (Drug)
Part 2: TC-2
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: VX-440 (Drug)
Part 1 Cohort 1B: TC High Dose
Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.
干预措施: TEZ (Drug)
Part 1 Cohort 1B: TC High Dose
Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.
干预措施: IVA (Drug)
Part 1 Cohort 1B: TC High Dose
Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.
干预措施: VX-440 (Drug)
Part 2: TEZ/IVA
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: TEZ (Drug)
Part 2: TEZ/IVA
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: IVA (Drug)
Part 2: TEZ/IVA
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: Matched Placebo (Drug)
Part 2: TC-2
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: TEZ (Drug)
Part 2: TC-2
Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period.
干预措施: IVA (Drug)
结局指标
主要结局
Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From first dose of Study Drug in the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2)
Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
时间窗: From Baseline through Day 29
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
次要结局
- Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score(From Baseline at Day 29)
- Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA(Predose at Day 8, Day 15 and Day 29)
- Relative Change in ppFEV1(From Baseline through Day 29)
- Absolute Change in Sweat Chloride Concentrations(From Baseline through Day 29)