A Phase 3 Rollover Study of Lumacaftor in Combination With Ivacaftor in Subjects 12 Years and Older With Cystic Fibrosis

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the efficacy and safety of long-term treatment with lumacaftor in combination with ivacaftor in people 12 years and older with Cystic Fibrosis.

Detailed Description
-----------------
This is a Phase 3, parallel group, multicenter, rollover study in participants with CF who are homozygous or heterozygous for the F508del CFTR mutation and who previously participated in Study 103 (Study VX12-809-103, NCT01807923), Study 104 (Study VX12-809-104, NCT01807949), or Cohort 4 of Study 102 (Study VX09-809-102, NCT01225211).

Official Title
-----------------
A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Conditions
-----------------
Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Intervention / Treatment
-----------------
* Drug: Lumacaftor Plus Ivacaftor Combination
* Drug: Ivacaftor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signed informed consent form (ICF), and where appropriate, signed assent form. Participants entering the Part A Treatment Cohort: Completed 24 weeks of study drug treatment in Study 103 or Study 104 and elect to enroll in Part A treatment cohort. Participants entering the Part B Treatment Cohort: Completed 56 days of study drug treatment in Cohort 4 of Study 102 and elect to enroll in Part B treatment cohort. Participants entering the Part A Observational Cohort: Completed 24 weeks of study drug treatment in Study 103 or Study 104, but do not elect to enroll in the Part A Treatment Cohort or do not qualify to enroll in Part A treatment cohort. Willing to remain on a stable CF medication regimen through the end of study (Part A and Part B Treatment Cohorts only). Exclusion Criteria: Any comorbidity or laboratory abnormality 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). Pregnant and nursing females. Females of childbearing potential must have a negative pregnancy test at the Day 1 Visit. History of drug intolerance in the prior study that would pose an additional risk to the participant in the opinion of investigator or Vertex. History of poor compliance with study drug and/or procedures in the previous study as deemed by the investigator. Participation in an investigational drug trial (including studies investigating lumacaftor and/or ivacaftor, or studies requiring blood collections with or without administration of study drug)

