A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02347657
• Collaborator: (none)
• Enrollment: 510
• Locations: 75
• Arms: 2
• Actual Duration (Months): 24.6
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a Phase 3, randomized, double blind, placebo controlled, parallel group, multicenter study in people with cystic fibrosis (CF) who are homozygous for the F508del CF transmembrane conductance regulator (CFTR) gene mutation.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: VX-661 Plus Ivacaftor Combination; Drug: Ivacaftor; Drug: VX-661 Plus Ivacaftor Combination Placebo; Drug: Ivacaftor placebo	Phase 3

Detailed Description

This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in people with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the efficacy and safety of VX-661 in combination with Ivacaftor (IVA, VX-770). The active treatment regimen comprised of a morning dose of a fixed-dose combination (FDC) tablet of 100 milligram (mg) VX-661/150 mg IVA once daily (qd) and an evening dose of IVA 150 mg to be taken approximately 12 hours after the morning dose. The placebo regimen was visually matched tablets to be taken with the same schedule as the active treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 510 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation
• Actual Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Jan 20, 2017
• Actual Study Completion Date: Jan 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	Drug: VX-661 Plus Ivacaftor Combination Placebo; FDC tablet, oral use; Drug: Ivacaftor placebo; Tablet, oral use
Experimental: VX-661/IVA VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.	Drug: VX-661 Plus Ivacaftor Combination; FDC tablet, oral use; Drug: Ivacaftor; Tablet, oral use

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24 [Day 1, Through Week 24]

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

Secondary Outcome Measures

1. Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24 [Day 1, Through Week 24]

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

2. Number of Pulmonary Exacerbations Per Year [Day 1 through Week 24]

   Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Pulmonary exacerbation events per year (48 weeks) were reported.

3. Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24 [Day 1, Week 24]

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

4. Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 [Day 1, Through Week 24]

   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.

5. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Day 1 up to Week 28]

   AE: 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, inpatient 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 to Week 28 was considered treatment-emergent.

6. Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 [Day 1 through Week 24]

   Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Time to event data was not collected and instead, Number of Subjects with first event were collected and are reported. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.

7. Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24 [Day 1, Through Week 24]

   Sweat samples were collected using an approved collection device.

8. Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening) [Day 1, Week 24]

   BMI was defined as weight in kg divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score).

9. Absolute Change From Baseline (Day 1) in Body Weight at Week 24 [Day 1, Week 24]

10. Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) [Pre-morning dose on Week 16]

    This outcome was not planned to be assessed in Placebo arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Homozygous for the F508del CFTR mutation, genotype to be confirmed at the Screening Visit

• Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis

• Forced expiratory volume at one second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, and height during screening

• Stable CF disease as judged by the investigator

• Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, the Safety Follow up Visit

Exclusion Criteria:

• History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant.

• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug)

• Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Day 1)

• Sexually active participants of reproductive potential who are not willing to follow the contraception requirements

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Long Beach	California	United States
3		Denver	Colorado	United States
4		Orlando	Florida	United States
5		Tampa	Florida	United States
6		Chicago	Illinois	United States
7		Peoria	Illinois	United States
8		Boston	Massachusetts	United States
9		Minneapolis	Minnesota	United States
10		Saint Louis	Missouri	United States
11		Manchester	New Hampshire	United States
12		Long Branch	New Jersey	United States
13		Albuquerque	New Mexico	United States
14		Albany	New York	United States
15		Buffalo	New York	United States
16		New Hyde Park	New York	United States
17		Rochester	New York	United States
18		Syracuse	New York	United States
19		Akron	Ohio	United States
20		Columbus	Ohio	United States
21		Oklahoma City	Oklahoma	United States
22		Charleston	South Carolina	United States
23		Sioux Falls	South Dakota	United States
24		Fort Worth	Texas	United States
25		Tyler	Texas	United States
26		Seattle	Washington	United States
27		Milwaukee	Wisconsin	United States
28		Calgary	Alberta	Canada
29		Vancouver	British Columbia	Canada
30		Halifax	Nova Scotia	Canada
31		Toronto	Ontario	Canada
32		Montreal	Quebec	Canada
33		Copenhagen O		Denmark
34		Marseille cedex 20	Bouches-du-Rhone	France
35		Roscoff	Finistere	France
36		Bordeaux	Girande	France
37		Lille Cedex	Nord	France
38		Paris cedex 14	Paris	France
39		Paris Cedex 19	Paris	France
40		Pierre Benite cedex	Rhone	France
41		Heidelberg	Baden Wuerttemberg	Germany
42		Muenchen	Bayern	Germany
43		Wuerzburg	Bayern	Germany
44		Belfast	Berlin	Germany
45		Frankfurt	Hessen	Germany
46		Giessen	Hessen	Germany
47		Berlin		Germany
48		Cork		Ireland
49		Dublin		Ireland
50		Genova		Italy
51		Palermo		Italy
52		Roma		Italy
53		Torino		Italy
54		Verona		Italy
55		Den Haag		Netherlands
56		Groningen		Netherlands
57		Nijmegen		Netherlands
58		Rotterdam		Netherlands
59		Utrecht		Netherlands
60		Barcelona		Spain
61		Madrid		Spain
62		Sevilla		Spain
63		Valencia		Spain
64		Goteborg		Sweden
65		Stockholm		Sweden
66		Uppsala		Sweden
67		Bern		Switzerland
68		Zuerich		Switzerland
69		Exeter	Devon	United Kingdom
70		Liverpool	Lancashire	United Kingdom
71		Sheffield	South Yorkshire	United Kingdom
72		Newcastle Upon Tyne	Tyne & Wear	United Kingdom
73		Birmingham	West Midlands	United Kingdom
74		Belfast		United Kingdom
75		London		United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 6, 2016
• Statistical Analysis Plan - Feb 9, 2017

