TRANSPORT: A Study of Lumacaftor in Combination With Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Who Are Homozygous for the F508del-CFTR Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01807949
• Collaborator: (none)
• Enrollment: 563
• Locations: 82
• Arms: 3
• Duration (Months): 12
• Patients Per Site: 6.9
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The primary objective of the study was to evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in participants aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis, Homozygous for the F508del CFTR Mutation	Drug: Placebo; Drug: Lumacaftor Plus Ivacaftor Combination; Drug: Ivacaftor	Phase 3

Detailed Description

This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group multicenter study of orally administered lumacaftor in combination with ivacaftor in participants aged 12 years and older with CF who are homozygous for the F508del-CFTR mutation.

The study included a Screening Period (Day -28 through Day -1), a Treatment Period (Day 1 [first dose of study drug] to Week 24 ± 5 days), and a Safety Follow-up Visit (4 weeks ± 7 days after the Week 24 Visit).

Study Design

• Study Type: Interventional
• Actual Enrollment: 563 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double Blind, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Lumacaftor in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Homozygous for the F508del CFTR Mutation
• Study Start Date: Apr 1, 2013
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.	Drug: Placebo; Matching placebo tablet
Experimental: LUM 600 mg qd/IVA 250 mg q12h LUM 600 milligram (mg) plus IVA 250 mg fixed-dose combination (FDC) tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	Drug: Lumacaftor Plus Ivacaftor Combination; Fixed dose combination tablet; Other Names: VX-809+VX-770, LUM+IVA ; Drug: Ivacaftor; Film-coated tablet; Other Names: VX-770, IVA
Experimental: LUM 400 mg q12h/ IVA 250 mg q12h LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.	Drug: Lumacaftor Plus Ivacaftor Combination; Fixed dose combination tablet; Other Names: VX-809+VX-770, LUM+IVA

Outcome Measures

Primary Outcome Measures

1. Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24 [Baseline, Week 16 and 24]

   Absolute change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.

Secondary Outcome Measures

1. Relative Change From Baseline in Percent Predicted FEV1 at Week 24 [Baseline, Week 16 and 24]

   Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1.

2. Absolute Change From Baseline in Body Mass Index (BMI) at Week 24 [Baseline, Week 24]

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

3. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24 [Baseline, Week 24]

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

4. Percentage of Participants With Response Based on Percent Predicted FEV1 [Week 16 and 24]

   A participant was considered as a responder if the participant had >=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder.

5. Number of Pulmonary Exacerbation Events [through Week 24]

   The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.

6. Absolute Change From Baseline in Weight at Week 24 [Baseline, Week 24]

7. Absolute Change From Baseline in BMI-for-age Z-score at Week 24 [Baseline, Week 24]

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

8. Time-to-First Pulmonary Exacerbation [through Week 24]

   Time to first pulmonary exacerbation was assessed using Cox Regression method. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit.

9. Percentage of Participants With At Least 1 Pulmonary Exacerbation Event [through Week 24]

10. Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24 [Baseline, Week 24]

    EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.

11. Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24 [Baseline, Week 24]

    The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state.

12. Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24 [Baseline, Week 24]

    The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.

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

    AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent.

14. Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg) [For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16]

    Ctrough, Ctrough,avg, C3-6h, and C3-6h,avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,avg is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,avg is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of CF

• Homozygous for the F508del CFTR mutation

• Forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) and less than or equal to (=<) 90% of predicted normal for age, sex, and height

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

Exclusion Criteria:

• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before first dose of study drug

• History of solid organ or hematological transplantation

• History of alcohol or drug abuse in the past year

• Ongoing or prior participation in an investigational drug study (including studies investigating lumacaftor and/or ivacaftor) within 30 days of screening.

• Use of strong inhibitors, moderate inducers, or strong inducers of Cytochrome P450 3A (CYP3A) within 14 days before Day 1 of dosing

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Oakland	California	United States
2		Sacramento	California	United States
3		Aurora	Colorado	United States
4		Hartford	Connecticut	United States
5		New Haven	Connecticut	United States
6		Jacksonville	Florida	United States
7		Miami	Florida	United States
8		Indianapolis	Indiana	United States
9		Iowa City	Iowa	United States
10		Kansas City	Kansas	United States
11		Lexington	Kentucky	United States
12		Portland	Maine	United States
13		Worcester	Massachusetts	United States
14		Detroit	Michigan	United States
15		Grand Rapids	Michigan	United States
16		Minneapolis	Minnesota	United States
17		Jackson	Mississippi	United States
18		St. Louis	Missouri	United States
19		Omaha	Nebraska	United States
20		Morristown	New Jersey	United States
21		New Brunswick	New Jersey	United States
22		Alburquerque	New Mexico	United States
23		Albany	New York	United States
24		Buffalo	New York	United States
25		New York	New York	United States
26		Rochester	New York	United States
27		Syracuse	New York	United States
28		Cleveland	Ohio	United States
29		Columbus	Ohio	United States
30		Toledo	Ohio	United States
31		Oklahoma City	Oklahoma	United States
32		Philadelphia	Pennsylvania	United States
33		Pittsburgh	Pennsylvania	United States
34		Charleston	South Carolina	United States
35		Sioux Falls	South Dakota	United States
36		Memphis	Tennessee	United States
37		Nashville	Tennessee	United States
38		Dallas	Texas	United States
39		Fort Worth	Texas	United States
40		Houston	Texas	United States
41		San Antonio	Texas	United States
42		Salt Lake City	Utah	United States
43		Richmond	Virginia	United States
44		Seattle	Washington	United States
45		Spokane	Washington	United States
46		Milwaukee	Wisconsin	United States
47		Brisbane	Queensland	Australia
48		Chermside	Queensland	Australia
49		Herston	Queensland	Australia
50		South Brisbane	Queensland	Australia
51		Nedlands	Western Australia	Australia
52		Subiaco	Western Australia	Australia
53		Innsbruck		Austria
54		Wels		Austria
55		Bruxelles		Belgium
56		Gent		Belgium
57		Leuven		Belgium
58		Liège		Belgium
59		Calgary	Alberta	Canada
60		Edmonton	Alberta	Canada
61		Vancouver	British Columbia	Canada
62		Montreal	Quebec	Canada
63		København Ø		Denmark
64		Marseille	Bouches-du-Rhône	France
65		Toulouse cedex 9	Haute Garonne	France
66		Montpellier cedex 5	Herault	France
67		Lille	Nord	France
68		Bordeaux Cedex		France
69		Paris		France
70		Muenchen	Bayern	Germany
71		Frankfurt	Hessen	Germany
72		Giessen	Hessen	Germany
73		Hannover	Niederachsen	Germany
74		Bochum	Nordrhein Westfalen	Germany
75		Jena	Thueringen	Germany
76		Barcelona		Spain
77		Valencia		Spain
78		Bristol	Avon	United Kingdom
79		London	Greater London	United Kingdom
80		Liverpool	Merseyside	United Kingdom
81		Newcastle upon Tyne	Tyne & Wear	United Kingdom
82		Leeds	West Yorkshire	United Kingdom

