Study of VX-661 Alone and in Combination With Ivacaftor in Subjects Homozygous or Heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) Mutation

Sponsor

Vertex Pharmaceuticals Incorporated (Industry)

Overall Status

Completed

CT.gov ID

NCT01531673

Collaborator

(none)

194

Enrollment

Locations

Arms

24.9

Duration (Months)

5.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) effects of VX-661 alone and when coadministered with ivacaftor in participants with cystic fibrosis (CF) who are homozygous or heterozygous for the F508del-CFTR mutation.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: VX-661 Drug: Ivacaftor Drug: Placebo matched to VX-661 Drug: Placebo matched to ivacaftor	Phase 2

Detailed Description

This is a Phase 2, randomized, multicenter, double-blinded, placebo-controlled, study of VX-661 monotherapy, and VX-661/ivacaftor co-therapy in participants with CF who are homozygous or heterozygous for the F508del CFTR mutation.

This study is separated into seven groups: Group 1-7, respectively. Approximately 180 participants were randomized in a ratio of 4:1; active drug to matching placebo in each group.

Study Design

Study Type:

Interventional

Actual Enrollment :

194 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase 2, Multicenter, Double-Blinded, Placebo Controlled Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of VX-661 Monotherapy and VX-661/Ivacaftor Cotherapy in Subjects With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

Study Start Date :

Feb 1, 2012

Actual Primary Completion Date :

Mar 1, 2014

Actual Study Completion Date :

Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Group 1-6d Combined: Placebo All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.	Drug: Placebo matched to VX-661 Drug: Placebo matched to ivacaftor
Experimental: Group 1: VX-661 10 mg qd All participants in group 1 who received VX-661 10 milligram (mg) tablet orally once daily (qd) for up to 28 days.	Drug: VX-661
Experimental: Group 2a: VX-661 30 mg qd All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet every 12 hours (q12h) for up to 28 days.	Drug: VX-661 Drug: Placebo matched to ivacaftor
Experimental: Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Experimental: Group 3a: VX-661 100 mg qd All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	Drug: VX-661 Drug: Placebo matched to ivacaftor
Experimental: Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Experimental: Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Experimental: Group 5a: VX-661 150 mg qd All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	Drug: VX-661
Experimental: Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Experimental: Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Experimental: Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	Drug: VX-661 Drug: Ivacaftor
Placebo Comparator: Group 7: Placebo All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days.	Drug: Ivacaftor Drug: Placebo matched to VX-661
Experimental: Group 7: VX-661 100 mg qd All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco (Ivacaftor) for up to 28 days.	Drug: VX-661 Drug: Ivacaftor

Outcome Measures

Primary Outcome Measures

Safety as Determined by Adverse Events (AEs) [Start of study drug through the Follow-up Visit (Up to Day 56)]
An AE is defined as any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. AE includes serious as well as non-serious AEs. Serious Adverse Event (SAE) is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit (28 days after last dose of study drug) or premature discontinuation.
Change in Sweat Chloride From Baseline Through Study Day 28 for Group 1-5b [Baseline through Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6 [Baseline through Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7 [Baseline through Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.

Secondary Outcome Measures

Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 1-5b [Baseline, Day 7, Day 14, Day 21, Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6 [Baseline, Day 7, Day 14, Day 21, Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7 [Baseline, Day 7, Day 14, Day 21, Day 28]
Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [Baseline, Day 7, Day 14, Day 21, Day 28]
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b [Baseline, Day 14, Day 28]
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.
Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6 [Baseline, Day 14, Day 28]
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. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7 [Baseline, Day 14, Day 28]
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.
Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 After Administration of VX-661 Monotherapy [Day 28]
Participants who received VX-661 monotherapy (Group 1, 2a, 3a and 5a) were analyzed for this outcome measure. PK analysis (AUC0-24h) was not planned for placebo reporting arms.
AUC0-24h of VX-661 and AUC0-12h of Ivacaftor After Administration of VX-661 in Combination With Ivacaftor [Day 28]
Participants who received VX-661 in combination with Ivacaftor (Group 2b, 3b, 4, 5b, 6a, 6d and 7) were analyzed for this outcome measure. PK analysis was not planned for placebo reporting arms.

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female with confirmed diagnosis of CF
Must have the F508del-CFTR gene mutation in both alleles (Groups 1, 2, 3, 4, 5, 6). Group 7 participants must have the F508del-CFTR mutation on 1 allele, and gating mutation G551D on the second allele and have been on their physician prescribed 150 mg KalydecoTM q12h (commercially available ivacaftor) for at least 28 days at the Screening Visit.
Forced expiratory volume in 1 second(FEV1) 40% to 90% (inclusive) of predicted normal for age, gender, and height (Knudson standards) at screening
Weight >40 kg and BMI >18.5
Participants of child-bearing potential and who are sexually active must meet the contraception requirements.