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02347657
• Other Study ID Numbers: VX14-661-106
• First Posted: Jan 27, 2015
• Last Update Posted: Jun 12, 2018
• Last Verified: May 1, 2018

• Keywords provided by Vertex Pharmaceuticals Incorporated: Homozygous for the F508del CFTR Mutation
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Recruitment Details	The study was conducted across 91 sites in 12 countries.
Pre-assignment Detail	A total of 510 participants were randomized and 509 participants were treated in the study.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus Ivacaftor (IVA, VX-770) fixed dose combination (FDC) tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 milligram (mg) plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Period Title: Overall Study
STARTED	259	251
Treated	258	251
COMPLETED	241	236
NOT COMPLETED	18	15

Baseline Characteristics

Arm/Group Title	Placebo	VX-661/IVA	Total
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.	Total of all reporting groups
Overall Participants	256	248	504
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.7 (9.5)	26.9 (11.2)	26.3 (10.4)
Sex: Female, Male (Count of Participants)
Female	125 48.8%	121 48.8%	246 48.8%
Male	131 51.2%	127 51.2%	258 51.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 1.2%	9 3.6%	12 2.4%
Not Hispanic or Latino	250 97.7%	234 94.4%	484 96%
Unknown or Not Reported	3 1.2%	5 2%	8 1.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 0.8%	0 0%	2 0.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 0.4%	1 0.2%
White	254 99.2%	245 98.8%	499 99%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 0.8%	2 0.4%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Day 1, Through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	256	245
Least Squares Mean (95% Confidence Interval) [Percentage of predicted FEV1]	-0.6	3.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments	Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed model for repeated measures (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 95%; 3.1 to 4.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Day 1, Through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	256	245
Least Squares Mean (95% Confidence Interval) [percent change]	-0.5	6.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments	Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	6.8
	Confidence Interval	(2-Sided) 95%; 5.3 to 8.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Pulmonary Exacerbations Per Year
Description	Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Pulmonary exacerbation events per year (48 weeks) were reported.
Time Frame	Day 1 through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	256	248
Number [pulmonary exacerbation events per year]	0.99	0.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments	Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0054
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Event Rate Ratio
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24
Description	BMI was defined as weight in kilograms (kg) divided by height in square meter (m^2).
Time Frame	Day 1, Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	245	237
Least Squares Mean (95% Confidence Interval) [kilogram per square meter (kg/m^2)]	0.12	0.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments	Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4127
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24
Description	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.
Time Frame	Day 1, Through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	256	246
Least Squares Mean (95% Confidence Interval) [units on a scale]	-0.1	5.0

6. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: 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, inpatient 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 to Week 28 was considered treatment-emergent.
Time Frame	Day 1 up to Week 28

Outcome Measure Data

Analysis Population Description

Safety Set included all participants who received at least 1 dose of the study drug.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	258	251
Participants with AEs	245 95.7%	227 91.5%
Participants with SAEs	47 18.4%	31 12.5%

7. Secondary Outcome

Title	Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24
Description	Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Time to event data was not collected and instead, Number of Subjects with first event were collected and are reported. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.
Time Frame	Day 1 through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	256	248
Count of Participants [Participants]	88 34.4%	62 25%

8. Secondary Outcome

Title	Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24
Description	Sweat samples were collected using an approved collection device.
Time Frame	Day 1, Through Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	242	240
Least Squares Mean (95% Confidence Interval) [millimole per liter (mmol/L)]	0.2	-9.9

9. Secondary Outcome

Title	Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening)
Description	BMI was defined as weight in kg divided by height in m^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score).
Time Frame	Day 1, Week 24

Outcome Measure Data

Analysis Population Description

Analysis population included all randomized participants who received at least 1 dose of study drug and were <20 years of age at the time of screening. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	74	76
Least Squares Mean (95% Confidence Interval) [z-score]	-0.02	-0.06

10. Secondary Outcome

Title	Absolute Change From Baseline (Day 1) in Body Weight at Week 24
Time Frame	Day 1, Week 24

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	245	237
Least Squares Mean (95% Confidence Interval) [kg]	0.6	0.7

11. Secondary Outcome

Title	Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
Description	This outcome was not planned to be assessed in Placebo arm.
Time Frame	Pre-morning dose on Week 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) set included all randomized participants who received any amount of study drug and had a PK assessment. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	VX-661/IVA
Arm/Group Description	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
Measure Participants	233
VX-661	1890 (1150)
M1 VX-661	4730 (1730)
M2 VX-661	4830 (2750)
IVA	815 (572)
M1 IVA	1590 (961)

