A Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02516410
• Collaborator: (none)
• Enrollment: 168
• Locations: 43
• Arms: 2
• Duration (Months): 10.2
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Study to evaluate the efficacy of VX-661 in combination with ivacaftor (IVA, VX-770) through Week 12 in participants with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or IVA therapy (F508del/not responsive [NR]).

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 168 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, Heterozygous for the F508del-CFTR Mutation and With a Second CFTR Mutation That Is Not Likely to Respond to VX-661 and/or Ivacaftor Therapy (F508del/NR)
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Jun 7, 2016
• Actual Study Completion Date: Jun 7, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VX-661/IVA VX-661 100 milligram (mg) plus IVA 150 mg fixed dose combination (FDC) tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.	Drug: VX-661 plus ivacaftor combination; Drug: Ivacaftor; Other Names: IVA VX-770
Placebo Comparator: Placebo Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.	Drug: Placebo (matched to VX-661 plus ivacaftor combination); Drug: Placebo (matched to ivacaftor)

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12 [Baseline, Through Week 12]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.

Secondary Outcome Measures

1. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12 [Baseline, Through Week 12]

   The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.

2. Number of Pulmonary Exacerbation Events [Baseline through Week 12]

   Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.

3. Number of Pulmonary Exacerbation Events Per Year [Baseline through Week 12]

   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. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.

4. Absolute Change From Baseline in Body Mass Index (BMI) at Week 12 [Baseline, Week 12]

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

5. Relative Change From Baseline in Percent Predicted FEV1 Through Week 12 [Baseline, Through Week 12]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.

6. Absolute Change From Baseline in Sweat Chloride Through Week 12 [Baseline, Through Week 12]

   Sweat samples were collected using an approved collection device.

7. Number of Participants With at Least One Pulmonary Exacerbation Through Week 12 [Baseline through Week 12]

   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. 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.

8. Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening) [Baseline, Week 12]

   Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.

9. Absolute Change From Baseline in Body Weight at Week 12 [Baseline, Week 12]

10. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to Week 16]

    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 16 was considered treatment-emergent.

11. Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) [Pre-morning dose on Week 2, Week 4, Week 8 and Week 12]

    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:

• Confirmed diagnosis of CF defined as a sweat chloride value greater than or equal to (>=)60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis.

• Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit.

• Forced Expiratory Volume in 1 Second (FEV1) >=40 percent (%) and less than or equal to (<=)90% of predicted normal for age, sex, and height at Screening 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).

• History of solid organ or hematological transplantation.

• Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator within 30 days of screening.

• Pregnant or nursing females.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		La Jolla	California	United States
3		Los Angeles	California	United States
4		Denver	Colorado	United States
5		Miami	Florida	United States
6		Atlanta	Georgia	United States
7		Chicago	Illinois	United States
8		Indianapolis	Indiana	United States
9		New Orleans	Louisiana	United States
10		Ann Arbor	Michigan	United States
11		Detroit	Michigan	United States
12		Minneapolis	Minnesota	United States
13		Kansas City	Missouri	United States
14		Omaha	Nebraska	United States
15		New York	New York	United States
16		Cincinnati	Ohio	United States
17		Memphis	Tennessee	United States
18		Austin	Texas	United States
19		Dallas	Texas	United States
20		Richmond	Virginia	United States
21		Seattle	Washington	United States
22		Spokane	Washington	United States
23		Brisban	Queensland	Australia
24		Chermside		Australia
25		Herston		Australia
26		Innsbruck		Australia
27		Westmead		Australia
28		Graz		Austria
29		Innsbruck		Austria
30		Salzburg		Austria
31		Vancouver	British Columbia	Canada
32		Montreal		Canada
33		Bron Cedex		France
34		Montpellier Cedex 5		France
35		Paris Cedex 14		France
36		Paris Cedex 19		France
37		Paris		France
38		Haifa		Israel
39		Hashomer		Israel
40		Jerusalem		Israel
41		Petah Tikva		Israel
42		Barcelona		Spain
43		Valencia		Spain

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT02516410
• Other Study ID Numbers: VX14-661-107; 2014-004787-37
• First Posted: Aug 5, 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	The study was conducted across 38 sites in 7 countries.
Pre-assignment Detail	A total of 168 participants were randomized and 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 milligram (mg) plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Period Title: Overall Study
STARTED	85	83
COMPLETED	85	81
NOT COMPLETED	0	2

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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.	Total of all reporting groups
Overall Participants	85	83	168
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26 (8.8)	26.2 (9.6)	26.1 (9.2)
Sex: Female, Male (Count of Participants)
Female	42 49.4%	39 47%	81 48.2%
Male	43 50.6%	44 53%	87 51.8%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Time Frame	Baseline, Through Week 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	82
Least Squares Mean (Standard Error) [Percentage of predicted FEV1]	-0.1 (0.6)	1 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, VX-661/IVA
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	= 0.1176
	Comments
	Method	Mixed-effect repeated measure (MMRM)
	Comments
Method of Estimation	Estimation Parameter	Least squares (LS) mean difference
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -0.3 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12
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 (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame	Baseline, Through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	83
Least Squares Mean (95% Confidence Interval) [Units on a scale]	3.8	5.9