Exclusion Criteria:

History of any illness 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 4 weeks before Study Day

History of solid organ or hematological transplantation
Participation in a clinical study involving administration of either an investigational or a marketed drug within 30 days or 5 terminal half-lives (whichever is longer) before screening
History of alcohol, medication, or illicit drug abuse within 1 year prior to screening
Pregnant, breast-feeding, or not willing to follow contraception requirements

Contacts and Locations

Locations

	Site	City	State	Country
1	Vertex Investigational Site	Birmingham	Alabama	United States
2	Vertex Investigational Site	Oakland	California	United States
3	Vertex Investigational Site	Boise	Idaho	United States
4	Vertex Investigational Site	Chicago	Illinois	United States
5	Vertex Investigational Site	Boston	Massachusetts	United States
6	Vertex Investigational Site	Grand Rapids	Michigan	United States
7	Vertex Investigational Site	Kansas City	Missouri	United States
8	Vertex Investigational Site	Long Branch	New Jersey	United States
9	Vertex Investigational Site	New Hyde Park	New York	United States
10	Vertex Investigational Site	Chapel Hill	North Carolina	United States
11	Vertex Investigational Site	Cincinnati	Ohio	United States
12	Vertex Investigational Site	Columbus	Ohio	United States
13	Vertex Investigational Site	Oklahoma City	Oklahoma	United States
14	Vertex Investigational Site	Hershey	Pennsylvania	United States
15	Vertex Investigational Site	Pittsburgh	Pennsylvania	United States
16	Vertex Investigational Site	Charleston	South Carolina	United States
17	Vertex Investigational Site	Salt Lake City	Utah	United States
18	Vertex Investigational Site	Burlington	Vermont	United States
19	Vertex Investigational Site	Seattle	Washington	United States
20	Vertex Investigational Site	Calgary	Alberta	Canada
21	Vertex Investigational Site	Vancouver	British Columbia	Canada
22	Vertex Investigational Site	Halifax	Nova Scotia	Canada
23	Vertex Investigational Site	Toronto	Ontario	Canada
24	Vertex Investigational Site	Erlangen	Bayern	Germany
25	Vertex Investigational Site	Frankfurt	Hessen	Germany
26	Vertex Investigational Site	Hannover	Niedersachsen	Germany
27	Vertex Investigational Site	Koeln	Nordrhein Westfalen	Germany
28	Vertex Investigational Site	Berlin		Germany
29	Vertex Investigational Site	Bochum		Germany
30	Vertex Investigational Site	Jena		Germany
31	Vertex Investigational Site	Munich		Germany
32	Vertex Investigational Site	Cambridge	Cambridgeshire	United Kingdom
33	Vertex Investigational Site	London	Greater London	United Kingdom
34	Vertex Investigational Site	Manchester	Greater Manchester	United Kingdom
35	Vertex Investigational Site	Southhampton	Hampshire	United Kingdom
36	Vertex Investigational Site	Cardiff	Vale Of Glamorgen	United Kingdom

Sponsors and Collaborators

Vertex Pharmaceuticals Incorporated

Investigators

Principal Investigator: Scott Donaldson, MD, University of North Carolina

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Vertex Pharmaceuticals Incorporated

ClinicalTrials.gov Identifier:

NCT01531673

Other Study ID Numbers:

VX11-661-101
2011-003821-93

First Posted:

Feb 13, 2012

Last Update Posted:

Apr 13, 2018

Last Verified:

Mar 1, 2018

Additional relevant MeSH terms:

Cystic Fibrosis

Fibrosis

Ivacaftor

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	A total of 194 participants were randomized of which 190 participants were treated.

Arm/Group Title	Group 1-6d Combined: Placebo	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.	All participants in group 1 who received VX-661 10 milligram (mg) tablet orally once daily (qd) for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet every 12 hours (q12h) for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Period Title: Overall Study
STARTED	33	8	8	18	8	19	17	9	17	19	16	4	14
COMPLETED	33	7	8	17	7	18	17	9	17	18	16	4	14
NOT COMPLETED	0	1	0	1	1	1	0	0	0	1	0	0	0

Baseline Characteristics

Arm/Group Title	Group 1-6d Combined: Placebo	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 7: Placebo	Group 7: VX-661 100 mg qd	Total
Arm/Group Description	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	Total of all reporting groups
Overall Participants	33	8	8	18	8	19	17	9	17	19	16	4	14	190
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.7 (8.42)	35.3 (8.26)	30.8 (6.63)	28.3 (7.05)	29.1 (7.12)	29.2 (6.39)	31 (9.3)	28.2 (8.6)	28.2 (6.46)	27.9 (5.58)	32.8 (11.92)	34.5 (7.59)	26.6 (7.01)	29.8 (7.97)
Sex: Female, Male (Count of Participants)
Female	13 39.4%	4 50%	4 50%	6 33.3%	3 37.5%	6 31.6%	11 64.7%	3 33.3%	10 58.8%	7 36.8%	7 43.8%	3 75%	6 42.9%	83 43.7%
Male	20 60.6%	4 50%	4 50%	12 66.7%	5 62.5%	13 68.4%	6 35.3%	6 66.7%	7 41.2%	12 63.2%	9 56.3%	1 25%	8 57.1%	107 56.3%

