Trial Outcomes & Findings for A Study to Evaluate the Safety and Efficacy of Long Term Treatment With VX-661 in Combination With Ivacaftor in Participants With Cystic Fibrosis Who Have an F508del-CFTR Mutation (NCT NCT02565914)

NCT ID: NCT02565914

Last Updated: 2023-09-28

Results Overview

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1131 participants

Primary outcome timeframe

Day 1 up to Week 100

Results posted on

2023-09-28

Participant Flow

This study consisted of 3 parts: Parts A, B, and C.

A total 1131 participants enrolled in the study (1044 in Part A, 464 in Part B and 204 in Part C).

Participant milestones

Participant milestones
Measure	TEZ/IVA Part A: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part B: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, 109, 112 and 114 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part C: Participants who received TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, and 114 were administered TEZ 100 mg/IVA 150 mg fixed dose tablet in the morning and IVA 150 mg mono tablet in the evening for 192 weeks.
Part A (Up to 96 Weeks) STARTED	1044
Part A (Up to 96 Weeks) Safety Set	1042
Part A (Up to 96 Weeks) COMPLETED	951
Part A (Up to 96 Weeks) NOT COMPLETED	93
Part B (Up to 96 Weeks) STARTED	464
Part B (Up to 96 Weeks) Safety Set	463
Part B (Up to 96 Weeks) COMPLETED	228
Part B (Up to 96 Weeks) NOT COMPLETED	236
Part C (Up to 192 Weeks) STARTED	204
Part C (Up to 192 Weeks) Safety Set	204
Part C (Up to 192 Weeks) COMPLETED	7
Part C (Up to 192 Weeks) NOT COMPLETED	197

Reasons for withdrawal

Reasons for withdrawal
Measure	TEZ/IVA Part A: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part B: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, 109, 112 and 114 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part C: Participants who received TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, and 114 were administered TEZ 100 mg/IVA 150 mg fixed dose tablet in the morning and IVA 150 mg mono tablet in the evening for 192 weeks.
Part A (Up to 96 Weeks) Adverse Event	17
Part A (Up to 96 Weeks) Withdrawal of consent (not due to AE)	25
Part A (Up to 96 Weeks) Lost to Follow-up	12
Part A (Up to 96 Weeks) Death (not treatment emergent)	1
Part A (Up to 96 Weeks) Other noncompliance	6
Part A (Up to 96 Weeks) Physician Decision	6
Part A (Up to 96 Weeks) Parent study termination by sponsor	1
Part A (Up to 96 Weeks) Commercial drug available	5
Part A (Up to 96 Weeks) Other	18
Part A (Up to 96 Weeks) Enrolled, but did not receive study drug	2
Part B (Up to 96 Weeks) Physician Decision	1
Part B (Up to 96 Weeks) Other	1
Part B (Up to 96 Weeks) Enrolled, but did not receive study drug	1
Part B (Up to 96 Weeks) Adverse Event	4
Part B (Up to 96 Weeks) Sponsor Decision	2
Part B (Up to 96 Weeks) Rolled over into another study	25
Part B (Up to 96 Weeks) Withdrawal of consent (not due to AE)	6
Part B (Up to 96 Weeks) Commercial drug is available for participant	196
Part C (Up to 192 Weeks) Physician Decision	5
Part C (Up to 192 Weeks) Adverse Event	1
Part C (Up to 192 Weeks) Other non-compliance	2
Part C (Up to 192 Weeks) Rolled over into another study	11
Part C (Up to 192 Weeks) Withdrawal of consent (not due to AE)	4
Part C (Up to 192 Weeks) Commercial drug is available for participant	174

