Study of VX-661 Alone and in Combination With Ivacaftor in Subjects Homozygous or Heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) Mutation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) effects of VX-661 alone and when coadministered with ivacaftor in participants with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del-CFTR mutation.

Detailed Description
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This is a Phase 2, randomized, multicenter, double-blinded, placebo-controlled, study of VX-661 monotherapy, and VX-661/ivacaftor co-therapy in participants with CF who are homozygous or heterozygous for the F508del CFTR mutation. This study is separated into seven groups: Group 1-7, respectively. Approximately 180 participants were randomized in a ratio of 4:1; active drug to matching placebo in each group.

Official Title
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A Phase 2, Multicenter, Double-Blinded, Placebo Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 Monotherapy and VX-661/Ivacaftor Cotherapy in Subjects With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: VX-661
* Drug: Ivacaftor
* Drug: Placebo matched to VX-661
* Drug: Placebo matched to ivacaftor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female with confirmed diagnosis of CF Must have the F508del-CFTR gene mutation in both alleles (Groups 1, 2, 3, 4, 5, 6). Group 7 participants must have the F508del-CFTR mutation on 1 allele, and gating mutation G551D on the second allele and have been on their physician prescribed 150 mg KalydecoTM q12h (commercially available ivacaftor) for at least 28 days at the Screening Visit. Forced expiratory volume in 1 second(FEV1) 40% to 90% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at screening Weight >40 kg and BMI >18.5 Participants of child-bearing potential and who are sexually active must meet the contraception requirements. Exclusion Criteria: History of any illness 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 participant. An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before Study Day 1. History of solid organ or hematological transplantation Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer) before screening History of alcohol, medication, or illicit drug abuse within 1 year prior to screening Pregnant, breast-feeding, or not willing to follow contraception requirements

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Group 1-6d Combined: Placebo<br>All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days. | Drug: Placebo matched to VX-661<br> <br> Drug: Placebo matched to ivacaftor<br> <br> |
| Experimental: Group 1: VX-661 10 mg qd<br>All participants in group 1 who received VX-661 10 milligram (mg) tablet orally once daily (qd) for up to 28 days. | Drug: VX-661<br> <br> |
| Experimental: Group 2a: VX-661 30 mg qd<br>All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet every 12 hours (q12h) for up to 28 days. | Drug: VX-661<br> <br> Drug: Placebo matched to ivacaftor<br> <br> |
| Experimental: Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h<br>All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Group 3a: VX-661 100 mg qd<br>All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days. | Drug: VX-661<br> <br> Drug: Placebo matched to ivacaftor<br> <br> |
| Experimental: Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h<br>All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h<br>All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Group 5a: VX-661 150 mg qd<br>All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days. | Drug: VX-661<br> <br> |
| Experimental: Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h<br>All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h<br>All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Experimental: Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h<br>All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |
| Placebo Comparator: Group 7: Placebo<br>All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days. | Drug: Ivacaftor<br> <br> Drug: Placebo matched to VX-661<br> <br> |
| Experimental: Group 7: VX-661 100 mg qd<br>All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days. | Drug: VX-661<br> <br> Drug: Ivacaftor<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Determined by Adverse Events (AEs) | An AE is defined as any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. AE includes serious as well as non-serious AEs. Serious Adverse Event (SAE) is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit (28 days after last dose of study drug) or premature discontinuation. | Start of study drug through the Follow-up Visit (Up to Day 56) | 
| Change in Sweat Chloride From Baseline Through Study Day 28 for Group 1-5b | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. | Baseline through Day 28 | 
| Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6 | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6. | Baseline through Day 28 | 
| Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7 | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. | Baseline through Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 1-5b | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6 | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7 | Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Baseline, Day 7, Day 14, Day 21, Day 28 | 
| Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Baseline, Day 14, Day 28 | 
| Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6. | Baseline, Day 14, Day 28 | 
| Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. | Baseline, Day 14, Day 28 | 
| Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 After Administration of VX-661 Monotherapy | Participants who received VX-661 monotherapy (Group 1, 2a, 3a and 5a) were analyzed for this outcome measure. PK analysis (AUC0-24h) was not planned for placebo reporting arms. | Day 28 | 
| AUC0-24h of VX-661 and AUC0-12h of Ivacaftor After Administration of VX-661 in Combination With Ivacaftor | Participants who received VX-661 in combination with Ivacaftor (Group 2b, 3b, 4, 5b, 6a, 6d and 7) were analyzed for this outcome measure. PK analysis was not planned for placebo reporting arms. | Day 28 |