Outcome Measures

1. Primary Outcome

Title	Safety as Determined by Adverse Events (AEs)
Description	An AE is defined as any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the Informed Consent Form is signed. AE includes serious as well as non-serious AEs. Serious Adverse Event (SAE) is any AE that results in any of the following: death; life-threatening condition; inpatient hospitalization or prolongation of hospitalization; persistent or significant disability or incapacity; congenital anomaly or birth defect; or other important medical event. Treatment-emergent adverse events are defined as adverse events that were reported or worsened on or after start of study drug through the Follow-up Visit (28 days after last dose of study drug) or premature discontinuation.
Time Frame	Start of study drug through the Follow-up Visit (Up to Day 56)

Outcome Measure Data

Analysis Population Description
Analysis was done using safety set which included all participants who received at least 1 dose of study drug.

Arm/Group Title	Group 1-6d Combined: Placebo	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	33	8	8	18	8	19	17	9	17	19	16	4	14
Participants with AEs	30 90.9%	8 100%	7 87.5%	15 83.3%	7 87.5%	18 94.7%	10 58.8%	8 88.9%	17 100%	16 84.2%	16 100%	2 50%	12 85.7%
Participants with SAEs	5 15.2%	1 12.5%	1 12.5%	1 5.6%	0 0%	2 10.5%	2 11.8%	0 0%	0 0%	1 5.3%	2 12.5%	0 0%	1 7.1%

2. Primary Outcome

Title	Change in Sweat Chloride From Baseline Through Study Day 28 for Group 1-5b
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Time Frame	Baseline through Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using Full Analysis Set (FAS) which included all randomized participants who received at least 1 dose of study drug. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint.

Arm/Group Title	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 1-5b Combined Placebo
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	8	6	18	8	18	17	9	17	24
Least Squares Mean (95% Confidence Interval) [millimole per liter (mmol/L)]	3.92	-4.76	-5.06	-20.43	-6	-6.04	-10.46	-2.63	-0.86

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1-6d Combined: Placebo, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0647
	Comments
	Method	Mixed-effect repeated measure (MMRM)
	Comments

Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	4.77
	Confidence Interval	(2-Sided) 95% -0.3 to 9.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group 1: VX-661 10 mg qd, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.1686
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.91
	Confidence Interval	(2-Sided) 95% -9.5 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Group 2a: VX-661 30 mg qd, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0348
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95% -8.1 to -0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	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	-19.58
	Confidence Interval	(2-Sided) 95% -24.57 to -14.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Group 3a: VX-661 100 mg qd, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0101
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.14
	Confidence Interval	(2-Sided) 95% -9.03 to -1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.19
	Confidence Interval	(2-Sided) 95% -9.16 to -1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	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	-9.6
	Confidence Interval	(2-Sided) 95% -14.38 to -4.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Group 5a: VX-661 150 mg qd, Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.3745
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.77
	Confidence Interval	(2-Sided) 95% -5.71 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change in Sweat Chloride From Baseline Through Study Day 28 for Group 6
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Time Frame	Baseline through Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using Full Analysis Set (FAS) which included all randomized participants who received at least 1 dose of study drug. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint.

Arm/Group Title	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 4 and 6 Combined: Placebo
Arm/Group Description	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet q12h and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	18	16	14
Least Squares Mean (95% Confidence Interval) [mmol/L]	-6.07	-7.89	-1.19

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1: VX-661 10 mg qd, Group 2a: VX-661 30 mg qd
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0357
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.7
	Confidence Interval	(2-Sided) 95% -12.94 to -0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change in Sweat Chloride From Baseline Through Study Day 28 for Group 7
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Time Frame	Baseline through Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number of participants analyzed' = those participants who were evaluable for this endpoint.

