A Phase 3, Randomized, Double-Blind, Placebo- Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis who Have the R117H-CFTR Mutation

Summary

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter
study of orally administered ivacaftor in subjects with CF who have the R117H-CFTR
mutation.
A minimum of 40 (maximum of approximately 80) subjects with CF, aged 6 years or older,
will be randomized to receive ivacaftor 150 mg or placebo every 12 hours (q12h). A
schematic of the study design is provided in Figure 9-1.

This study includes:
-Screening Period: Day -35 to Day -15 relative to the first dose of study drug
-Run-in Period: Day -14 to Day -1 relative to the first dose of study drug
-Treatment Period: Day 1 (first dose of study drug) through Week 24
-Follow-up Visit: 4 weeks (±7 days) after the last dose of study drug

Primary Endpoint:
Absolute change from baseline in percent predicted forced expiratory volume in 1 second
(FEV1) through Week 24.

Secondary Endpoints:
- Change from baseline in body mass index (BMI) at Week 24
- Change from baseline in sweat chloride through Week 24
- Change from baseline in the respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) through Week 24
- Time to first pulmonary exacerbation
- Safety, as determined by adverse events, clinical laboratory values (serum chemistry, hematology, and coagulation), electrocardiogram (ECG), and vital signs

Tertiary Endpoints:
- PK parameter estimates of ivacaftor and metabolites, M1 and M6, derived from plasma
concentration time data
- Pulmonary exacerbations
- Change from baseline in nonrespiratory domains of the CFQ-R
- Change from baseline in weight
- Change from baseline in height
- CF-related complications (pancreatitis or distal ileal obstruction syndrome [DIOS])

Participant Eligibility

1. Male or female with confirmed diagnosis of CF,49 defined as:
- a sweat chloride value greater than or qual to 60 mmol/L by quantitative pilocarpine iontophoresis
OR
2 CF-causing mutations (all as documented in the subject’s medical record)
AND
- chronic sinopulmonary disease
2. Must have at least 1 allele of the R117H-CFTR mutation
3. FEV1 predicted normal for age, sex, and height (Hankinson50 or Wang51 equations) at
screening:
- 40% to 90% inclusive for subjects aged 12 years or older
- 40% to 105% inclusive for subjects aged 6 to 11 years
4. 6 years of age or older on the date of signed informed consent form (ICF), and where
appropriate, date of assent
5. Minimum weight of 15 kg at screening
6. Females of childbearing potential must have a negative serum pregnancy test at screening
7. Hematology, serum chemistry, coagulation, and urinalysis results at screening with no
clinically significant abnormalities that would interfere with the study assessments, as
judged by the investigator
8. Able to understand and comply with protocol requirements, restrictions, and instructions
and likely to complete the study as planned, as judged by the investigator
9. If sexually active, male subjects who can father a child and female subjects of
childbearing potential must agree to meet the contraception requirements
10. Signed ICF, and where appropriate, signed Assent Form