Baseline Characteristics

The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	TEZ/IVA n=1131 Participants Part A: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part B: Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, 109, 112 and 114 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks. Part C: Participants who received TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, and 114 were administered TEZ 100 mg/IVA 150 mg fixed dose tablet in the morning and IVA 150 mg mono tablet in the evening for 192 weeks.
Age, Continuous Part A	29.13 years STANDARD_DEVIATION 12.00 • n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Age, Continuous Part B	29.61 years STANDARD_DEVIATION 11.89 • n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Age, Continuous Part C	29.60 years STANDARD_DEVIATION 11.68 • n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part A · Female	505 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part A · Male	539 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part B · Female	221 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part B · Male	243 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part C · Female	89 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Sex: Female, Male Part C · Male	115 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A, Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Hispanic or Latino	25 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Not Hispanic or Latino	1002 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Not collected per local regulations	11 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Hispanic or Latino	6 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Not Hispanic or Latino	437 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Not collected per local regulations	13 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Hispanic or Latino	5 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Not Hispanic or Latino	184 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Not collected per local regulations	10 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · White	1017 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Black or African American	7 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Asian	2 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · American Indian or Alaska Native	1 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Native Hawaiian or Other Pacific Islander	0 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part A · Other	6 Participants n=1044 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · White	447 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Black or African American	1 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Asian	2 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · American Indian or Alaska Native	0 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Native Hawaiian or Other Pacific Islander	0 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part B · Other	1 Participants n=464 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · White	193 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Black or African American	0 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Asian	1 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · American Indian or Alaska Native	0 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Native Hawaiian or Other Pacific Islander	0 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.
Race/Ethnicity, Customized Part C · Other	0 Participants n=204 Participants • The Baseline data were planned to be presented separately for Part A , Part B and Part C. Here "Number Analyzed" signifies participants who were evaluable for the specified part of the study.

PRIMARY outcome

Timeframe: Day 1 up to Week 100

Population: Safety Set was defined as all participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=1042 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Participants with TEAEs	995 Participants
Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Participants with SAEs	351 Participants

PRIMARY outcome

Timeframe: Day 1 up to Week 100

Population: Safety set included all participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=463 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs Participants with TEAEs	427 Participants
Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs Participants with SAEs	136 Participants

PRIMARY outcome

Timeframe: Day 1 up to Week 196

Population: Safety set included all participants who received at least 1 dose of study drug.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=204 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part C: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Participants with TEAEs	168 Participants
Part C: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) Participants with SAEs	44 Participants

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=459 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	2.1 percentage points Interval 0.8 to 3.3
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	2.0 percentage points Interval 0.7 to 3.2

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=226 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	4.1 percentage points Interval 2.2 to 6.0
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	6.7 percentage points Interval 4.7 to 8.7
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	7.5 percentage points Interval 5.6 to 9.4

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 103/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 103 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=23 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 103/110 Efficacy Set	2.7 percentage points Standard Deviation 10.0

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 111/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 111 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=33 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	4.1 percentage points Standard Deviation 10.2
Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	2.6 percentage points Standard Deviation 6.6

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=459 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	4.3 percent change Interval 2.1 to 6.5
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	4.2 percent change Interval 2.0 to 6.4

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=226 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	7.9 percent change Interval 4.7 to 11.1
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	11.6 percent change Interval 8.2 to 15.0
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	13.0 percent change Interval 9.7 to 16.2

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 103/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 103 and had pre-defined CFTR genotypes.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=23 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 103/110 Efficacy Set	6.4 percent change Standard Deviation 21.1

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 111/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 111 and had pre-defined CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=33 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	6.1 percent change Standard Deviation 14.4
Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	5.2 percent change Standard Deviation 11.5

SECONDARY outcome

Timeframe: From Baseline up to Study 110 Week 96

Population: The 106/110 PEx analysis set included study 106 participants who received TEZ/IVA in Study 106 or Study 110.

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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=479 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Number of Pulmonary Exacerbation (PEx) Events for 106/110 PEx Analysis Set Placebo-TEZ/IVA	306 PEx events
Part A: Number of Pulmonary Exacerbation (PEx) Events for 106/110 PEx Analysis Set TEZ/IVA-TEZ/IVA	423 PEx events

SECONDARY outcome

Timeframe: From Baseline up to Week 96

Population: The 108/110 PEx analysis set included study 108 participants who received TEZ/IVA in Study 108 or Study 110.

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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=233 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Number of Pulmonary Exacerbation (PEx) Events for 108/110 PEx Analysis Set IVA-TEZ/IVA	51 PEx events
Part A: Number of Pulmonary Exacerbation (PEx) Events for 108/110 PEx Analysis Set Placebo-TEZ/IVA	89 PEx events
Part A: Number of Pulmonary Exacerbation (PEx) Events for 108/110 PEx Analysis Set TEZ/IVA-TEZ/IVA	46 PEx events

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=459 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Mass Index (BMI) for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.47 kg/m^2 Interval 0.3 to 0.65
Part A: Absolute Change in Body Mass Index (BMI) for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.38 kg/m^2 Interval 0.2 to 0.55

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=226 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Mass Index (BMI) for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	1.07 kg/m^2 Interval 0.59 to 1.55
Part A: Absolute Change in Body Mass Index (BMI) for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	0.96 kg/m^2 Interval 0.45 to 1.47
Part A: Absolute Change in Body Mass Index (BMI) for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	1.05 kg/m^2 Interval 0.56 to 1.55

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 103/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 103 and had pre-defined CFTR genotypes.