Arm/Group Title	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	4	13
Least Squares Mean (95% Confidence Interval) [mmol/L]	10.18	-7.02

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1-6d Combined: Placebo, Group 1: VX-661 10 mg qd
	Comments
	Type of Statistical Test	Superiority
	Comments

Statistical Test of Hypothesis	p-Value	0.0238
	Comments
	Method	MMRM
	Comments

Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-17.2
	Confidence Interval	(2-Sided) 95% -31.75 to -2.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 1-5b
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. 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	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 1-5b Combined Placebo
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	8	8	18	8	18	17	9	17	24
Day 7	1.73	-3.13	-5.37	-19.48	-5.02	-6.85	-13.89	-0.59	0.22
Day 14	0.91	-7.88	-6.55	-28.23	-6.77	-7.37	-10.28	-2.4	-1.32
Day 21	4.84	-4.61	-3.7	-18.78	-5.83	-4.26	-12.17	-3.9	-1.05
Day 28	8.19	-3.44	-4.62	-15.23	-6.37	-5.68	-5.5	-3.62	-1.27

6. Secondary Outcome

Title	Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 6
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. 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 group, respectively.

Arm/Group Title	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 4 and 6 Combined: Placebo
Arm/Group Description	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	19	16	14
Day 7	-6.61	-11.04	-0.36
Day 14	-7.9	-7.11	-2.1
Day 21	-6.34	-6.98	-2.47
Day 28	-3.44	-6.43	0.19

7. Secondary Outcome

Title	Change in Sweat Chloride From Baseline to Each Visit up to Study Day 28 for Group 7
Description	Sweat samples were collected using an approved collection device. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	4	14
Day 7	4.87	-7.28
Day 14	10.75	-8.95
Day 21	9.37	-4.14
Day 28	15.73	-7.72

8. Secondary Outcome

Title	Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 1-5b Combined Placebo
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	8	8	18	8	19	17	9	17	24
Post-Baseline Through Day 28	3.49	1.63	1.3	1.6	2.9	3.75	2.54	3.61	-0.14
Day 7	2.72	0.8	0.47	3	2.9	2.66	0.5	2.51	-0.41
Day 14	5.25	3.72	0.91	1.61	1.79	4.52	2.79	3.72	0.03
Day 21	2.71	1.8	1.84	0.25	3.88	3.37	4.52	4.08	0.18
Day 28	3.26	0.19	1.99	1.55	3.02	4.44	2.34	4.13	-0.36

9. Secondary Outcome

Title	Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 4 and 6 Combined: Placebo
Arm/Group Description	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	19	16	14
Post-Baseline Through Day 28	0.94	2.31	1.47
Day 7	1.37	1.95	1.09
Day 14	1.2	2.52	1.37
Day 21	0.36	3.21	1.73
Day 28	0.81	1.56	1.67

10. Secondary Outcome

Title	Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	4	14
Post-Baseline Through Day 28	1.4	4.6
Day 7	3	4.14
Day 14	0.98	5.22
Day 21	2.72	3.88
Day 28	-1.12	5.16

11. Secondary Outcome

Title	Change in FEV1 (Liter [L]) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 1-5b Combined Placebo
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	8	8	18	8	19	17	9	17	24
PB Through Day 28	0.14	0.07	0.05	0.04	0.1	0.14	0.1	0.12	0.01
Day 7	0.11	0.02	0.02	0.09	0.1	0.11	0.02	0.08	-0.01
Day 14	0.2	0.14	0.03	0.04	0.05	0.17	0.11	0.12	0.02
Day 21	0.12	0.08	0.07	0	0.14	0.13	0.18	0.14	0.02
Day 28	0.13	0.03	0.08	0.04	0.1	0.16	0.09	0.15	0.01

12. Secondary Outcome

Title	Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 4 and 6 Combined: Placebo
Arm/Group Description	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	19	16	14
Post-Baseline Through Day 28	0.02	0.09	0.07
Day 7	0.04	0.06	0.05
Day 14	0.03	0.1	0.06
Day 21	-0.01	0.13	0.08
Day 28	0.02	0.06	0.08

13. Secondary Outcome

Title	Change in FEV1 (L) From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time Frame	Baseline, Day 7, Day 14, Day 21, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	4	14
Post-Baseline Through Day 28	0.09	0.16
Day 7	0.14	0.15
Day 14	0.08	0.18
Day 21	0.14	0.13
Day 28	-0.01	0.19

14. Secondary Outcome

Title	Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 1-5b
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, Day 14, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3a: VX-661 100 mg qd	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5a: VX-661 150 mg qd	Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h	Group 1-5b Combined Placebo
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a and 5b who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	8	8	18	8	19	17	9	17	24
PB Through Day 28	4.02	5.54	3.8	0.61	3.52	5.15	2.58	7.62	1.69
Day 14	6.67	4.84	4.29	0.27	2.81	4.41	4.13	7.13	0.53
Day 28	1.38	6.23	3.31	0.95	4.22	5.9	1.03	8.1	2.85

15. Secondary Outcome

Title	Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 6
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. As per planned analysis, participants who received placebo in Group 4 and 6 were combined and compared with Group 6.
Time Frame	Baseline, Day 14, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h	Group 4 and 6 Combined: Placebo
Arm/Group Description	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.
Measure Participants	19	16	14
Post-Baseline Through Day 28	0.87	1.91	1.65
Day 14	2.02	0.87	2.78
Day 28	-0.27	2.96	0.53

16. Secondary Outcome

Title	Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline to Each Visit and From Baseline Through Study Day 28 for Group 7
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, Day 14, Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using FAS which included all randomized participants who received at least 1 dose of study drug. Here, 'Number Analyzed' = those participants who were evaluable at the specified time points for each group, respectively.

