Study of VX-809 Alone and in Combination With VX-770 in Cystic Fibrosis (CF) Patients Homozygous or Heterozygous for the F508del-CFTR Mutation

Study Overview
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Brief Summary
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The purpose of this study is to evaluate of the safety, efficacy, pharmacokinetics (PK) and pharmacodynamic (PD) effects of lumacaftor (VX-809) alone and when coadministered with ivacaftor (VX-770) in participants with cystic fibrosis, homozygous or heterozygous for the F508del-CFTR mutation.

Official Title
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A Phase 2, Multicenter, Double-Blinded, Placebo-Controlled, Multiple-Dose Study to Evaluate Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Lumacaftor Monotherapy, and Lumacaftor and Ivacaftor Combination Therapy 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: Lumacaftor
* Drug: Ivacaftor
* Drug: Lumacaftor Placebo
* Drug: Ivacaftor Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants with confirmed diagnosis of CF Must have the F508del-CFTR mutation on at least 1 allele. FEV1 greater than equal (>=) 40% of predicted normal for age, gender, and height (Knudson standards)(Cohort 1, 2, and 3); FEV1 40-90% of predicted normal for age, gender, and height (Hankinson standards (Cohort 4) Participant of child-bearing potential and who are sexually active must meet the contraception requirements Exclusion Criteria: History of any illness or condition 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 (e.g., cirrhosis with portal hypertension). An acute illness including acute upper or lower respiratory infection, pulmonary exacerbation or changes in therapy (including antibiotics) for pulmonary disease within 14 days (Cohort 1, 2, and 3) or 28 days (Cohort 4) before receiving the first dose of study drug. History of solid organ or hematological transplantation. History of alcohol abuse or drug addiction in the past year, including cannabis, cocaine, and opiates. Ongoing participation in another therapeutic clinical study, or prior participation in an investigational drug study without appropriate washout Pregnant or nursing females; females of childbearing potential who are unwilling or unable to use an acceptable method of non-hormonal contraception Participants enrolled in Cohort 1 or Cohort 2 will not be eligible for Cohort 3 Ongoing or prior participation in an investigational drug study within 30 days of the Screening Visit Heterozygous participants who participated in Cohort 2 and meet the eligibility criteria for Cohort 4 may participate in Cohort 4 Evidence of lens opacity or cataract as determined by the ophthalmologic examination (Cohort 4 only)

