|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Medical condition in easily understood language
|Diseases [C] - Respiratory Tract Diseases [C08]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To evaluate the efficacy of VX-661 in combination with ivacaftor through Week 12 in subjects with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy (F508del/not responsive [NR])
|Secondary objectives of the trial
|To evaluate the safety of VX-661 in combination with ivacaftor and to investigate the pharmacokinetics (PK) of VX-661 and its metabolite M1-661, and ivacaftor and its metabolite M1-ivacaftor
|Trial contains a sub-study
|Principal inclusion criteria
|Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy. If the CFTR screening genotype result is not received before randomization, a previous CFTR genotype laboratory report may be used to establish eligibility.
Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis (as documented in the subject’s medical record OR from sweat chloride test result obtained at the Screening, if subject does not have a sweat chloride test result in the medical record).
FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria20 for acceptability and repeatability.
Stable CF disease as judged by the investigator.
Willing to remain on a stable CF medication regimen through Week 12 or, if applicable, the Safety Follow-up Visit.
|Principal exclusion criteria
|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.
An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at Screening and Day 1.
|E.5 End points
|Primary end point(s)
|Absolute change in percent predicted forced expiratory volume in 1 second (FEV1) from baseline through Week 12.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|Relative change in percent predicted FEV1 from baseline through Week 12
Absolute change in sweat chloride from baseline through Week 12
Absolute change in body mass index (BMI) from baseline at Week 12
Absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline through Week 12
Number of pulmonary exacerbations through Week 12
Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values (i.e., hematology, coagulation studies, serum chemistry, vitamin levels, lipid panel, and urinalysis), standard digital electrocardiograms (ECGs), vital signs, and pulse oximetry
Time-to-first pulmonary exacerbation through Week 12
Absolute change in BMI z-score from baseline at Week 12 (in subjects <20 years old at time of screening)
Absolute change in body weight from baseline at Week 12
PK parameters of VX-661, M1-661, ivacaftor, and M1 ivacaftor
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days