Arm/Group Title	Group 7: Placebo	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
Measure Participants	4	14
Post-Baseline Through Day 28	-3.02	3.79
Day 14	1.83	5.24
Day 28	-7.87	2.33

17. Secondary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24h) of VX-661 After Administration of VX-661 Monotherapy
Description	Participants who received VX-661 monotherapy (Group 1, 2a, 3a and 5a) were analyzed for this outcome measure. PK analysis (AUC0-24h) was not planned for placebo reporting arms.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using Pharmacokinetics (PK) Set.

Arm/Group Title	Group 1: VX-661 10 mg qd	Group 2a: VX-661 30 mg qd	Group 3a: VX-661 100 mg qd	Group 5a: VX-661 150 mg qd
Arm/Group Description	All participants in group 1 who received VX-661 10 mg tablet orally qd for up to 28 days.	All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.	All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.
Measure Participants	7	8	8	9
Mean (Standard Deviation) [nanogramhour per milliliter (nghr/mL)]	6260 (2650)	23000 (6550)	88100 (51100)	98900 (20200)

18. Secondary Outcome

Title	AUC0-24h of VX-661 and AUC0-12h of Ivacaftor After Administration of VX-661 in Combination With Ivacaftor
Description	Participants who received VX-661 in combination with Ivacaftor (Group 2b, 3b, 4, 5b, 6a, 6d and 7) were analyzed for this outcome measure. PK analysis was not planned for placebo reporting arms.
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description
The analysis was done using PK Set.

Arm/Group Title	Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h	Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h	Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h	Group 5b: VX-661 150 mg qd/ Ivacaftor 150 mg q12h	Group 6a: VX-661 100 mg qd/ Ivacaftor 50 mg q12h	Group 6d: VX-661 50 mg q12h/ Ivacaftor 150 mg q12h	Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.	All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.	All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician prescribed Kalydeco for up to 28 days.
Measure Participants	17	13	15	16	17	15	14
AUC0-24h of VX-661	8950 (2370)	26300 (5870)	82700 (23300)	138000 (49700)	77600 (17800)	73300 (22900)	90600 (30800)
AUC0-12h of Ivacaftor	10100 (4380)	11700 (4870)	10900 (3890)	16000 (10400)	3690 (1460)	11700 (5450)	12400 (6170)

Adverse Events

	Group 1-6d Combined: Placebo		Group 1: VX-661 10 mg qd		Group 2a: VX-661 30 mg qd		Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h		Group 3a: VX-661 100 mg qd		Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h		Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h		Group 5a: VX-661 150 mg qd		Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h		Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h		Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h		Group 7: Placebo		Group 7: VX-661 100 mg qd
Time Frame	Start of study drug through the Follow-up Visit (Up to Day 56)
Adverse Event Reporting Description