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01807949
• Other Study ID Numbers: VX12-809-104
• First Posted: Mar 8, 2013
• Last Update Posted: Sep 27, 2016
• Last Verified: Aug 1, 2016

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

Study Results

Participant Flow

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.	LUM 600 milligram (mg) plus IVA 250 mg fixed-dose combination (FDC) tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Period Title: Overall Study
STARTED	187	187	189
COMPLETED	185	180	180
NOT COMPLETED	2	7	9

Baseline Characteristics

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h	Total
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.	Total of all reporting groups
Overall Participants	187	185	187	559
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.7 (10.02)	24.3 (8.31)	25.0 (9.03)	25.0 (9.16)
Sex: Female, Male (Count of Participants)
Female	97 51.9%	96 51.9%	98 52.4%	291 52.1%
Male	90 48.1%	89 48.1%	89 47.6%	268 47.9%

Outcome Measures

1. Primary Outcome

Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24
Description	Absolute change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, race, and height). The Hankinson standard was used for male participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Time Frame	Baseline, Week 16 and 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all randomized participants who received any amount of study drug. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	183	181	180
Least Squares Mean (Standard Error) [percent predicted of FEV1]	-0.15 (0.539)	2.46 (0.540)	2.85 (0.540)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using mixed-effects model for repeated measures (MMRM) model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (less than [<] 18 versus greater than equal to [>=]18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Least Squares (LS) Mean Difference
	Estimated Value	2.62
	Confidence Interval	(2-Sided) 95%; 1.18 to 4.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model, as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.00
	Confidence Interval	(2-Sided) 95%; 1.56 to 4.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Relative Change From Baseline in Percent Predicted FEV1 at Week 24
Description	Assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in Outcome Measure (OM) 1.
Time Frame	Baseline, Week 16 and 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	183	181	180
Least Squares Mean (Standard Error) [percent change]	0.00 (0.960)	4.42 (0.961)	5.25 (0.961)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	4.42
	Confidence Interval	(2-Sided) 95%; 1.86 to 6.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model, as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.25
	Confidence Interval	(2-Sided) 95%; 2.69 to 7.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	183	180	180
Least Squares Mean (Standard Error) [kilogram per square meter (kg/m^2)]	0.07 (0.066)	0.48 (0.066)	0.43 (0.066)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.41
	Confidence Interval	(2-Sided) 95%; 0.23 to 0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model, as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.36
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.54
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Week 24
Description	The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), the scaled score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	185	180	179
Least Squares Mean (Standard Error) [units on a scale]	2.81 (1.153)	5.02 (1.166)	5.66 (1.169)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline CFQ-R respiratory domain score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1651
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95%; -0.91 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model, as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0736
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.85
	Confidence Interval	(2-Sided) 95%; -0.27 to 5.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With Response Based on Percent Predicted FEV1
Description	A participant was considered as a responder if the participant had >=5% increase from baseline in average percent predicted FEV1 at Week 16 and at Week 24 (relative change). FEV1 and percent predicted FEV1 are defined in OM 1. A participant with a missing average relative change from baseline in percent predicted FEV1 at Week 16 and at Week 24 was considered as a non-responder.
Time Frame	Week 16 and 24

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	187	185	187
Number [percentage of participants]	22.5 12%	45.9 24.8%	41.2 22%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Odds Ratio (OR) and 95% confidence intervals (Cis) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.9568
	Confidence Interval	(2-Sided) 95%; 1.8829 to 4.6431
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.3834
	Confidence Interval	(2-Sided) 95%; 1.5234 to 3.7286
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Pulmonary Exacerbation Events
Description	The total number of days on study is equal to the Week 24 date or the last dose date (whichever occurred last) minus the first dose date plus 1. The total number of years (48 weeks) on study is equal to the number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Time Frame	through Week 24