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1: Placebo<br>Participants homozygous (HO) for the F508del-CF transmembrane conductance regulator gene (CFTR) mutation received lumacaftor matched placebo once daily (qd) (Day 1 through Day 14), followed by lumacaftor matched placebo qd in combination with ivacaftor matched placebo every 12 hours (q12h) (Day 15 through Day 21). | Drug: Lumacaftor Placebo<br>* Matching placebo tablet.<br>Drug: Ivacaftor Placebo<br>* Matching placebo tablet.<br>|
| Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 150 mg q12h<br>Participants homozygous for the F508del-CFTR mutation received 200 milligram (mg) of lumacaftor (LUM) qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 150 mg of ivacaftor (IVA) q12h (Day 15 through Day 21). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Experimental: Cohort 1: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h<br>Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 14), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 15 through Day 21). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Placebo Comparator: Cohort 2 and 3: Placebo (HO and HE)<br>Participants homozygous or heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo qd (Day 1 through Day 28), followed by lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 29 through Day 56). | Drug: Lumacaftor Placebo<br>* Matching placebo tablet.<br>Drug: Ivacaftor Placebo<br>* Matching placebo tablet.<br>|
| Experimental: Cohort 2: LUM 200 mg qd/LUM 200 mg qd+IVA 250 mg q12h (HO)<br>Participants homozygous for the F508del-CFTR mutation received 200 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 200 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Experimental: Cohort 2: LUM 400 mg qd/LUM 400 mg qd+IVA 250 mg q12h (HO)<br>Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 400 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Experimental: Cohort 2: LUM 600 mg qd/LUM 600 mg qd+IVA 250 mg q12h (HO&HE)<br>Participants homozygous or heterozygous for the F508del-CFTR mutation received 600 mg of lumacaftor alone qd (Day 1 through Day 28), followed by 600 mg of lumacaftor qd in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Experimental: Cohort 3: LUM 400 mg q12h/LUM 400 mg q12h+IVA 250 mg q12h (HO)<br>Participants homozygous for the F508del-CFTR mutation received 400 mg of lumacaftor alone q12h (Day 1 through Day 28), followed by 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 29 through Day 56). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|
| Placebo Comparator: Cohort 4: Placebo<br>Participants heterozygous for the F508del-CFTR mutation received lumacaftor matched placebo in combination with ivacaftor matched placebo q12h (Day 1 through Day 56). | Drug: Lumacaftor Placebo<br>* Matching placebo tablet.<br>Drug: Ivacaftor Placebo<br>* Matching placebo tablet.<br>|
| Experimental: Cohort 4: LUM 400 mg q12h+IVA 250 mg q12h<br>Participants heterozygous for the F508del-CFTR mutation received 400 mg of lumacaftor q12h in combination with 250 mg of ivacaftor q12h (Day 1 through Day 56). | Drug: Lumacaftor<br>* Tablet<br>* Other names: VX-809, LUM;Drug: Ivacaftor<br>* Tablet.<br>* Other names: VX-770, IVA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Safety and Tolerability Based on Adverse Events (AEs) | AE: any untoward medical occurrence in a participant during study; irrespective of relationship with treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after informed consent. AE includes serious AEs (SAEs) as well as Non-SAEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Number of participants with AEs and SAEs are reported. AE that started at/after initial dosing of study drug, or increased in severity after initial dosing of study drug is considered treatment-emergent. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 14) and combination therapy period (Period 2: Day 15 to Day 21). | Cohort 1: Day 1 up to 28 days after last dose (Last dose = Day 21) | 
| Cohort 2 and 3: Safety and Tolerability Based on Adverse Events (AEs) | Detailed description is provided in Outcome Measure 1. Results are reported separately for monotherapy period (Period 1: Day 1 to Day 28) and combination therapy period (Period 2: Day 29 to Day 56). | Cohort 2 and 3: Day 1 up to 28 days after last dose (Last dose = Day 56) | 
| Cohort 4: Safety and Tolerability Assessed by Number of Participants With AEs and SAEs | AEs and SAEs are defined in Outcome Measure 1. | Cohort 4: Day 1 up to 28 days after last dose (Last dose = Day 56) | 
| Cohort 1: Absolute Change From Day 14 in Sweat Chloride at Day 21 |  | Cohort 1: Day 14, Day 21 | 
| Cohort 2 And 3: Absolute Change From Day 28 in Sweat Chloride at Day 56 |  | Cohort 2 and 3: Day 28, Day 56 | 
| Cohort 4: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 56 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Hankinson method. | Cohort 4: Baseline, Day 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Absolute Change From Baseline in Sweat Chloride at Day 14 |  | Cohort 1: Baseline, Day 14 | 
| Cohort 2 And 3: Absolute Change From Baseline in Sweat Chloride at Day 14 |  | Cohort 2: Baseline, Day 14 | 
| Cohort 4: Absolute Change From Baseline in Sweat Chloride at Day 56 |  | Cohort 4: Baseline, Day 56 | 
| Cohort 1: Absolute Change From Day 14 in FEV1 at Day 21 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | Cohort 1: Day 14, Day 21 | 
| Cohort 1: Absolute Change From Day 14 in ppFEV1 at Day 21 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 1: Day 14, Day 21 | 
| Cohort 2 and 3: Absolute Change From Day 28 in ppFEV1 at Day 56 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 2 and 3: Day 28, Day 56 | 
| Cohort 2 and 3: Relative Change From Day 28 in ppFEV1 at Day 56 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 2 and 3: Day 28, Day 56 | 
| Cohort 2 and 3: Absolute Change From Baseline in ppFEV1 at Day 28 and 56 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 2 and 3: Baseline, Day 28 and 56 | 
| Cohort 2 and 3: Relative Change From Baseline in FEV1 at Day 28 and 56 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 2 and 3: Baseline, Day 28 and 56 | 
| Cohort 4: Relative Change From Baseline in Percent Predicted FEV1 at Day 56 | FEV1 and ppFEV1 are defined in Outcome Measure 6. | Cohort 4: Baseline, Day 56 | 
| Cohort 2 and 3: Absolute Change From Day 28 in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 56 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for subjects 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. | Cohort 2 and 3: Day 28, Day 56 | 
| Cohort 4: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 56 | CFQ-R respiratory domain is defined in Outcome Measure 17. | Cohort 4: Baseline, Day 56 | 
| Cohort 4: Absolute Change From Baseline in Body Mass Index (BMI) at Day 56 | BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2). | Cohort 4: Baseline, Day 56 | 
| Cohort 4: Absolute Change From Baseline in Weight at Day 56 |  | Cohort 4: Baseline, Day 56 |