Arm/Group Title	Group 1-6d Combined: Placebo		Group 1: VX-661 10 mg qd		Group 2a: VX-661 30 mg qd		Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h		Group 3a: VX-661 100 mg qd		Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h		Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h		Group 5a: VX-661 150 mg qd		Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h		Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h		Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h		Group 7: Placebo		Group 7: VX-661 100 mg qd
Arm/Group Description	All participants in group 1, 2a, 2b, 3a, 3b, 4, 5a, 5b, 6a and 6d who received placebo matched to VX-661 tablet and/or placebo matched to ivacaftor tablet for up to 28 days.		All participants in group 1 who received VX-661 10 milligram (mg) tablet orally qd for up to 28 days.		All participants in group 2a who received VX-661 30 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.		All participants in group 2b who received VX-661 10 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.		All participants in group 3a who received VX-661 100 mg tablet orally qd and placebo matched to Ivacaftor tablet q12h for up to 28 days.		All participants in group 3b who received VX-661 30 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.		All participants in group 4 who received VX-661 100 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.		All participants in group 5a who received VX-661 150 mg tablet orally qd for up to 28 days.		All participants in group 5b who received VX-661 150 mg tablet qd and Ivacaftor 150 mg tablet q12h orally for up to 28 days.		All participants in group 6a who received VX-661 100 mg tablet qd and Ivacaftor 50 mg tablet q12h orally for up to 28 days.		All participants in group 6d who received VX-661 50 mg tablet and Ivacaftor 150 mg tablet q12h orally for up to 28 days.		All participants in group 7 who received placebo matched to VX-661 tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.		All participants in group 7 who received VX-661 100 mg tablet orally qd in combination with physician-prescribed Kalydeco for up to 28 days.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Group 1-6d Combined: Placebo		Group 1: VX-661 10 mg qd		Group 2a: VX-661 30 mg qd		Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h		Group 3a: VX-661 100 mg qd		Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h		Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h		Group 5a: VX-661 150 mg qd		Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h		Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h		Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h		Group 7: Placebo		Group 7: VX-661 100 mg qd
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/33 (15.2%)		1/8 (12.5%)		1/8 (12.5%)		1/18 (5.6%)		0/8 (0%)		2/19 (10.5%)		2/17 (11.8%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		2/16 (12.5%)		0/4 (0%)		1/14 (7.1%)
Gastrointestinal disorders
Diarrhoea	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
General disorders
Pyrexia	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	5/33 (15.2%)		1/8 (12.5%)		1/8 (12.5%)		1/18 (5.6%)		0/8 (0%)		1/19 (5.3%)		2/17 (11.8%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		2/16 (12.5%)		0/4 (0%)		0/14 (0%)
Gastroenteritis	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Arthritis	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	Group 1-6d Combined: Placebo		Group 1: VX-661 10 mg qd		Group 2a: VX-661 30 mg qd		Group 2b: VX-661 10 mg qd/Ivacaftor 150 mg q12h		Group 3a: VX-661 100 mg qd		Group 3b: VX-661 30 mg qd/Ivacaftor 150 mg q12h		Group 4: VX-661 100 mg qd/Ivacaftor 150 mg q12h		Group 5a: VX-661 150 mg qd		Group 5b: VX-661 150 mg qd/Ivacaftor 150 mg q12h		Group 6a: VX-661 100 mg qd/Ivacaftor 50 mg q12h		Group 6d: VX-661 50 mg q12h/Ivacaftor 150 mg q12h		Group 7: Placebo		Group 7: VX-661 100 mg qd
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/33 (90.9%)		8/8 (100%)		7/8 (87.5%)		15/18 (83.3%)		7/8 (87.5%)		18/19 (94.7%)		9/17 (52.9%)		8/9 (88.9%)		17/17 (100%)		16/19 (84.2%)		16/16 (100%)		2/4 (50%)		12/14 (85.7%)
Blood and lymphatic system disorders
Anaemia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Ear and labyrinth disorders
Ear pain	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Ear discomfort	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		1/4 (25%)		0/14 (0%)
Vertigo	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Eye disorders
Conjunctival haemorrhage	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Conjunctival irritation	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dry eye	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vision blurred	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Gastrointestinal disorders
Nausea	1/33 (3%)		1/8 (12.5%)		2/8 (25%)		2/18 (11.1%)		1/8 (12.5%)		2/19 (10.5%)		1/17 (5.9%)		4/9 (44.4%)		0/17 (0%)		1/19 (5.3%)		5/16 (31.3%)		0/4 (0%)		2/14 (14.3%)
Diarrhoea	2/33 (6.1%)		1/8 (12.5%)		1/8 (12.5%)		2/18 (11.1%)		1/8 (12.5%)		1/19 (5.3%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		0/19 (0%)		2/16 (12.5%)		0/4 (0%)		0/14 (0%)
Vomiting	1/33 (3%)		0/8 (0%)		1/8 (12.5%)		1/18 (5.6%)		1/8 (12.5%)		2/19 (10.5%)		0/17 (0%)		2/9 (22.2%)		1/17 (5.9%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		1/14 (7.1%)
Abdominal pain	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		3/19 (15.8%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Abdominal pain upper	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		2/17 (11.8%)		2/19 (10.5%)		0/16 (0%)		1/4 (25%)		0/14 (0%)
Constipation	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		2/17 (11.8%)		0/19 (0%)		2/16 (12.5%)		0/4 (0%)		0/14 (0%)
Flatulence	0/33 (0%)		0/8 (0%)		2/8 (25%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Abdominal distension	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Dry mouth	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Abdominal discomfort	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Abdominal pain lower	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Change of bowel habit	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dental caries	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Enteritis	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Faecaloma	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Faeces discoloured	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Frequent bowel movements	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Paraesthesia oral	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Retching	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Toothache	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
General disorders
Fatigue	3/33 (9.1%)		4/8 (50%)		1/8 (12.5%)		1/18 (5.6%)		1/8 (12.5%)		3/19 (15.8%)		0/17 (0%)		1/9 (11.1%)		2/17 (11.8%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		1/14 (7.1%)
Pyrexia	2/33 (6.1%)		2/8 (25%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		2/14 (14.3%)
Application site rash	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Pain	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Thirst	1/33 (3%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Application site erythema	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Catheter site haematoma	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Chest pain	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Disease progression	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Feeling abnormal	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Feeling hot	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Infusion site pain	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Infusion site swelling	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Malaise	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Medical device complication	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Non-cardiac chest pain	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vessel puncture site haematoma	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vessel puncture site reaction	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Immune system disorders
Seasonal allergy	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Drug hypersensitivity	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Hypersensitivity	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	8/33 (24.2%)		0/8 (0%)		0/8 (0%)		4/18 (22.2%)		1/8 (12.5%)		4/19 (21.1%)		3/17 (17.6%)		1/9 (11.1%)		2/17 (11.8%)		2/19 (10.5%)		3/16 (18.8%)		1/4 (25%)		3/14 (21.4%)
Upper respiratory tract infection	3/33 (9.1%)		0/8 (0%)		0/8 (0%)		2/18 (11.1%)		1/8 (12.5%)		2/19 (10.5%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		2/19 (10.5%)		0/16 (0%)		0/4 (0%)		3/14 (21.4%)
Nasopharyngitis	1/33 (3%)		0/8 (0%)		1/8 (12.5%)		1/18 (5.6%)		0/8 (0%)		2/19 (10.5%)		0/17 (0%)		0/9 (0%)		3/17 (17.6%)		0/19 (0%)		3/16 (18.8%)		1/4 (25%)		1/14 (7.1%)
Sinusitis	3/33 (9.1%)		2/8 (25%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Viral upper respiratory tract infection	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		1/19 (5.3%)		1/17 (5.9%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Oral candidiasis	1/33 (3%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Acute sinusitis	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Gastroenteritis	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Oral herpes	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Bronchitis	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Gastroenteritis viral	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Otitis media	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rhinitis	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Bronchopulmonary aspergillosis allergic	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Cellulitis	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Lower respiratory tract infection viral	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Paronychia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Pneumonia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Respiratory syncytial virus infection	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Respiratory tract infection	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Injury, poisoning and procedural complications