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	187	185	187
Number [pulmonary exacerbation events per year]	1.18	0.82	0.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using regression analysis for a negative binomial distribution with sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70) as covariates with the logarithm of time on study as the offset.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0116
	Comments	This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Event Rate Ratio
	Estimated Value	0.6912
	Confidence Interval	(2-Sided) 95%; 0.5187 to 0.9209
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Event Rate Ratio
	Estimated Value	0.5659
	Confidence Interval	(2-Sided) 95%; 0.4191 to 0.7641
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Absolute Change From Baseline in Weight at Week 24
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	183	180	180
Least Squares Mean (Standard Error) [kilograms (kg)]	0.44 (0.187)	1.57 (0.188)	1.38 (0.187)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline weight.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Absolute Change From Baseline in BMI-for-age Z-score at Week 24
Description	Z-Score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is with range from -infinity to +infinity; 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the pediatric population.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Only participants who were <20 years of age were analyzed.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	53	54	58
Least Squares Mean (Standard Error) [z-score]	-0.0674 (0.04706)	0.1640 (0.04652)	0.1544 (0.04513)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline BMI z-score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.2313
	Confidence Interval	(2-Sided) 95%; 0.1037 to 0.3589
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.2217
	Confidence Interval	(2-Sided) 95%; 0.0961 to 0.3473
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Time-to-First Pulmonary Exacerbation
Description	Time to first pulmonary exacerbation was assessed using Cox Regression method. For participants who completed 24 weeks of treatment, participants without a pulmonary exacerbation before treatment completion were considered censored at the time of treatment completion or at the Week 24 Visit (whichever occurred last). For participants who prematurely discontinued study treatment, participants without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit.
Time Frame	through Week 24

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	187	185	187
Median (Full Range) [days]	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using Cox proportional hazard regression, time is the time-to-first event or censoring, with adjustment for sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0384
	Comments
	Method	Cox Proportional Hazard Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.716
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	Cox Proportional Hazard Regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.533
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Participants With At Least 1 Pulmonary Exacerbation Event
Time Frame	through Week 24

Outcome Measure Data

Analysis Population Description

FAS.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	187	185	187
Number [percentage of participants]	47.1 25.2%	36.8 19.9%	28.9 15.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	OR and 95% confidence intervals (CIs) are Mantel-Haenszel estimates. P values are from a Cochran-Mantel-Haenszel test stratified by sex (male versus female), age group at baseline (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0393
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.6373
	Confidence Interval	(2-Sided) 95%; 0.4160 to 0.9764
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.4429
	Confidence Interval	(2-Sided) 95%; 0.2863 to 0.6851
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24
Description	EQ-5D-3L: participant rated questionnaire to assess health-related quality of life. It consists of EQ-5D descriptive system and EQ-5D Visual Analog Scale (VAS). EQ-5D-3L descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems (1), some problems (2), and extreme problems (3). The 5 dimensional 3-level systems are converted into a single index utility score. Values for theoretically possible health states are calculated using a regression model and weighted according to the social preferences of the Unites States (US) general population. For this population, the possible EQ-5D-3L index scores ranges from -0.11 (that is, 3 for all 5 dimensions) to 1.0 (that is, 1 for all 5 dimensions), where higher scores indicate a better health state.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	183	178	176
Least Squares Mean (Standard Error) [units on a scale]	0.0117 (0.00673)	0.0090 (0.00682)	0.0108 (0.00683)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L index score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7679
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.0028
	Confidence Interval	(2-Sided) 95%; -0.0211 to 0.0156
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9214
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.0009
	Confidence Interval	(2-Sided) 95%; -0.0192 to 0.0174
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24
Description	The EQ-5D-3L VAS records the participant's self-rated health on a vertical, visual analogue scale where the best state a participant can imagine is marked 100 and the worst state a participant can imagine is marked 0, higher scores indicates a better health state.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	182	177	177
Least Squares Mean (Standard Error) [units on a scale]	3.3 (1.07)	5.7 (1.08)	6.6 (1.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline EQ-5D-3L VAS score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1034
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.4
	Confidence Interval	(2-Sided) 95%; -0.5 to 5.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0262
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 95%; 0.4 to 6.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24
Description	The TSQM is a 14-item self-administered questionnaire which measures participants' experiences with their medication on four dimensions: effectiveness, side effects, convenience and global satisfaction. For each dimension, responses are added and transformed to a scale from 0 to 100, where higher scores indicate greater satisfaction.
Time Frame	Baseline, Week 24

Outcome Measure Data

Analysis Population Description

FAS. Here, "n" signifies participants who were evaluable for specified category for each arm, respectively.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	187	185	187
Effectiveness (n = 159, 161, 161)	-8.49 (1.814)	0.15 (1.807)	3.12 (1.793)
Side Effects (n = 157, 159, 161)	2.03 (1.144)	-1.14 (1.137)	-2.26 (1.121)
Convenience (n = 158, 160, 161)	4.57 (1.525)	4.57 (1.523)	4.88 (1.501)
Global Satisfaction (n= 158, 160, 161)	-9.62 (1.841)	-4.98 (1.845)	-2.46 (1.814)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Effectiveness: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM effectiveness score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	8.64
	Confidence Interval	(2-Sided) 95%; 3.77 to 13.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Effectiveness: analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	11.61
	Confidence Interval	(2-Sided) 95%; 6.75 to 16.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Side Effects: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM side effects score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0403
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-3.18
	Confidence Interval	(2-Sided) 95%; -6.21 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Side Effects: analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0054
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4.29
	Confidence Interval	(2-Sided) 95%; -7.31 to -1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Convenience: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM convenience score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.0000
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -4.07 to 4.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Convenience: analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8777
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95%; -3.74 to 4.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 600 mg qd/IVA 250 mg q12h
	Comments	Global Satisfaction: analysis was performed using MMRM model including treatment, visit, and treatment-by-visit interaction as fixed effects with adjustments for sex (male versus female), age group at baseline (<18 versus >=18 years old), percent predicted FEV1 severity at Screening (<70 versus >=70), and baseline TSQM global satisfaction score.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0668
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	4.64
	Confidence Interval	(2-Sided) 95%; -0.32 to 9.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, LUM 400 mg q12h/ IVA 250 mg q12h
	Comments	Global Satisfaction: analysis was performed as described in Statistical Analysis 1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0045
	Comments
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.16
	Confidence Interval	(2-Sided) 95%; 2.23 to 12.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)
Description	AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as Non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or that was newly developed at or after the initial dosing of study drug to 28 days after the last dose of study drug is considered treatment-emergent.
Time Frame	up to Week 28

Outcome Measure Data

Analysis Population Description

Safety Set (SS) included all randomized participants who received any amount of study drug. Participants were analyzed as per actual treatment received.