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=23 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Mass Index (BMI) for 103/110 Efficacy Set	1.38 kg/m^2 Standard Deviation 1.73

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 111/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 111 and had pre-defined CFTR genotypes.

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=33 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Mass Index (BMI) for Study 111/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	1.59 kg/m^2 Standard Deviation 2.08
Part A: Absolute Change in Body Mass Index (BMI) for Study 111/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.26 kg/m^2 Standard Deviation 0.88

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants \<20 years of age at Screening who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=93 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in BMI Z-score for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	-0.14 z-score Interval -0.28 to 0.0
Part A: Absolute Change in BMI Z-score for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.10 z-score Interval -0.04 to 0.25

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants \<20 years of age at Screening who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=30 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in BMI Z-score for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.11 z-score Interval -0.32 to 0.54
Part A: Absolute Change in BMI Z-score for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	0.07 z-score Interval -0.52 to 0.65
Part A: Absolute Change in BMI Z-score for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.30 z-score Interval -0.21 to 0.8

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=459 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	1.7 units on a scale Interval -0.6 to 4.0
Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	3.0 units on a scale Interval 0.7 to 5.3

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=226 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	10.3 units on a scale Interval 7.0 to 13.6
Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	11.2 units on a scale Interval 7.7 to 14.7
Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	13.8 units on a scale Interval 10.3 to 17.2

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 103/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 103 and had pre-defined CFTR genotypes.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=23 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 103/110 Efficacy Set	8.6 units on a scale Standard Deviation 12.1

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 106/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 106 and had pre-defined CFTR genotypes.

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=459 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight for Study 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	2.1 kg Interval 1.5 to 2.6
Part A: Absolute Change in Body Weight for Study 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	2.0 kg Interval 1.4 to 2.5

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 108/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 108 and had pre-defined CFTR genotypes.

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=226 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	3.5 kg Interval 1.9 to 5.1
Part A: Absolute Change in Body Weight for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	3.5 kg Interval 1.8 to 5.2
Part A: Absolute Change in Body Weight for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	3.6 kg Interval 2.0 to 5.2

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 103/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 103 and had pre-defined CFTR genotypes.

Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=23 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight for 103/110 Efficacy Set	4.0 kg Standard Deviation 5.0

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The 111/110 efficacy set included all enrolled participants who received at least 1 dose of study drug in Part A and rolled over from parent study 111 and had pre-defined CFTR genotypes.

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=33 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight for 111/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	4.2 kg Standard Deviation 5.7
Part A: Absolute Change in Body Weight for 111/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.6 kg Standard Deviation 2.6

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=93 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight Z-score for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.07 z-score Interval -0.06 to 0.2
Part A: Absolute Change in Body Weight Z-score for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	-0.06 z-score Interval -0.19 to 0.07

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=30 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Body Weight Z-score for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.15 z-score Interval -0.25 to 0.55
Part A: Absolute Change in Body Weight Z-score for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	0.09 z-score Interval -0.45 to 0.62
Part A: Absolute Change in Body Weight Z-score for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.43 z-score Interval -0.04 to 0.9

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=91 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Height Z-score for 106/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	0.01 z-score Interval -0.08 to 0.11
Part A: Absolute Change in Height Z-score for 106/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.13 z-score Interval 0.04 to 0.22

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=30 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Absolute Change in Height Z-score for 108/110 Efficacy Set Placebo-TEZ/IVA: Change at Week 96	-0.04 z-score Interval -0.23 to 0.15
Part A: Absolute Change in Height Z-score for 108/110 Efficacy Set IVA-TEZ/IVA: Change at Week 96	0.20 z-score Interval -0.05 to 0.45
Part A: Absolute Change in Height Z-score for 108/110 Efficacy Set TEZ/IVA-TEZ/IVA: Change at Week 96	0.23 z-score Interval 0.0 to 0.46

SECONDARY outcome

Timeframe: 96 weeks

Population: The 106/110 PEx analysis set included study 106 participants who received TEZ/IVA in Study 106 or Study 110.