3. Secondary Outcome

Title	Number of Pulmonary Exacerbation Events
Description	Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.
Time Frame	Baseline through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	83
Number [Pulmonary exacerbation events]	23	22

4. Secondary Outcome

Title	Number of Pulmonary Exacerbation Events Per Year
Description	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. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Time Frame	Baseline through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	83
Number [Pulmonary exacerbation events per year]	0.98	0.97

5. Secondary Outcome

Title	Absolute Change From Baseline in Body Mass Index (BMI) at Week 12
Description	BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	82
Least Squares Mean (95% Confidence Interval) [Kg/m^2]	0.22	0.14

6. Secondary Outcome

Title	Relative Change From Baseline in Percent Predicted FEV1 Through Week 12
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Time Frame	Baseline, Through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	82
Least Squares Mean (95% Confidence Interval) [Percent Change]	0.1	2.1

7. Secondary Outcome

Title	Absolute Change From Baseline in Sweat Chloride Through Week 12
Description	Sweat samples were collected using an approved collection device.
Time Frame	Baseline, Through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	84	79
Least Squares Mean (95% Confidence Interval) [Millimole per liter (mmol/L)]	-1.2	-4.7

8. Secondary Outcome

Title	Number of Participants With at Least One Pulmonary Exacerbation Through Week 12
Description	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. 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	Baseline through Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	83
Count of Participants [Participants]	21 24.7%	19 22.9%

9. Secondary Outcome

Title	Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening)
Description	Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.
Time Frame	Baseline, Week 12

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.

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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	22	25
Least Squares Mean (95% Confidence Interval) [Z-score]	0.07	0.02

10. Secondary Outcome

Title	Absolute Change From Baseline in Body Weight at Week 12
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of study drug. Here 'Number of participants analysed' 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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	82
Least Squares Mean (95% Confidence Interval) [Kilograms (kg)]	0.7	0.6

11. 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 16 was considered treatment-emergent.
Time Frame	Baseline up to Week 16

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 film-coated tablet administered orally in the evening up to Week 12.	VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	85	83
Participants with any AEs	68 80%	64 77.1%
Participants with any SAEs	14 16.5%	11 13.3%

12. Secondary Outcome

Title	Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 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 2, Week 4, Week 8 and Week 12

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' = those participants who were evaluable for this endpoint and 'Number Analyzed' = those participants who were evaluable at the specified time points for each arm, respectively.

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 film-coated tablet administered orally in the evening up to Week 12.
Measure Participants	82
Week 2: VX-661	1880 (1230)
Week 2: M1 VX-661	4600 (1430)
Week 2: IVA	831 (607)
Week 2: M1-IVA	1580 (879)
Week 4: VX-661	1780 (1010)
Week 4: M1 VX-661	4420 (1340)
Week 4: IVA	770 (596)
Week 4: M1-IVA	1500 (898)
Week 8: VX-661	1920 (2170)
Week 8: M1 VX-661	4330 (1980)
Week 8: IVA	747 (745)
Week 8: M1-IVA	1370 (1070)
Week 12: VX-661	1700 (1220)
Week 12: M1 VX-661	4290 (1730)
Week 12: IVA	776 (690)
Week 12: M1-IVA	1620 (1160)

Adverse Events

Time Frame	Baseline up to Week 16
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 film-coated tablet administered orally in the evening up to Week 12.		VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
All Cause Mortality
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/85 (0%)		0/83 (0%)
Serious Adverse Events
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/85 (16.5%)		11/83 (13.3%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome	0/85 (0%)		3/83 (3.6%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	12/85 (14.1%)		6/83 (7.2%)
Lower respiratory tract infection bacterial	0/85 (0%)		1/83 (1.2%)
Influenza	1/85 (1.2%)		0/83 (0%)
Sinusitis	1/85 (1.2%)		0/83 (0%)
Investigations
Pulmonary function test decreased	1/85 (1.2%)		0/83 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/85 (0%)		1/83 (1.2%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/85 (1.2%)		2/83 (2.4%)
Productive cough	1/85 (1.2%)		0/83 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		VX-661/IVA
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	63/85 (74.1%)		62/83 (74.7%)
Gastrointestinal disorders
Nausea	6/85 (7.1%)		6/83 (7.2%)
General disorders
Fatigue	4/85 (4.7%)		10/83 (12%)
Pyrexia	5/85 (5.9%)		5/83 (6%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	15/85 (17.6%)		17/83 (20.5%)
Nasopharyngitis	5/85 (5.9%)		2/83 (2.4%)
Nervous system disorders
Headache	7/85 (8.2%)		5/83 (6%)
Respiratory, thoracic and mediastinal disorders
Cough	27/85 (31.8%)		19/83 (22.9%)
Haemoptysis	6/85 (7.1%)		8/83 (9.6%)
Nasal congestion	8/85 (9.4%)		7/83 (8.4%)
Sputum increased	12/85 (14.1%)		7/83 (8.4%)
Dyspnoea	7/85 (8.2%)		5/83 (6%)
Oropharyngeal pain	6/85 (7.1%)		5/83 (6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Restriction Description: PI is free to publish results of the study after (1)first multi-center publication, (2)if 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