Arm/Group Title	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	186	186	187
Participants With Treatment-Emergent AEs	181 96.8%	181 97.8%	177 94.7%
Participants With Treatment-Emergent SAEs	57 30.5%	51 27.6%	31 16.6%

15. Secondary Outcome

Title	Pre-dose Concentration (Ctrough), Average Pre-dose Concentration (Ctrough,Avg), 3 to 6 Hours Post-dose Concentration (C3-6h), and Average 3 to 6 Hours Post-dose Concentration (C3-6h,Avg)
Description	Ctrough, Ctrough,avg, C3-6h, and C3-6h,avg for lumacaftor, M28 lumacaftor (lumacaftor metabolite), ivacaftor, M1 ivacaftor (ivacaftor metabolite), and M6 ivacaftor (ivacaftor metabolite) were calculated. C3-6h,avg is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,avg is average of individual pre-dose observed concentrations across Weeks 4, 8, and 16. This outcome was not planned to be assessed in Placebo arm.
Time Frame	For C3-6h: 3 to 6 hours after morning dose on Day 1 and 15, Week 4 and 8; For C3-6h,avg 3 to 6 hours after morning dose on Day 15, Week 4 and 8; For Ctrough and Ctrough,avg: before morning dose on Week 4, 8, and 16

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population included all randomized participants who received at least one dose of study drug and had a PK assessment. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and "n" signifies participants evaluable for specified category for each arm, respectively.

Arm/Group Title	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.	LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
Measure Participants	182	182
LUM, Day 1: C3-6h (n = 181, 180)	30.8 (12.6)	20.2 (8.33)
LUM, Day 15: C3-6h (n = 174, 176)	30.4 (11.2)	23.9 (8.87)
LUM, Week 4: Ctrough (n = 174, 179)	8.11 (5.21)	13.2 (6.28)
LUM, Week 4: C3-6h (n = 164, 168)	29.2 (12.1)	24.5 (8.75)
LUM, Week 8: Ctrough (n = 177, 177)	7.87 (5.71)	12.4 (6.87)
LUM, Week 8: C3-6h (n = 174, 170)	30.4 (11.6)	24.9 (9.79)
LUM, Week 16: Ctrough (n = 171, 173)	7.53 (6.05)	12.2 (6.87)
M-28 LUM, Day 1: C3-6h (n = 181, 180)	0.226 (0.103)	0.181 (0.0790)
M-28 LUM, Day 15: C3-6h (n = 174, 176)	1.43 (0.588)	1.39 (0.606)
M-28 LUM, Week 4: Ctrough (n = 174, 179)	1.32 (0.680)	1.42 (0.661)
M-28 LUM, Week 4: C3-6h (n = 164, 168)	1.39 (0.657)	1.45 (0.675)
M-28 LUM, Week 8: Ctrough (n = 177, 177)	1.34 (0.714)	1.44 (0.722)
M-28 LUM, Week 8: C3-6h (n = 174, 170)	1.41 (0.702)	1.48 (0.711)
M-28 LUM, Week 16: Ctrough (n = 171, 173)	1.27 (0.763)	1.43 (0.775)
IVA, Day 1: C3-6h (n = 181, 180)	1.34 (0.643)	1.36 (0.647)
IVA, Day 15: C3-6h (n = 174, 176)	0.647 (0.492)	0.469 (0.282)
IVA, Week 4: Ctrough (n = 174, 179)	0.164 (0.207)	0.108 (0.112)
IVA, Week 4: C3-6h (n = 164, 168)	0.636 (0.380)	0.473 (0.239)
IVA, Week 8: Ctrough (n = 177, 177)	0.182 (0.293)	0.102 (0.130)
IVA, Week 8: C3-6h (n = 174, 170)	0.710 (0.567)	0.513 (0.277)
IVA, Week 16: Ctrough (n = 171, 173)	0.163 (0.237)	0.113 (0.218)
M-1 IVA, Day 1: C3-6h (n = 181, 180)	2.51 (1.30)	2.65 (1.29)
M-1 IVA, Day 15: C3-6h (n = 174, 176)	2.21 (1.08)	1.85 (0.860)
M-1 IVA, Week 4: Ctrough (n = 174, 179)	0.676 (0.612)	0.501 (0.455)
M-1 IVA, Week 4: C3-6h (n = 164, 168)	2.11 (1.12)	1.88 (0.953)
M-1 IVA, Week 8: Ctrough (n = 177, 177)	0.672 (0.704)	0.463 (0.495)
M-1 IVA, Week 8: C3-6h (n = 174, 170)	2.15 (1.19)	1.91 (0.910)
M-1 IVA, Week 16: Ctrough (n = 171, 173)	0.643 (0.594)	0.465 (0.449)
M-6 IVA, Day 1: C3-6h (n = 181, 180)	0.993 (0.820)	0.996 (0.797)
M-6 IVA, Day 15: C3-6h (n = 174, 176)	3.62 (2.18)	2.99 (1.68)
M-6 IVA, Week 4: Ctrough (n = 174, 179)	1.73 (1.34)	1.64 (1.20)
M-6 IVA, Week 4: C3-6h (n = 164, 168)	3.07 (1.84)	2.64 (1.45)
M-6 IVA, Week 8: Ctrough (n = 177, 177)	1.60 (1.22)	1.47 (1.17)
M-6 IVA, Week 8: C3-6h (n = 174, 170)	3.00 (2.01)	2.56 (1.48)
M-6 IVA, Week 16: Ctrough (n = 171, 173)	1.51 (1.29)	1.42 (1.05)
LUM: Ctrough,avg (n = 179, 182)	7.81 (4.26)	12.7 (5.60)
LUM: C3-6h,avg (n = 182, 181)	29.9 (9.19)	24.3 (7.72)
M-28 LUM: Ctrough,avg (n = 179, 182)	1.31 (0.672)	1.42 (0.676)
M-28 LUM: C3-6h,avg (n = 182, 181)	1.41 (0.620)	1.43 (0.640)
IVA: Ctrough,avg (n = 179, 182)	0.170 (0.196)	0.110 (0.124)
IVA: C3-6h,avg (n = 182, 181)	0.668 (0.392)	0.484 (0.210)
M1-IVA: Ctrough,avg (n = 179, 182)	0.660 (0.504)	0.484 (0.391)
M1-IVA: C3-6h,avg (n = 182, 181)	2.14 (0.951)	1.87 (0.710)
M6-IVA: Ctrough,avg (n = 179, 182)	1.60 (1.08)	1.50 (0.897)
M6-IVA: C3-6h,avg (n = 182, 181)	3.18 (1.65)	2.70 (1.23)