Adverse Events

Time Frame	Day 1 up to Week 28
Adverse Event Reporting Description	Safety Set included all participants who received at least 1 dose of the study drug.
Arm/Group Title	Placebo		VX-661/IVA
Arm/Group Description	Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24.		VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24.
All Cause Mortality
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/258 (0%)		0/251 (0%)
Serious Adverse Events
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/258 (18.2%)		31/251 (12.4%)
Blood and lymphatic system disorders
Haemolytic anaemia	1/258 (0.4%)		0/251 (0%)
Gastrointestinal disorders
Inguinal hernia	0/258 (0%)		1/251 (0.4%)
Coeliac disease	1/258 (0.4%)		0/251 (0%)
Constipation	2/258 (0.8%)		0/251 (0%)
Faecaloma	1/258 (0.4%)		0/251 (0%)
Gastric ulcer	1/258 (0.4%)		0/251 (0%)
Gastritis	1/258 (0.4%)		0/251 (0%)
Pancreatitis acute	1/258 (0.4%)		0/251 (0%)
General disorders
Chest discomfort	1/258 (0.4%)		0/251 (0%)
Fatigue	1/258 (0.4%)		0/251 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	32/258 (12.4%)		23/251 (9.2%)
Pneumonia	1/258 (0.4%)		2/251 (0.8%)
Clostridium difficile colitis	0/258 (0%)		1/251 (0.4%)
Lung abscess	0/258 (0%)		1/251 (0.4%)
Respiratory tract infection viral	0/258 (0%)		1/251 (0.4%)
Acarodermatitis	1/258 (0.4%)		0/251 (0%)
Bronchitis	1/258 (0.4%)		0/251 (0%)
Bronchopulmonary aspergillosis allergic	1/258 (0.4%)		0/251 (0%)
Gastroenteritis viral	1/258 (0.4%)		0/251 (0%)
Influenza	1/258 (0.4%)		0/251 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	1/258 (0.4%)		0/251 (0%)
Toxicity to various agents	1/258 (0.4%)		0/251 (0%)
Wrist fracture	1/258 (0.4%)		0/251 (0%)
Investigations
Blood creatine phosphokinase increased	1/258 (0.4%)		1/251 (0.4%)
Blood glucose abnormal	1/258 (0.4%)		0/251 (0%)
Electrocardiogram ST segment elevation	1/258 (0.4%)		0/251 (0%)
Pulmonary function test decreased	1/258 (0.4%)		0/251 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/258 (0%)		1/251 (0.4%)
Nervous system disorders
Benign intracranial hypertension	0/258 (0%)		1/251 (0.4%)
Generalised tonic-clonic seizure	0/258 (0%)		1/251 (0.4%)
Migraine	0/258 (0%)		1/251 (0.4%)
Headache	1/258 (0.4%)		0/251 (0%)
Renal and urinary disorders
Acute kidney injury	2/258 (0.8%)		0/251 (0%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	3/258 (1.2%)		3/251 (1.2%)
Cough	1/258 (0.4%)		0/251 (0%)
Paranasal cyst	1/258 (0.4%)		0/251 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	243/258 (94.2%)		227/251 (90.4%)
Gastrointestinal disorders
Abdominal pain	22/258 (8.5%)		23/251 (9.2%)
Nausea	18/258 (7%)		23/251 (9.2%)
Diarrhoea	23/258 (8.9%)		17/251 (6.8%)
Vomiting	15/258 (5.8%)		13/251 (5.2%)
Abdominal pain upper	17/258 (6.6%)		10/251 (4%)
Constipation	14/258 (5.4%)		7/251 (2.8%)
General disorders
Pyrexia	32/258 (12.4%)		28/251 (11.2%)
Fatigue	30/258 (11.6%)		16/251 (6.4%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	75/258 (29.1%)		57/251 (22.7%)
Nasopharyngitis	39/258 (15.1%)		42/251 (16.7%)
Rhinitis	14/258 (5.4%)		10/251 (4%)
Investigations
Alanine aminotransferase increased	13/258 (5%)		8/251 (3.2%)
Bacterial test positive	16/258 (6.2%)		8/251 (3.2%)
Nervous system disorders
Headache	36/258 (14%)		44/251 (17.5%)
Respiratory, thoracic and mediastinal disorders
Cough	83/258 (32.2%)		66/251 (26.3%)
Sputum increased	42/258 (16.3%)		36/251 (14.3%)
Haemoptysis	33/258 (12.8%)		24/251 (9.6%)
Oropharyngeal pain	29/258 (11.2%)		22/251 (8.8%)
Dyspnoea	18/258 (7%)		16/251 (6.4%)
Rhinorrhoea	16/258 (6.2%)		8/251 (3.2%)
Skin and subcutaneous tissue disorders
Rash	13/258 (5%)		4/251 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI is free to publish results of the study after (1) the first multi-center publication, (2) if the sponsor elects not to publish the results, or (3) 18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.