A Phase 3 Study to Evaluate the Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02392234
• Collaborator: (none)
• Enrollment: 248
• Locations: 94
• Arms: 3
• Duration (Months): 23.1
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of VX-661 in combination with ivacaftor (IVA, VX-770) and IVA monotherapy in participants with Cystic Fibrosis (CF) who are heterozygous for F508del-CFTR allele and a second allele with a CFTR mutation predicted to have residual function.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: VX-661/Ivacaftor; Drug: Ivacaftor; Drug: Placebo matched to VX-661/ ivacaftor; Drug: Placebo matched to Ivacaftor	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 248 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of Ivacaftor and VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation, and a Second Allele With a CFTR Mutation Predicted to Have Residual Function
• Study Start Date: Mar 1, 2015
• Actual Primary Completion Date: Feb 1, 2017
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VX-661/Ivacaftor combination	Drug: VX-661/Ivacaftor; Fixed dose combination tablet, oral use; Other Names: VX-661+VX-770 ; Drug: Ivacaftor; Tablet, oral use; Other Names: IVA, VX-770 ; Drug: Placebo matched to Ivacaftor; Tablet, oral use
Experimental: Ivacaftor monotherapy	Drug: Ivacaftor; Tablet, oral use; Other Names: IVA, VX-770 ; Drug: Placebo matched to VX-661/ ivacaftor; Fixed dose combination tablet, oral use
Placebo Comparator: Placebo	Drug: Placebo matched to VX-661/ ivacaftor; Fixed dose combination tablet, oral use; Drug: Placebo matched to Ivacaftor; Tablet, oral use

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8 [Baseline, Week 4 and Week 8 of each treatment period]

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

Secondary Outcome Measures

1. Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8 [Baseline, Week 4 and Week 8 of each treatment period]

   The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life.

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

3. Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8 [Baseline, Week 4 and Week 8 of each treatment period]

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

4. Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8 [Baseline, Week 4 and Week 8 of each treatment period]

5. Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy [Pre-morning dose on Week 8 of each treatment period]

6. Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy [Pre-morning dose on Week 8 of each treatment period]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Heterozygous for F508del-CFTR and a second allele with a CFTR mutation predicted to have residual function

• Forced Expiratory Volume in 1 Second (FEV1) greater than or equal to (≥) 40 percent (%) and less than or equal to (≤) 90% of predicted normal for age, sex, and height during screening

• Sweat chloride value ≥60 millimole per liter (mmol/L) during screening OR as documented in the participant's medical record

• Stable CF disease as judged by the investigator

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

• History of solid organ or hematological transplantation

• Ongoing or prior participation in an investigational drug study (including studies investigating VX-661, lumacaftor [VX-809], and/or ivacaftor) within 30 days of screening