Adverse Events

Time Frame	up to Week 28
Adverse Event Reporting Description	Participants were analyzed as per actual treatment received. Other adverse events includes only non-serious AEs.
Arm/Group Title	Placebo		LUM 600 mg qd/IVA 250 mg q12h		LUM 400 mg q12h/ IVA 250 mg q12h
Arm/Group Description	Placebo matched to LUM and IVA tablet q12h, up to Week 24.		LUM 600 mg plus IVA 250 mg FDC tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.		LUM 400 mg plus IVA 250 mg FDC tablet in the morning and in the evening, up to Week 24.
All Cause Mortality
	Placebo		LUM 600 mg qd/IVA 250 mg q12h		LUM 400 mg q12h/ IVA 250 mg q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		LUM 600 mg qd/IVA 250 mg q12h		LUM 400 mg q12h/ IVA 250 mg q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/186 (30.6%)		51/186 (27.4%)		31/187 (16.6%)
Gastrointestinal disorders
Distal intestinal obstruction syndrome	3/186 (1.6%)		0/186 (0%)		0/187 (0%)
Constipation	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Abdominal pain	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Colitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Ileus	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
General disorders
Medical device complication	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Pyrexia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hepatobiliary disorders
Cholestasis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hepatitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	48/186 (25.8%)		36/186 (19.4%)		24/187 (12.8%)
Bronchitis	2/186 (1.1%)		1/186 (0.5%)		0/187 (0%)
Bronchopneumonia	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Bronchopulmonary aspergillosis allergic	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Appendicitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Bronchopulmonary aspergillosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Conjunctivitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Gastroenteritis viral	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Influenza	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Lung infection pseudomonal	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Pneumonia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Respiratory tract infection fungal	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Viraemia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Viral infection	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Injury, poisoning and procedural complications
Post procedural haematoma	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Suture related complication	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Investigations
Blood creatine phosphokinase increased	0/186 (0%)		0/186 (0%)		2/187 (1.1%)
Liver function test abnormal	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Bacterial test positive	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Electrocardiogram T wave inversion	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Hepatic enzyme increased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Nervous system disorders
Convulsion	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Hepatic encephalopathy	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Psychiatric disorders
Suicidal ideation	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Suicide attempt	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Renal and urinary disorders
Nephrolithiasis	2/186 (1.1%)		1/186 (0.5%)		0/187 (0%)
Proteinuria	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Renal failure acute	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/186 (0.5%)		4/186 (2.2%)		0/187 (0%)
Bronchospasm	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Dyspnoea	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Pulmonary cavitation	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Skin and subcutaneous tissue disorders
Rash	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vascular disorders
Axillary vein thrombosis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Deep vein thrombosis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Hypertension	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		LUM 600 mg qd/IVA 250 mg q12h		LUM 400 mg q12h/ IVA 250 mg q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	181/186 (97.3%)		179/186 (96.2%)		175/187 (93.6%)
Blood and lymphatic system disorders
Increased tendency to bruise	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Eosinophilia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Leukopenia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Lymphadenopathy	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Neutropenia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Cardiac disorders
Palpitations	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Tachycardia	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Atrioventricular block first degree	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Cyanosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Sinus arrhythmia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Sinus bradycardia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Ventricular extrasystoles	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes	5/186 (2.7%)		0/186 (0%)		2/187 (1.1%)
Talipes	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Ear and labyrinth disorders
Tinnitus	1/186 (0.5%)		1/186 (0.5%)		3/187 (1.6%)
Ear pain	0/186 (0%)		1/186 (0.5%)		3/187 (1.6%)
Ear discomfort	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Tympanic membrane disorder	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Vertigo	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Middle ear effusion	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Vertigo positional	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Endocrine disorders
Cushingoid	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Early menarche	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Eye disorders
Vision blurred	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Blepharospasm	0/186 (0%)		0/186 (0%)		2/187 (1.1%)
Eye pruritus	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Blindness transient	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Conjunctival hyperaemia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Eye irritation	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Eye pain	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Eye swelling	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Ocular hyperaemia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Periorbital oedema	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Photopsia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Visual acuity reduced	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Gastrointestinal disorders
Nausea	17/186 (9.1%)		20/186 (10.8%)		32/187 (17.1%)
Diarrhoea	18/186 (9.7%)		20/186 (10.8%)		21/187 (11.2%)
Abdominal pain	19/186 (10.2%)		15/186 (8.1%)		10/187 (5.3%)
Flatulence	10/186 (5.4%)		11/186 (5.9%)		13/187 (7%)
Abdominal pain upper	8/186 (4.3%)		15/186 (8.1%)		7/187 (3.7%)
Vomiting	9/186 (4.8%)		12/186 (6.5%)		9/187 (4.8%)
Constipation	8/186 (4.3%)		5/186 (2.7%)		6/187 (3.2%)
Abdominal distension	2/186 (1.1%)		6/186 (3.2%)		5/187 (2.7%)
Frequent bowel movements	2/186 (1.1%)		1/186 (0.5%)		7/187 (3.7%)
Dyspepsia	1/186 (0.5%)		3/186 (1.6%)		5/187 (2.7%)
Gastrooesophageal reflux disease	1/186 (0.5%)		1/186 (0.5%)		6/187 (3.2%)
Abdominal discomfort	0/186 (0%)		3/186 (1.6%)		3/187 (1.6%)
Steatorrhoea	2/186 (1.1%)		2/186 (1.1%)		1/187 (0.5%)
Eructation	1/186 (0.5%)		1/186 (0.5%)		2/187 (1.1%)
