|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 and ivacaftor monotherapy through 8 weeks of treatment in subjects with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and a second allele with a CFTR mutation predicted to have residual function.
|Secondary objectives of the trial
|•To evaluate the safety of VX-661 in combination with ivacaftor through 8 weeks of treatment
•To evaluate the safety of ivacaftor monotherapy through 8 weeks of treatment
•To investigate the pharmacokinetics (PK) of VX-661 and its metabolite M1 (M1-661), and ivacaftor and its metabolite M1 (M1-ivacaftor)
|Trial contains a sub-study
|Principal inclusion criteria
|• Subjects (males and females) will be aged 12 years or older on the date of informed consent or, where appropriate, assent.
• Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function. The results of the confirmatory genotype sample obtained at the Screening Visit must be reviewed before randomization.
• Forced Expiratory Volume in 1 Second (FEV1) greater than or equal to (≥) 40 percent (%) and less than or equal to (≤) 90% of predicted normal for age, sex, and height during screening.
• Sweat chloride value ≥ 60 mmol/L from test results obtained during screening OR as documented in the subject’s medical record.
• If the sweat chloride value is <60 mmol/L, there must be documented evidence of chronic sinopulmonary disease.
• Stable CF disease as judged by the investigator
|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
• A 12-lead electrocardiogram (ECG) demonstrating corrected QT interval (QTc) greater than (>) 450 milliseconds (msec) at the Screening Visit
• History of solid organ or hematological transplantation
• History or evidence of cataract, lens opacity, Y-suture, or lamellar rings determined to be clinically significant by the ophthalmologist during the ophthalmologic examination during the Screening Period. If the subject has documentation of bilateral lens removal, an ophthalmologic examination is not required and this criterion is not applicable.
• Ongoing or prior participation in an investigational drug study (including studies investigating VX-661, lumacaftor [VX-809], and/or ivacaftor) or use of commercially available CFTR modulator (e.g., Kalydeco) within 30 days of screening
• Use of restricted medications or foods within the specified window before the first dose of study drug
• Pregnant and nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Day 1).
• Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements
• Colonization with organisms associated with a more rapid decline in pulmonary status
|E.5 End points
|Primary end point(s)
|Absolute change in percent predicted forced expiratory volume in 1 second (FEV1) from study baseline to the average of the Week 4 and Week 8 measurements in each Treatment Period.
|Timepoint(s) of evaluation of this end point
|Baseline, Week 4 and week 8 of each treatment period
|Secondary end point(s)
|• Relative change in percent predicted FEV1 from study baseline to the average of the Week 4 and Week 8 measurements in each Treatment Period
• Absolute change in sweat chloride from study baseline to the average of the Week 4 and Week 8 measurements in each Treatment Period
• Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard digital electrocardiograms (ECGs), vital signs, pulse oximetry and spirometry.
• Absolute Change From study Baseline to Average of Week 4 and Week 8 Measurements in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
• PK parameters of VX-661, M1-661, ivacaftor, and M1-ivacaftor
|Timepoint(s) of evaluation of this end point
|• Relative change in percent predicted FEV1 from study baseline: Baseline, Week 4 and Week 8 of each treatment period
• Absolute change in sweat chloride from study baseline: Baseline, Week 4 and Week 8 of each treatment period
•Safety and tolerability assessments based on adverse events (AEs), clinical laboratory values, standard digital electrocardiograms (ECGs), vital signs, pulse oximetry and spirometry: Baseline up to 28 days after last dose (up to 28 weeks)
•Absolute Change From study Baseline in CFQ-R Respiratory Domain Score: Baseline, Week 4 and Week 8 of each treatment period
• PK parameters of VX-661, M1-661, ivacaftor, and M1-ivacaftor: day 1 through week 24
|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