Time-to-first pulmonary exacerbation was analyzed using Kaplan-Meier estimates and expressed in terms of event-free probability. PEx 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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=479 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Time-to-first Pulmonary Exacerbation (PEx) for 106/110 PEx Analysis Set Placebo-TEZ/IVA	0.470 event-free probability Interval 0.402 to 0.535
Part A: Time-to-first Pulmonary Exacerbation (PEx) for 106/110 PEx Analysis Set TEZ/IVA-TEZ/IVA	0.438 event-free probability Interval 0.374 to 0.501

SECONDARY outcome

Timeframe: 96 weeks

Population: The 108/110 PEx analysis set included study 108 participants who received TEZ/IVA in Study 108 or Study 110.

Time-to-first pulmonary exacerbation was analyzed using Kaplan-Meier estimates and expressed in terms of event-free probability. PEx 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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=233 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Time-to-first Pulmonary Exacerbation (PEx) for 108/110 PEx Analysis Set IVA-TEZ/IVA	0.493 event-free probability Interval 0.372 to 0.603
Part A: Time-to-first Pulmonary Exacerbation (PEx) for 108/110 PEx Analysis Set TEZ/IVA-TEZ/IVA	0.639 event-free probability Interval 0.519 to 0.737
Part A: Time-to-first Pulmonary Exacerbation (PEx) for 108/110 PEx Analysis Set Placebo-TEZ/IVA	0.497 event-free probability Interval 0.383 to 0.601

SECONDARY outcome

Timeframe: Week 24

Population: The Pharmacokinetic set included data for all participants who received TEZ/IVA treatment and met PK data inclusion and exclusion criteria.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=853 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part A: Plasma Concentrations of TEZ, TEZ Metabolite (M1-TEZ), Ivacaftor (IVA) and Ivacaftor Metabolite (M1-IVA) IVA	892 nanogram/milliliter (ng/mL) Standard Deviation 700
Part A: Plasma Concentrations of TEZ, TEZ Metabolite (M1-TEZ), Ivacaftor (IVA) and Ivacaftor Metabolite (M1-IVA) VX-661	2070 nanogram/milliliter (ng/mL) Standard Deviation 1390
Part A: Plasma Concentrations of TEZ, TEZ Metabolite (M1-TEZ), Ivacaftor (IVA) and Ivacaftor Metabolite (M1-IVA) M1-661	4580 nanogram/milliliter (ng/mL) Standard Deviation 2080
Part A: Plasma Concentrations of TEZ, TEZ Metabolite (M1-TEZ), Ivacaftor (IVA) and Ivacaftor Metabolite (M1-IVA) M1-IVA	1740 nanogram/milliliter (ng/mL) Standard Deviation 1070

SECONDARY outcome

Timeframe: From Baseline at Study 110 Week 96

Population: The efficacy set included all enrolled participants who received at least 1 dose of study drug in Part B and rolled over from parent studies and had pre-defined CFTR genotypes. It was performed on each of the CFTR mutation groups separately (F508del/F508del and F508del/Residual Function). Here, "Number Analyzed" signifies participants who were evaluable for the specific category of CFTR genotypes.

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=181 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) F/F Mutation	1.7 percentage points Standard Deviation 10.2
Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) F/RF Mutation	8.3 percentage points Standard Deviation 8.6

SECONDARY outcome

Timeframe: From Baseline at Week 96

BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=198 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part B: Absolute Change in Body Mass Index (BMI) F/F Mutation	0.70 kg/m^2 Standard Deviation 1.45
Part B: Absolute Change in Body Mass Index (BMI) F/RF Mutation	1.84 kg/m^2 Standard Deviation 2.21

SECONDARY outcome

Timeframe: From Baseline at Week 96

Population: The efficacy set included all enrolled participants who received at least 1 dose of study drug in Part B and rolled over from parent studies and had pre-defined CFTR genotypes. It was performed on each of the CFTR mutation groups separately (F508del/F508del and F508del/Residual Function).Here, "Number Analyzed" signifies participants who were evaluable for the specific category of CFTR genotypes.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=27 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part B: Absolute Change in BMI Z-score F/RF Mutation	0.21 z-score Standard Deviation 0.46
Part B: Absolute Change in BMI Z-score F/F Mutation	-0.03 z-score Standard Deviation 0.71

SECONDARY outcome

Timeframe: From Baseline up to Week 96

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.