Mouth ulceration	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Post-tussive vomiting	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Abdominal pain lower	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Abdominal tenderness	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Abnormal faeces	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Aerophagia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Distal intestinal obstruction syndrome	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Dry mouth	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Epigastric discomfort	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Faecaloma	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Faeces discoloured	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Faeces soft	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Food poisoning	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Gastritis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Gastrointestinal disorder	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Gastrointestinal motility disorder	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Gastrointestinal pain	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Gastrointestinal sounds abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Gastrointestinal tract irritation	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Haematochezia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Haemorrhoids	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Lip pain	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Lip ulceration	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Odynophagia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Oesophageal pain	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Oral pain	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Retching	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Tongue discolouration	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Tongue disorder	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Tooth development disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Tooth impacted	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Umbilical hernia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
General disorders
Pyrexia	22/186 (11.8%)		22/186 (11.8%)		16/187 (8.6%)
Fatigue	10/186 (5.4%)		13/186 (7%)		17/187 (9.1%)
Chest discomfort	4/186 (2.2%)		4/186 (2.2%)		4/187 (2.1%)
Pain	2/186 (1.1%)		1/186 (0.5%)		5/187 (2.7%)
Malaise	1/186 (0.5%)		4/186 (2.2%)		2/187 (1.1%)
Chills	2/186 (1.1%)		1/186 (0.5%)		3/187 (1.6%)
Chest pain	1/186 (0.5%)		0/186 (0%)		3/187 (1.6%)
Thirst	0/186 (0%)		2/186 (1.1%)		2/187 (1.1%)
Influenza like illness	2/186 (1.1%)		0/186 (0%)		1/187 (0.5%)
Medical device pain	1/186 (0.5%)		0/186 (0%)		2/187 (1.1%)
Sensation of foreign body	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Application site pruritus	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Application site rash	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Asthenia	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Device occlusion	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Energy increased	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Feeling jittery	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Infusion site pain	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Local swelling	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Oedema peripheral	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Vessel puncture site bruise	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Adverse drug reaction	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Application site irritation	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Application site reaction	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Device leakage	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Device malfunction	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Discomfort	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Feeling hot	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Infusion site bruising	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Injection site erythema	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Injection site pain	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Injection site warmth	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Medical device complication	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Non-cardiac chest pain	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Thrombosis in device	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vessel puncture site pain	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Hepatobiliary disorders
Biliary colic	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Cholecystitis acute	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Hepatic pain	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Immune system disorders
Seasonal allergy	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Drug hypersensitivity	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Food allergy	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	74/186 (39.8%)		58/186 (31.2%)		50/187 (26.7%)
Nasopharyngitis	20/186 (10.8%)		14/186 (7.5%)		22/187 (11.8%)
Upper respiratory tract infection	10/186 (5.4%)		8/186 (4.3%)		20/187 (10.7%)
Viral upper respiratory tract infection	13/186 (7%)		13/186 (7%)		10/187 (5.3%)
Sinusitis	7/186 (3.8%)		17/186 (9.1%)		11/187 (5.9%)
Rhinitis	6/186 (3.2%)		14/186 (7.5%)		8/187 (4.3%)
Influenza	3/186 (1.6%)		6/186 (3.2%)		11/187 (5.9%)
Gastroenteritis	5/186 (2.7%)		4/186 (2.2%)		4/187 (2.1%)
Pharyngitis	4/186 (2.2%)		3/186 (1.6%)		3/187 (1.6%)
Viral infection	4/186 (2.2%)		4/186 (2.2%)		0/187 (0%)
Vulvovaginal mycotic infection	0/186 (0%)		5/186 (2.7%)		3/187 (1.6%)
Respiratory tract infection viral	1/186 (0.5%)		3/186 (1.6%)		2/187 (1.1%)
Bronchitis	1/186 (0.5%)		2/186 (1.1%)		2/187 (1.1%)
Ear infection	3/186 (1.6%)		1/186 (0.5%)		1/187 (0.5%)
Oral candidiasis	1/186 (0.5%)		2/186 (1.1%)		2/187 (1.1%)
Respiratory tract infection	2/186 (1.1%)		2/186 (1.1%)		1/187 (0.5%)
Respiratory tract infection bacterial	0/186 (0%)		2/186 (1.1%)		3/187 (1.6%)
Gastroenteritis viral	1/186 (0.5%)		1/186 (0.5%)		2/187 (1.1%)
Upper respiratory tract infection bacterial	0/186 (0%)		3/186 (1.6%)		1/187 (0.5%)
Urinary tract infection	1/186 (0.5%)		2/186 (1.1%)		1/187 (0.5%)
Vulvovaginal candidiasis	2/186 (1.1%)		1/186 (0.5%)		1/187 (0.5%)
Acute sinusitis	2/186 (1.1%)		0/186 (0%)		1/187 (0.5%)
Bronchopulmonary aspergillosis allergic	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Laryngitis	0/186 (0%)		2/186 (1.1%)		1/187 (0.5%)
Lower respiratory tract infection bacterial	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Bronchopulmonary aspergillosis	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Clostridium difficile infection	0/186 (0%)		0/186 (0%)		2/187 (1.1%)
Conjunctivitis	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Gingivitis	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Infectious mononucleosis	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Oral fungal infection	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Oral herpes	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Otitis externa	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Rash pustular	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Acarodermatitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Asymptomatic bacteriuria	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Bacterial disease carrier	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Bronchitis viral	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Cellulitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Chronic sinusitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Clostridium difficile colitis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Cystitis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Device related infection	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Epididymitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Eye infection	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Eyelid infection	