• Pregnant and nursing females

• 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		Birmingham	Alabama	United States
2		Phoenix	Arizona	United States
3		Tucson	Arizona	United States
4		Long Beach	California	United States
5		Oakland	California	United States
6		Palo Alto	California	United States
7		Sacramento	California	United States
8		Aurora	Colorado	United States
9		Denver	Colorado	United States
10		Gainesville	Florida	United States
11		Miami	Florida	United States
12		Orlando	Florida	United States
13		Pensacola	Florida	United States
14		Tampa	Florida	United States
15		Atlanta	Georgia	United States
16		Chicago	Illinois	United States
17		Park Ridge	Illinois	United States
18		Iowa City	Iowa	United States
19		Baltimore	Maryland	United States
20		Boston	Massachusetts	United States
21		Ann Arbor	Michigan	United States
22		Grand Rapids	Michigan	United States
23		Minneapolis	Minnesota	United States
24		Saint Louis	Missouri	United States
25		Lebanon	New Hampshire	United States
26		New York	New York	United States
27		Syracuse	New York	United States
28		Valhalla	New York	United States
29		Chapel Hill	North Carolina	United States
30		Akron	Ohio	United States
31		Cincinnati	Ohio	United States
32		Cleveland	Ohio	United States
33		Toledo	Ohio	United States
34		Portland	Oregon	United States
35		Philadelphia	Pennsylvania	United States
36		Pittsburgh	Pennsylvania	United States
37		Charleston	South Carolina	United States
38		Sioux Falls	South Dakota	United States
39		Memphis	Tennessee	United States
40		Austin	Texas	United States
41		Dallas	Texas	United States
42		Tyler	Texas	United States
43		Salt Lake City	Utah	United States
44		Norfolk	Virginia	United States
45		Seattle	Washington	United States
46		Spokane	Washington	United States
47		Milwaukee	Wisconsin	United States
48		Adelaide		Australia
49		Melbourne		Australia
50		South Brisbane		Australia
51		Westmead		Australia
52		Gent		Belgium
53		Montreal		Canada
54		Quebec City		Canada
55		Toronto		Canada
56		Vancouver		Canada
57		Marseille cedex 20	Bouches-du-Rhone	France
58		Montpellier cedex 5	Herault	France
59		Rennes cedex 09	Ille Et Vilaine	France
60		Lille cedex	Nord	France
61		Paris cedex 14	Paris	France
62		Paris cedex 15	Paris	France
63		Bron	Rhone	France
64		Bordeaux Cedex		France
65		Muenchen	Bayern	Germany
66		Munchen	Bayern	Germany
67		Hannover	Niedersachsen	Germany
68		Essen	Nordrhein Westfalen	Germany
69		Jena	Thueringen	Germany
70		Berlin		Germany
71		Haifa		Israel
72		Jerusalem		Israel
73		Petach-Tikva		Israel
74		Ramat-Gan		Israel
75		Ancona		Italy
76		Milano		Italy
77		Orbassano		Italy
78		Potenza		Italy
79		Roma		Italy
80		Verona		Italy
81		Amsterdam		Netherlands
82		Den Haag		Netherlands
83		Rotterdam		Netherlands
84		Utrecht		Netherlands
85		Bern		Switzerland
86		St Gallen		Switzerland
87		Zuerich		Switzerland
88		Exeter	Devon	United Kingdom
89		London	Greater London	United Kingdom
90		Manchester	Greater Manchester	United Kingdom
91		Southampton	Hampshire	United Kingdom
92		Liverpool	Lancashire	United Kingdom
93		Glasgow	Strathclyde	United Kingdom
94		Leeds	West Yorkshire	United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 10, 2016
• Statistical Analysis Plan - Feb 24, 2017

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02392234
• Other Study ID Numbers: VX14-661-108; 2014-004788-18
• First Posted: Mar 18, 2015
• Last Update Posted: Jun 12, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Recruitment Details	A total of 248 participants were enrolled. Out of which, 246 received at least 1 dose of study drug were included in safety set and 244 participants who carried intended cystic fibrosis transmembrane conductance regulator (CFTR) mutations were included in Full analysis set.
Pre-assignment Detail	Participants were randomized to 1 of 6 treatment sequences, each of which included 2 treatment periods and 2 of 3 potential treatments (placebo, VX-661/ivacaftor [IVA], IVA). Treatment periods were separated by an 8 week wash-out period.