Muscle strain	1/33 (3%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Concussion	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Contusion	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Excoriation	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Laceration	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Ligament sprain	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Limb injury	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Post concussion syndrome	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Procedural pain	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Scratch	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Skeletal injury	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Sunburn	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Investigations
Pulmonary function test decreased	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		2/19 (10.5%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Weight decreased	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Alanine aminotransferase increased	1/33 (3%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood glucose decreased	1/33 (3%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Hepatic enzyme increased	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Liver function test abnormal	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Aspartate aminotransferase increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood bilirubin increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood bilirubin unconjugated increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood creatinine increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood phosphorus increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Blood potassium increased	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Gastrointestinal examination abnormal	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Neutrophil count decreased	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Platelet count decreased	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Transaminases increased	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Urinary casts present	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Urine colour abnormal	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Vitamin D decreased	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
White blood cell count decreased	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
White blood cells urine positive	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Metabolism and nutrition disorders
Decreased appetite	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Hypoglycaemia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dehydration	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Hyperglycaemia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Hypocalcaemia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Hyponatraemia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Increased appetite	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vitamin E deficiency	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vitamin K deficiency	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
Myalgia	3/33 (9.1%)		1/8 (12.5%)		0/8 (0%)		2/18 (11.1%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		2/16 (12.5%)		0/4 (0%)		0/14 (0%)
Musculoskeletal chest pain	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		2/8 (25%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Back pain	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		1/19 (5.3%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Pain in extremity	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Arthralgia	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Arthritis	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Joint swelling	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Musculoskeletal pain	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Nervous system disorders
Headache	8/33 (24.2%)		1/8 (12.5%)		1/8 (12.5%)		2/18 (11.1%)		1/8 (12.5%)		4/19 (21.1%)		0/17 (0%)		1/9 (11.1%)		2/17 (11.8%)		4/19 (21.1%)		4/16 (25%)		0/4 (0%)		3/14 (21.4%)
Sinus headache	2/33 (6.1%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Dizziness	0/33 (0%)		0/8 (0%)		3/8 (37.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Lethargy	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Migraine	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Neuralgia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dysgeusia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Partial seizures	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Presyncope	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Somnolence	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Syncope	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Psychiatric disorders
Abnormal dreams	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Anxiety	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Depression	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Insomnia	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Thinking abnormal	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Renal and urinary disorders
Leukocyturia	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Pollakiuria	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Urine odour abnormal	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Reproductive system and breast disorders
Breast tenderness	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dysmenorrhoea	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Menstrual disorder	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Metrorrhagia	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vaginal haemorrhage	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	6/33 (18.2%)		3/8 (37.5%)		3/8 (37.5%)		2/18 (11.1%)		2/8 (25%)		3/19 (15.8%)		2/17 (11.8%)		2/9 (22.2%)		3/17 (17.6%)		4/19 (21.1%)		3/16 (18.8%)		0/4 (0%)		4/14 (28.6%)
Sputum increased	2/33 (6.1%)		2/8 (25%)		2/8 (25%)		2/18 (11.1%)		1/8 (12.5%)		1/19 (5.3%)		2/17 (11.8%)		2/9 (22.2%)		1/17 (5.9%)		2/19 (10.5%)		3/16 (18.8%)		0/4 (0%)		0/14 (0%)
Haemoptysis	2/33 (6.1%)		2/8 (25%)		0/8 (0%)		0/18 (0%)		2/8 (25%)		1/19 (5.3%)		1/17 (5.9%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		1/14 (7.1%)
Oropharyngeal pain	3/33 (9.1%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		1/8 (12.5%)		1/19 (5.3%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		2/16 (12.5%)		0/4 (0%)		2/14 (14.3%)
Nasal congestion	1/33 (3%)		2/8 (25%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		2/19 (10.5%)		1/16 (6.3%)		1/4 (25%)		1/14 (7.1%)
Rales	0/33 (0%)		2/8 (25%)		0/8 (0%)		2/18 (11.1%)		0/8 (0%)		1/19 (5.3%)		2/17 (11.8%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		1/4 (25%)		1/14 (7.1%)
Respiration abnormal	2/33 (6.1%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		2/19 (10.5%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Respiratory tract congestion	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		1/19 (5.3%)		1/17 (5.9%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Sinus congestion	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		2/17 (11.8%)		1/19 (5.3%)		1/16 (6.3%)		1/4 (25%)		0/14 (0%)
Dyspnoea	1/33 (3%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Rhinorrhoea	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		1/17 (5.9%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Epistaxis	1/33 (3%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dysphonia	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dyspnoea exertional	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Increased viscosity of bronchial secretion	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Productive cough	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Sputum discoloured	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Wheezing	0/33 (0%)		1/8 (12.5%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Asthma	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Bronchial obstruction	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Bronchial secretion retention	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Bronchiectasis	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Increased bronchial secretion	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Nasal obstruction	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		1/8 (12.5%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Nasal oedema	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Painful respiration	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Paranasal sinus hypersecretion	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Respiratory tract irritation	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Upper respiratory tract congestion	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Pruritus	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Night sweats	2/33 (6.1%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rash	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		1/17 (5.9%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Cold sweat	0/33 (0%)		0/8 (0%)		1/8 (12.5%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Dry skin	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		1/9 (11.1%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Eczema	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/4 (0%)		0/14 (0%)
Nail disorder	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Photosensitivity reaction	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rash erythematous	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rash follicular	0/33 (0%)		0/8 (0%)		0/8 (0%)		1/18 (5.6%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rash macular	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Rash papular	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		1/19 (5.3%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Red man syndrome	1/33 (3%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		0/14 (0%)
Vascular disorders
Hot flush	0/33 (0%)		0/8 (0%)		0/8 (0%)		0/18 (0%)		0/8 (0%)		0/19 (0%)		0/17 (0%)		0/9 (0%)		0/17 (0%)		0/19 (0%)		0/16 (0%)		0/4 (0%)		1/14 (7.1%)

