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

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.

Time frame: Day 1 up to Week 105 (Study 105)

Population: Safety Set (study 105) included all participants in Treatment Cohort Part A who were exposed to any amount of study drug.

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.

Time frame: Day 1 up to Week 105 (Study 105)

Population: Safety Set (study 105) included all participants in the Treatment Cohort Part B who were exposed to any amount of study drug.

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.

Time frame: up to 2 years

Population: Safety Set (study 105) included all participants who were enrolled in Part A Observation Cohort.

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.

Time frame: Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Population: FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Population: FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 48, 72 (Study 105)

Population: FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: Full Analysis Set (FAS) study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: 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)

Population: FAS (Study 103/104) was used for Arm 1 \& 3, \& included all participants randomized in previous studies \& dosed. FAS (Study 105) was used for Arm 2 \& 4, \& included all participants randomized in Part A Treatment Cohort \& dosed in current study 105. 'Number Analyzed'=those participants who were evaluable at specified time points for each arm.

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.

Time frame: 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)

Population: FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

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.

Time frame: Baseline (Study 103/104/105); Day 15, Week 8, 16, 24, 36, 48, 60, 72, 84, 96 (Study 105)

Population: FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

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.

Time frame: Baseline (Study 103/104/105), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: FAS study 105 (NCT01931839) included all participants randomized in the Part A Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: 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)

Population: FAS (Study 103/104) was used for Arm 1 and 3, and included all participants randomized in the previous studies and dosed. FAS (Study 105) was used for Arm 2 and 4, and included all participants randomized in the Part A Treatment Cohort and dosed in current study 105.

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.

Time frame: Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

Analysis was performed using baseline of Cohort 4 of previous study VX09-809-102 (NCT01225211) for Arm 6 and 7.

Time frame: Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Population: FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 102 Study), Day 15, Week 8, 16, 24, 48, 72 (Study 105)

Population: FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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.

Time frame: Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60, 72 (Study 105)

Population: FAS (Study 102) was used for Arm 6 and 7, and included all participants randomized in the cohort 4 of study 102 and dosed.

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.

Time frame: Baseline (Study 102), Day 15, Week 8, 16, 24, 36, 48, 60 , 72 (Study 105)

Population: FAS (study 105) included all participants randomized in the Part B Treatment Cohort and dosed. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.