Arm/Group Title	First VX-661/IVA, Then IVA	First VX-661/IVA, Then Placebo	First IVA, Then Placebo	First IVA, Then VX- 661/IVA	First Placebo, Then VX- 661/IVA	First Placebo, Then IVA
Arm/Group Description	VX-661 100 milligram (mg) plus IVA 150 mg fixed dose combination (FDC) tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.
Period Title: Treatment Period 1 (8 Weeks)
STARTED	41	43	40	42	41	41
Treated	41	43	39	42	40	41
COMPLETED	38	43	38	41	37	38
NOT COMPLETED	3	0	2	1	4	3
Period Title: Treatment Period 1 (8 Weeks)
STARTED	38	43	38	41	37	38
COMPLETED	37	43	38	41	37	38
NOT COMPLETED	1	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	First VX- 661/IVA, Then IVA	First VX-661/IVA, Then Placebo	First IVA, Then Placebo	First IVA, Then VX- 661/IVA	First Placebo, Then VX- 661/IVA	First Placebo, Then IVA	Total
Arm/Group Description	VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by VX-661 100 mg plus IVA 150 mg FDC tablet and placebo matched to IVA tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	Placebo matched to VX-661 plus IVA FDC tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 followed by IVA 150 mg tablet and placebo matched to VX-661 plus IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 2. Each treatment period was separated by a minimum 8 weeks of washout period.	Total of all reporting groups
Overall Participants	41	43	40	42	41	41	248
Age (Count of Participants)
<=18 years	5 12.2%	6 14%	7 17.5%	5 11.9%	5 12.2%	6 14.6%	34 13.7%
Between 18 and 65 years	36 87.8%	37 86%	33 82.5%	37 88.1%	34 82.9%	35 85.4%	212 85.5%
>=65 years	0 0%	0 0%	0 0%	0 0%	2 4.9%	0 0%	2 0.8%
Sex: Female, Male (Count of Participants)
Female	23 56.1%	25 58.1%	19 47.5%	21 50%	23 56.1%	23 56.1%	134 54%
Male	18 43.9%	18 41.9%	21 52.5%	21 50%	18 43.9%	18 43.9%	114 46%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.4%	0 0%	1 2.5%	3 7.1%	2 4.9%	2 4.9%	9 3.6%
Not Hispanic or Latino	40 97.6%	43 100%	39 97.5%	39 92.9%	37 90.2%	39 95.1%	237 95.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	2 4.9%	0 0%	2 0.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.4%	1 0.4%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 4.9%	0 0%	0 0%	0 0%	0 0%	1 2.4%	3 1.2%
White	39 95.1%	42 97.7%	40 100%	42 100%	39 95.1%	39 95.1%	241 97.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 2.3%	0 0%	0 0%	2 4.9%	0 0%	3 1.2%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Study Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Average of Week 4 and Week 8
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Week 4 and Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who carry the protocol specified cystic fibrosis transmembrane conductance regulator gene (CFTR) mutations and had received at least 1 dose of study drug. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.

Arm/Group Title	Placebo	Ivacaftor	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.	VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	160	156	159
Least Squares Mean (95% Confidence Interval) [percentage of predicted FEV1]	-0.3	4.4	6.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	4.7
	Confidence Interval	(2-Sided) 95%; 3.7 to 5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	6.8
	Confidence Interval	(2-Sided) 95%; 5.7 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Absolute Change From Study Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Average of Week 4 and Week 8
Description	The CFQ-R assessed respiratory symptoms on a scale with scores ranging from 0 to 100; where higher scores indicated fewer symptoms and better health-related quality of life.
Time Frame	Baseline, Week 4 and Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.

Arm/Group Title	Placebo	Ivacaftor	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	160	156	161
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.0	8.7	10.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 7.2 to 12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	11.1
	Confidence Interval	(2-Sided) 95%; 8.7 to 13.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 study drug.

Arm/Group Title	Placebo	Ivacaftor	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.	VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	162	157	162
Participants with any AEs	126 307.3%	114 265.1%	117 292.5%
Participants with SAEs	14 34.1%	10 23.3%	8 20%

4. Secondary Outcome

Title	Relative Change From Study Baseline in ppFEV1 at Average of Week 4 and Week 8
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Week 4 and Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.

Arm/Group Title	Placebo	Ivacaftor	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.	VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	160	156	159
Least Squares Mean (95% Confidence Interval) [percent change]	-0.2	7.9	11.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	8.1
	Confidence Interval	(2-Sided) 95%; 6.3 to 9.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	11.4
	Confidence Interval	(2-Sided) 95%; 9.6 to 13.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Absolute Change From Study Baseline in Sweat Chloride at Average of Week 4 and Week 8
Time Frame	Baseline, Week 4 and Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

FAS was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.

Arm/Group Title	Placebo	Ivacaftor	VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.	VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	151	153	151
Least Squares Mean (95% Confidence Interval) [millimoles per liter (mmol/L)]	-0.4	-4.9	-9.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Ivacaftor
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.5
	Confidence Interval	(2-Sided) 95%; -6.7 to -2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Linear Mixed Effects Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-9.5
	Confidence Interval	(2-Sided) 95%; -11.7 to -7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661), IVA and IVA Metabolite (M1 IVA) After Administration of VX-661/IVA Combination Therapy
Time Frame	Pre-morning dose on Week 8 of each treatment period

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.

Arm/Group Title	VX-661/IVA
Arm/Group Description	VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	161
VX-661	2370 (1330)
M1 VX-661	5230 (1940)
IVA	909 (530)
M1 IVA	2010 (1050)

7. Secondary Outcome

Title	Ctrough of IVA and IVA Metabolite (M1 IVA) After Administration of IVA Monotherapy
Time Frame	Pre-morning dose on Week 8 of each treatment period

Outcome Measure Data

Analysis Population Description

PK set was used. Here 'Overall Number of participants analyzed' signifies those participants who had evaluable data for this outcome measure.