Limitations/Caveats

Pharmacokinetic (PK) final data are not yet available. Once the data are available for PK endpoints, the posting will be updated to include the same.

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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.

Results Point of Contact

Name/Title	Medical Monitor
Organization	Vertex Pharmaceuticals Incorporated
Phone	617-341-6777
Email	medicalinfo@vrtx.com

Responsible Party:

Vertex Pharmaceuticals Incorporated

ClinicalTrials.gov Identifier:

NCT01531673

Other Study ID Numbers:

VX11-661-101
2011-003821-93

First Posted:

Feb 13, 2012

Last Update Posted:

Apr 13, 2018

Last Verified:

Mar 1, 2018

Study of VX-661 Alone and in Combination With Ivacaftor in Subjects Homozygous or Heterozygous to the F508del-Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) Mutation

Study Details

Study Description

Brief Summary

Detailed Description

Study Design

Arms and Interventions

Outcome Measures

Primary Outcome Measures

Secondary Outcome Measures

Eligibility Criteria

Criteria

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

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Sponsors and Collaborators

Investigators

Study Documents (Full-Text)

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Study Results

Participant Flow

Baseline Characteristics

Outcome Measures

Outcome Measure Data

Outcome Measure Data

Statistical Analysis 1

Statistical Analysis 2

Statistical Analysis 3

Statistical Analysis 4

Statistical Analysis 5

Statistical Analysis 6

Statistical Analysis 7

Statistical Analysis 8

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Statistical Analysis 1

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Outcome Measure Data

Adverse Events

All Cause Mortality

Serious Adverse Events

Other (Not Including Serious) Adverse Events

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