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Fungal infection	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Genital herpes	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Gynaecological chlamydia infection	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Herpes simplex	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Herpes zoster	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hordeolum	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Infected bites	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Infusion site infection	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Localised infection	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Lower respiratory tract infection	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Lower respiratory tract infection viral	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Lung infection	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Lung infection pseudomonal	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Nipple infection	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Otitis media	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pharyngitis bacterial	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pneumonia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pseudomonas bronchitis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Tinea versicolour	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Tonsillitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Tooth abscess	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Tooth infection	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vaginitis bacterial	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Injury, poisoning and procedural complications
Ligament sprain	2/186 (1.1%)		3/186 (1.6%)		3/187 (1.6%)
Muscle strain	2/186 (1.1%)		1/186 (0.5%)		3/187 (1.6%)
Laceration	1/186 (0.5%)		3/186 (1.6%)		1/187 (0.5%)
Procedural pain	1/186 (0.5%)		1/186 (0.5%)		2/187 (1.1%)
Joint injury	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Sunburn	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Arthropod bite	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Concussion	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Limb injury	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Vaccination complication	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Alcohol poisoning	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Animal bite	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Ankle fracture	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Arthropod sting	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Contusion	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Foreign body	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Iliotibial band syndrome	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Joint dislocation	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Ligament injury	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Rib fracture	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Road traffic accident	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Splinter	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Stoma site irritation	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Thermal burn	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Traumatic haematoma	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Investigations
Blood creatine phosphokinase increased	10/186 (5.4%)		4/186 (2.2%)		12/187 (6.4%)
Pulmonary function test decreased	14/186 (7.5%)		5/186 (2.7%)		3/187 (1.6%)
Aspartate aminotransferase increased	5/186 (2.7%)		3/186 (1.6%)		5/187 (2.7%)
Bacterial test positive	1/186 (0.5%)		4/186 (2.2%)		7/187 (3.7%)
Alanine aminotransferase increased	4/186 (2.2%)		2/186 (1.1%)		4/187 (2.1%)
Weight decreased	2/186 (1.1%)		3/186 (1.6%)		2/187 (1.1%)
Forced expiratory volume decreased	4/186 (2.2%)		0/186 (0%)		2/187 (1.1%)
Hepatic enzyme increased	0/186 (0%)		4/186 (2.2%)		2/187 (1.1%)
Blood glucose increased	1/186 (0.5%)		3/186 (1.6%)		1/187 (0.5%)
Sputum abnormal	2/186 (1.1%)		0/186 (0%)		2/187 (1.1%)
Blood alkaline phosphatase increased	2/186 (1.1%)		0/186 (0%)		1/187 (0.5%)
Blood creatinine increased	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Blood glucose decreased	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Body temperature increased	0/186 (0%)		2/186 (1.1%)		1/187 (0.5%)
Gamma-glutamyltransferase increased	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Blood lactate dehydrogenase increased	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Eosinophil count increased	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Fungal test positive	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Haemoglobin decreased	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Atypical mycobacterium test positive	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Blood bicarbonate decreased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Blood calcium increased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Blood immunoglobulin E increased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Blood iron decreased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Blood pressure increased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Blood sodium decreased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Blood sodium increased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Blood urine present	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Breath sounds abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
C-reactive protein increased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Coagulation test abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Crystal urine present	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Electrocardiogram PR shortened	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Electrocardiogram T wave abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Glycosylated haemoglobin increased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Haemophilus test positive	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Liver function test abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Lymphocyte count decreased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Mean cell haemoglobin decreased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Mean cell volume increased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Neutrophil count increased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Oxygen saturation decreased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Red blood cell count decreased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Serum ferritin decreased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Transaminases increased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Vitamin D decreased	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Weight increased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
White blood cell count decreased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
White blood cell count increased	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Metabolism and nutrition disorders
Decreased appetite	5/186 (2.7%)		7/186 (3.8%)		12/187 (6.4%)
Hypoglycaemia	5/186 (2.7%)		4/186 (2.2%)		2/187 (1.1%)
Hyperglycaemia	1/186 (0.5%)		2/186 (1.1%)		3/187 (1.6%)
Gout	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Dehydration	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Vitamin D deficiency	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Diabetes mellitus inadequate control	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Glucose tolerance impaired	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Hypokalaemia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Hypomagnesaemia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hyponatraemia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Increased appetite	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Vitamin A deficiency	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vitamin E deficiency	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Musculoskeletal and connective tissue disorders