Arm/Group Title	Ivacaftor
Arm/Group Description	IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
Measure Participants	155
IVA	696 (435)
M1 IVA	1550 (808)

Adverse Events

Time Frame	Day 1 up to Week 28
Arm/Group Title	Placebo		Ivacaftor		VX-661/IVA
Arm/Group Description	Placebo matched to VX-661/Ivacaftor (IVA) fixed dose combination (FDC) tablet and placebo matched to IVA tablet in the morning, placebo matched to IVA tablet in the evening for 8 weeks in treatment period 1 and 2.		IVA 150 milligram (mg) tablet and placebo matched to VX-661/IVA FDC tablet in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.		VX-661 100 mg/IVA 150 mg FDC tablet and placebo matched to IVA in the morning, IVA 150 mg tablet in the evening for 8 weeks in treatment period 1 and 2.
All Cause Mortality
	Placebo		Ivacaftor		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/162 (0%)		0/157 (0%)		0/162 (0%)
Serious Adverse Events
	Placebo		Ivacaftor		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/162 (8.6%)		10/157 (6.4%)		8/162 (4.9%)
Gastrointestinal disorders
Abdominal pain	2/162 (1.2%)		0/157 (0%)		0/162 (0%)
Distal intestinal obstruction syndrome	0/162 (0%)		1/157 (0.6%)		0/162 (0%)
Pancreatitis	0/162 (0%)		1/157 (0.6%)		0/162 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	8/162 (4.9%)		6/157 (3.8%)		4/162 (2.5%)
Influenza	0/162 (0%)		0/157 (0%)		1/162 (0.6%)
Pneumonia	2/162 (1.2%)		0/157 (0%)		0/162 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/162 (0%)		0/157 (0%)		1/162 (0.6%)
Investigations
Blood creatine phosphokinase increased	0/162 (0%)		2/157 (1.3%)		0/162 (0%)
Pulmonary function test decreased	1/162 (0.6%)		0/157 (0%)		0/162 (0%)
Nervous system disorders
Headache	0/162 (0%)		0/157 (0%)		1/162 (0.6%)
Psychiatric disorders
Mental status changes	1/162 (0.6%)		0/157 (0%)		0/162 (0%)
Renal and urinary disorders
Urethral stenosis	1/162 (0.6%)		0/157 (0%)		0/162 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	1/162 (0.6%)		0/157 (0%)		1/162 (0.6%)
Acute respiratory failure	1/162 (0.6%)		0/157 (0%)		0/162 (0%)
Haemoptysis	2/162 (1.2%)		1/157 (0.6%)		0/162 (0%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	1/162 (0.6%)		0/157 (0%)		0/162 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Ivacaftor		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	87/162 (53.7%)		54/157 (34.4%)		80/162 (49.4%)
Gastrointestinal disorders
Diarrhoea	10/162 (6.2%)		5/157 (3.2%)		13/162 (8%)
Nausea	10/162 (6.2%)		3/157 (1.9%)		9/162 (5.6%)
General disorders
Fatigue	16/162 (9.9%)		7/157 (4.5%)		12/162 (7.4%)
Pyrexia	12/162 (7.4%)		2/157 (1.3%)		8/162 (4.9%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	25/162 (15.4%)		14/157 (8.9%)		19/162 (11.7%)
Nasopharyngitis	5/162 (3.1%)		6/157 (3.8%)		13/162 (8%)
Nervous system disorders
Headache	13/162 (8%)		11/157 (7%)		18/162 (11.1%)
Respiratory, thoracic and mediastinal disorders
Cough	30/162 (18.5%)		17/157 (10.8%)		23/162 (14.2%)
Sputum increased	11/162 (6.8%)		12/157 (7.6%)		14/162 (8.6%)
Haemoptysis	12/162 (7.4%)		17/157 (10.8%)		12/162 (7.4%)
Dyspnoea	11/162 (6.8%)		3/157 (1.9%)		9/162 (5.6%)
Oropharyngeal pain	9/162 (5.6%)		7/157 (4.5%)		9/162 (5.6%)
Nasal congestion	9/162 (5.6%)		3/157 (1.9%)		6/162 (3.7%)

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.