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 Part A: LUM 600 mg qd/ IVA 250 mg q12h<br>Participants who received lumacaftor (LUM, VX-809) 600 milligram (mg) plus ivacaftor (IVA, VX-770) 250 mg fixed-dose combination (FDC) tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening, in the previous study VX12-809-103 or VX12-809-104, and will receive the same treatment in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>Drug: Ivacaftor<br>* Film-coated tablet, oral use<br>|
| Experimental: Arm 2 Part A: Placebo - LUM 600 mg qd/ IVA 250 mg q12h<br>Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, and will receive LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>Drug: Ivacaftor<br>* Film-coated tablet, oral use<br>|
| Experimental: Arm 3 Part A: LUM 400 mg q12h/ IVA 250 mg q12h<br>Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in the previous study VX12-809-103 or VX12-809-104, and will receive the same treatment in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>|
| Experimental: Arm 4 Part A: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h<br>Participants who received placebo matched to LUM and IVA tablet in the previous study VX12-809-103 or VX12-809-104, and will receive LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>|
| No Intervention: Arm 5 Part A: Observational Cohort<br>Participants who received either LUM 600 mg plus IVA 250 mg FDC tablet orally in the morning and IVA 250 mg film-coated tablet orally in the evening OR LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening OR placebo matched to LUM and IVA in the morning and evening, in the previous study VX12-809-103 or VX12-809-104, and will be observed (will not receive study drug) in this study VX12-809-105 for up to 2 years. | |
| Experimental: Arm 6 Part B: LUM 400 mg q12h/ IVA 250 mg q12h<br>Participants who received LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in Cohort 4 of the previous study VX09-809-102, and will receive the same treatment in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>|
| Experimental: Arm 7 Part B: Placebo - LUM 400 mg q12h/ IVA 250 mg q12h<br>Participants who received placebo matched to LUM and IVA tablet in Cohort 4 of the previous study VX09-809-102, and will receive LUM 400 mg plus IVA 250 mg FDC tablet orally in the morning and evening in this study VX12-809-105 up to Week 96. | Drug: Lumacaftor Plus Ivacaftor Combination<br>* Fixed dose combination tablet, oral use<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A Treatment Cohort: Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | AE: 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 informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or newly developed at or after initial dosing of study drug was considered treatment-emergent. | Day 1 up to Week 105 (Study 105) | 
| Part B Treatment Cohort: Number of Participants With Treatment-Emergent AEs and SAEs | AE: 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 informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. Any AE that increased in severity or newly developed at or after initial dosing of study drug was considered treatment-emergent. | Day 1 up to Week 105 (Study 105) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A Treatment Cohort: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) At Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part B Treatment Cohort: Absolute Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. | Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part A Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part B Treatment Cohort: Relative Change From Baseline in Percent Predicted FEV1 at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. | Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part A Treatment Cohort: Absolute Change From Baseline in Body Mass Index (BMI) at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | BMI = (Weight in kilogram [kg]) divided by (Stature in meters [m]) ^2. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part B Treatment Cohort: Absolute Change From Baseline in BMI at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | BMI = (Weight [in kg]) divided by (Stature [in meters]) ^2. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. | Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105) | 
| Part A Treatment Cohort: Number of Pulmonary Exacerbations Events Per Patient-Year | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events per patient year were reported, where patient years = total number of days on study/336. Analysis includes all events in the Cumulative Study Period for Arm 1 and 3, and all events in the Current Study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period. | Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period) | 
| Part A Treatment Cohort: Absolute Change From Baseline in Cystic Fibrosis Questionnaire - Revised (CFQ-R) Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 | 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), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 48, 72 (Study 105) | 
| Part B Treatment Cohort: Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 15, Week 8, 16, 24, 48 and 72 | 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), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. | Baseline (Study 102 Study), Day 15, Week 8, 16, 24, 48, 72 (Study 105) | 
| Part A Treatment Cohort: Absolute Change From Baseline in BMI Z-score at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the pediatric population. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105) | 
| Part A Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. | Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105) | 
| Part B Treatment Cohort: Absolute Change From Baseline in Body Weight at Day 15, Week 8, 16, 24, 36, 48, 60 and 72 | Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. | Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105) | 
| Part A Treatment Cohort: Time-to-First Pulmonary Exacerbation | Time-to-first pulmonary exacerbation was analyzed using the Kaplan-Meier estimates. Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period. | Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period) | 
| Part A Treatment Cohort: Percentage of Participants With at Least 1 Pulmonary Exacerbation | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Analysis was performed for the Cumulative Study Period for Arm 1 and 3, and for the current study period (Study 105) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period. | Baseline (Study 103/104) up to Week 100 (Study 105) for Arm 1 and 3 (Cumulative study period); Baseline (Study 105) up to Week 100 (Study 105) for Arm 2 and 4 (current study period) | 
| Part A Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). Percentage of participants with at least 5% and 10% relative change in percent predicted FEV1 from baseline were reported. Analysis was performed using baseline of the previous study VX12-809-103 (NCT01807923) and Study VX12-809-104 (NCT01807949) for Arm 1 and 3. Analysis was performed using baseline of the current study VX12-809-105 (NCT01931839) for Arm 2 and 4. As per planned analysis, endpoint evaluation included subjects from the parent study VX12-809-103 and VX12-809-104 as well for cumulative study period. | Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105) | 
| Part B Treatment Cohort: Percentage of Participants With Response Based on Relative Change in Percent Predicted FEV1 From Baseline | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). Percentage of participants with at least 5% relative change in percent predicted FEV1 from Baseline were reported. Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7. As per planned analysis, endpoint evaluation included subjects from the parent study VX09-809-102 as well. | Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105) | 
| Part A Observation Cohort: Number of Participants With Serious Adverse Events (SAEs) | AE: 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. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the 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. | up to 2 years |