A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation, and a Second Allele With a CFTR Mutation Predicted to Have Residual Function

Study ID
STU 032015-001

Cancer Related
No

Healthy Volunteers
No

Study Sites

  • CTRC Outpatient
  • Children’s Medical Center (Dallas, Plano, Southlake)
  • Clements University Hospital
  • UT Southwestern Ambulatory Services

Contact
Laura Nnadi
214/648-3891
Laura.Nnadi@UTSouthwestern.edu

Principal Investigator
Raksha Jain, M.D.

Summary

This is a Phase 3, randomized, double-blind, placebo-controlled, 2-period, 3-treatment, crossover, multicenter study in subjects aged 12 years and older with CF, heterozygous for
the F508del-CFTR mutation, and a second allele with a CFTR mutation predicted to have
residual function. a summary of mutations predicted to have residual function is in
Section 16. This study is designed to evaluate (i) the efficacy and safety of VX-661 in
combination with ivacaftor and (ii) the efficacy and safety of ivacaftor monotherapy in this
patient population using an incomplete block design.
The treatment regimens will be
* - VX-661/ivacaftor combination treatment
o Morning dose: 1 tablet fixed-dose combination of VX-661 100 mg/ivacaftor 150 mg
and 1 tablet ivacaftor placebo
o evening dose: 1 tablet ivacaftor 150 mg
- ivacaftor monotherapy
o Morning dose: 1 tablet placebo visually matched to the fixed-dose combination tablet
and 1 tablet ivacaftor 150 mg
o evening dose: 1 tablet ivacaftor 150 mg
* - Placebo
o Morning dose: 1 tablet placebo visually matched to the fixed-dose combination tablet
and 1 tablet placebo visually matched to ivacaftor 150 mg
o evening dose: 1 tablet placebo visually matched to ivacaftor 150 mg

This study includes a Screening Period (approximately 28 days), Treatment Period 1
(8 weeks), Washout Period (8 weeks), Treatment Period 2 (8 weeks), and Safety Follow-up
Visit (approximately 28 days). approximately 300 subjects (50 per sequence) will be
enrolled and stratified by age at the Screening Visit ([Less Than]18 versus [GreaterThanorequalTo]18 years of age), FeV1
severity (determined during the Screening Visit; [Less Than]70% versus [GreaterThanorequalTo]70% predicted), and type of
residual function mutation on the second CFTR allele (Class V non-canonical splice mutation
versus Classes ii to iV residual function mutation; see Section 16), and then randomized
(1:1:1:1:1:1) to 1 of the 6 treatment sequences, as shown in Figure 8-1.
* -Sequence 1: VX-661/ivacaftor in Treatment Period 1[?]washout[?]ivacaftor monotherapy
in Treatment Period 2
* -Sequence 2: ivacaftor monotherapy in Treatment Period 1[?]washout[?]VX-661/ivacaftor
in Treatment Period 2
* -Sequence 3: VX-661/ivacaftor in Treatment Period 1[?]washout[?]placebo in Treatment
Period 2
* -Sequence 4: placebo in Treatment Period 1[?]washout[?]VX-661/ivacaftor in Treatment
Period 2
* -Sequence 5: ivacaftor monotherapy in Treatment Period 1[?]washout[?] placebo in
Treatment Period 2
* -Sequence 6: placebo in Treatment Period 1[?]washout[?]ivacaftor monotherapy in
Treatment Period 2

Primary endpoints
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.

Key Secondary endpoints
* - 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
* absolute change in sweat chloride from study baseline to the average of the Week 4 and Week 8 measurements in each Treatment Period: analysis of this variable will be similar to that of the primary analysis of the primary efficacy endpoint.

Participant Eligibility

Subjects who meet all of the following inclusion criteria will be eligible:
1. Subject (or their legally appointed and authorized representative) will sign and date an
informed consent form (ICF) and, where appropriate, an assent form.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions,
laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects (males and females) will be aged 12 years or older on the date of informed
consent or, where appropriate, assent.
4. Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to
have residual function (see Section 16);). The results of the confirmatory genotype sample obtained during screening must be reviewed before randomization. CFTR mutations that are predicted to have residual function were defined using the parameters in Section 16.
5. FEV1 >=40% and <=90% of predicted normal for age, sex, and height (equations of Wang
et al. or Hankinson et al.)34,35 during screening. Spirometry measurements must meet
ATS/ERS criteria20 for acceptability and repeatability (Section 8.1.1.1).
6. Sweat chloride value >=60 mmol/L from test results obtained during screening OR as
documented in the subject[Single Quote]s medical record.
7. If the sweat chloride value is <60 mmol/L there must be documented evidence of chronic
sinopulmonary disease36 manifested by (but not limited to):
o Persistent colonization/infection with typical CF pathogens, including Staphylococcus
aureus, Haemophilus influenzae, and mucoid and nonmucoid Pseudomonas
aeruginosa
o Chronic cough and sputum production
o Persistent chest radiograph abnormalities (e.g., bronchiectasis, atelectasis, infiltrates,
hyperinflation)
o Nasal polyps, chronic sinusitis; radiographic or computed tomographic abnormalities
of the paranasal sinuses
Specific criteria for such subjects must be discussed with and approved by the medical
monitor prior to randomization.

Subjects must meet inclusion criteria 6 or 7.

8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF medication regimen through Week 24 or, if applicable,
the Safety Follow-up Visit.