Outcome measures

Outcome measures
Measure	Part A: TEZ/IVA n=453 Participants Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.
Part B: Number of Pulmonary Exacerbation (PEx) Events F/F Mutation	386 PEx events
Part B: Number of Pulmonary Exacerbation (PEx) Events F/RF Mutation	94 PEx events

Adverse Events

Part A: TEZ/IVA

Serious events: 351 serious events

Other events: 938 other events

Deaths: 1 deaths

Part B: TEZ/IVA

Serious events: 136 serious events

Other events: 391 other events

Deaths: 0 deaths

Part C: TEZ/IVA

Serious events: 44 serious events

Other events: 149 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Monitor

Vertex Pharmaceuticals Incorporated

Phone: 617-341-6777

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Part A: TEZ/IVA n=1042 participants at risk Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 103,106,107,108,109 and 111 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.	Part B: TEZ/IVA n=463 participants at risk Participants who received either TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, 109, 112 and 114 were administered TEZ 100 mg/IVA 150 mg fixed-dose tablet in the morning and IVA 150 mg mono tablet in the evening for 96 weeks.	Part C: TEZ/IVA n=204 participants at risk Participants who received TEZ/IVA, IVA monotherapy or Placebo in parent studies 106, 108, and 114 were administered TEZ 100 mg/IVA 150 mg fixed dose tablet in the morning and IVA 150 mg mono tablet in the evening for 192 weeks.
Gastrointestinal disorders Abdominal pain	9.7% 101/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	7.6% 35/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.4% 7/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Gastrointestinal disorders Abdominal pain upper	4.2% 44/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.6% 26/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.98% 2/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Gastrointestinal disorders Constipation	6.6% 69/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.2% 24/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.9% 8/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Gastrointestinal disorders Diarrhoea	10.1% 105/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.8% 27/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	2.5% 5/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Gastrointestinal disorders Nausea	10.1% 105/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.5% 21/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.4% 9/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Gastrointestinal disorders Vomiting	7.7% 80/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	2.6% 12/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.4% 7/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
General disorders Fatigue	9.6% 100/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.0% 23/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.4% 7/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
General disorders Pyrexia	13.0% 135/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	8.6% 40/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	9.8% 20/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Immune system disorders Immunisation reaction	0.00% 0/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.00% 0/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	7.4% 15/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations COVID-19	0.00% 0/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.22% 1/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	8.8% 18/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Infective pulmonary exacerbation of cystic fibrosis	42.6% 444/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	43.6% 202/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	42.6% 87/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Influenza	6.0% 62/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.6% 26/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.98% 2/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Nasopharyngitis	21.8% 227/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	19.0% 88/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.4% 13/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Rhinitis	5.3% 55/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.0% 28/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	2.5% 5/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Sinusitis	7.7% 80/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.3% 20/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.4% 7/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Upper respiratory tract infection	13.0% 135/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	9.3% 43/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.9% 12/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Infections and infestations Viral upper respiratory tract infection	6.6% 69/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.2% 15/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.49% 1/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Investigations Aspartate aminotransferase increased	5.1% 53/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	1.5% 7/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.00% 0/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Investigations Bacterial test positive	4.6% 48/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.0% 28/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.4% 11/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Investigations Blood creatine phosphokinase increased	7.3% 76/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.65% 3/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.00% 0/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Investigations Pulmonary function test decreased	5.3% 55/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	1.7% 8/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	1.5% 3/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Musculoskeletal and connective tissue disorders Arthralgia	6.0% 62/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.3% 29/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.4% 9/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Musculoskeletal and connective tissue disorders Back pain	5.5% 57/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.0% 23/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	5.4% 11/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Nervous system disorders Headache	14.0% 146/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	10.2% 47/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	9.8% 20/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Cough	35.9% 374/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	24.2% 112/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	14.2% 29/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Dyspnoea	9.5% 99/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.0% 28/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.4% 9/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Haemoptysis	16.0% 167/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	13.8% 64/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	12.3% 25/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Nasal congestion	7.4% 77/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	1.5% 7/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.98% 2/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	13.1% 136/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	8.4% 39/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	4.4% 9/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Productive cough	5.4% 56/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.2% 15/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	1.5% 3/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	5.3% 55/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	3.5% 16/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.49% 1/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Sinus congestion	5.1% 53/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.43% 2/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	0.98% 2/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)
Respiratory, thoracic and mediastinal disorders Sputum increased	21.4% 223/1042 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	9.9% 46/463 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)	6.4% 13/204 • Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, up to Week 100 for Part B and up to Week 196 for Part C)