Back pain	6/186 (3.2%)		5/186 (2.7%)		9/187 (4.8%)
Myalgia	8/186 (4.3%)		6/186 (3.2%)		3/187 (1.6%)
Arthralgia	7/186 (3.8%)		2/186 (1.1%)		6/187 (3.2%)
Musculoskeletal chest pain	1/186 (0.5%)		8/186 (4.3%)		1/187 (0.5%)
Flank pain	2/186 (1.1%)		3/186 (1.6%)		3/187 (1.6%)
Pain in extremity	2/186 (1.1%)		3/186 (1.6%)		2/187 (1.1%)
Musculoskeletal pain	1/186 (0.5%)		2/186 (1.1%)		3/187 (1.6%)
Muscle spasms	2/186 (1.1%)		1/186 (0.5%)		0/187 (0%)
Muscle twitching	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Neck pain	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Joint swelling	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Muscle tightness	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Tendonitis	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Arthritis	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Arthropathy	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Bone cyst	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Chondritis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Foot deformity	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hypermobility syndrome	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Intervertebral disc protrusion	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Muscle contracture	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Muscular weakness	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Musculoskeletal discomfort	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Musculoskeletal stiffness	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pubic pain	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Rhabdomyolysis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Temporomandibular joint syndrome	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Tendon pain	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Nervous system disorders
Headache	33/186 (17.7%)		30/186 (16.1%)		29/187 (15.5%)
Sinus headache	7/186 (3.8%)		15/186 (8.1%)		7/187 (3.7%)
Dizziness	5/186 (2.7%)		7/186 (3.8%)		3/187 (1.6%)
Lethargy	3/186 (1.6%)		3/186 (1.6%)		2/187 (1.1%)
Migraine	2/186 (1.1%)		1/186 (0.5%)		1/187 (0.5%)
Dysgeusia	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Hypoaesthesia	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Tremor	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Amnesia	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Intercostal neuralgia	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Paraesthesia	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Parosmia	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Ageusia	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Cervicogenic headache	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Convulsion	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Coordination abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Disturbance in attention	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Epilepsy	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hyperaesthesia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hypertonia	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hyposmia	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Loss of consciousness	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Muscle contractions involuntary	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Nerve compression	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Presyncope	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Syncope	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Psychiatric disorders
Insomnia	7/186 (3.8%)		5/186 (2.7%)		2/187 (1.1%)
Anxiety	2/186 (1.1%)		2/186 (1.1%)		2/187 (1.1%)
Depression	3/186 (1.6%)		1/186 (0.5%)		1/187 (0.5%)
Libido decreased	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Mental disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Mood altered	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Nervousness	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Nightmare	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Sleep disorder	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Renal and urinary disorders
Nephrolithiasis	1/186 (0.5%)		2/186 (1.1%)		1/187 (0.5%)
Pollakiuria	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Proteinuria	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Calculus ureteric	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Haematuria	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Renal colic	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Urinary incontinence	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Urine odour abnormal	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Reproductive system and breast disorders
Menstruation irregular	0/186 (0%)		3/186 (1.6%)		3/187 (1.6%)
Dysmenorrhoea	0/186 (0%)		2/186 (1.1%)		3/187 (1.6%)
Metrorrhagia	1/186 (0.5%)		2/186 (1.1%)		1/187 (0.5%)
Menorrhagia	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Polymenorrhoea	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Amenorrhoea	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Breast tenderness	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Endometriosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Haemorrhagic ovarian cyst	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Oligomenorrhoea	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Uterine spasm	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Vaginal haemorrhage	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Vulvovaginal pain	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vulvovaginal pruritus	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	82/186 (44.1%)		69/186 (37.1%)		56/187 (29.9%)
Sputum increased	47/186 (25.3%)		40/186 (21.5%)		29/187 (15.5%)
Dyspnoea	15/186 (8.1%)		32/186 (17.2%)		31/187 (16.6%)
Haemoptysis	26/186 (14%)		28/186 (15.1%)		20/187 (10.7%)
Nasal congestion	19/186 (10.2%)		24/186 (12.9%)		13/187 (7%)
Oropharyngeal pain	20/186 (10.8%)		20/186 (10.8%)		13/187 (7%)
Respiration abnormal	13/186 (7%)		14/186 (7.5%)		18/187 (9.6%)
Rhinorrhoea	10/186 (5.4%)		11/186 (5.9%)		11/187 (5.9%)
Productive cough	14/186 (7.5%)		11/186 (5.9%)		5/187 (2.7%)
Sinus congestion	11/186 (5.9%)		8/186 (4.3%)		8/187 (4.3%)
Respiratory tract congestion	6/186 (3.2%)		8/186 (4.3%)		9/187 (4.8%)
Wheezing	9/186 (4.8%)		7/186 (3.8%)		6/187 (3.2%)
Paranasal sinus hypersecretion	5/186 (2.7%)		8/186 (4.3%)		6/187 (3.2%)
Dysphonia	4/186 (2.2%)		3/186 (1.6%)		7/187 (3.7%)
Sputum discoloured	6/186 (3.2%)		3/186 (1.6%)		3/187 (1.6%)
Rales	6/186 (3.2%)		2/186 (1.1%)		2/187 (1.1%)
Asthma	2/186 (1.1%)		4/186 (2.2%)		2/187 (1.1%)
Epistaxis	2/186 (1.1%)		5/186 (2.7%)		1/187 (0.5%)
Upper-airway cough syndrome	2/186 (1.1%)		2/186 (1.1%)		3/187 (1.6%)
Bronchial obstruction	2/186 (1.1%)		1/186 (0.5%)		1/187 (0.5%)
Painful respiration	1/186 (0.5%)		0/186 (0%)		3/187 (1.6%)
Increased viscosity of bronchial secretion	3/186 (1.6%)		0/186 (0%)		0/187 (0%)
Nasal discharge discolouration	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Pleuritic pain	1/186 (0.5%)		1/186 (0.5%)		1/187 (0.5%)
Rhinitis allergic	2/186 (1.1%)		1/186 (0.5%)		0/187 (0%)
Sneezing	0/186 (0%)		1/186 (0.5%)		2/187 (1.1%)
Throat irritation	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Bronchospasm	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Dyspnoea exertional	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Nasal polyps	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Sputum decreased	0/186 (0%)		2/186 (1.1%)		0/187 (0%)
Bronchial hyperreactivity	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Bronchial secretion retention	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Hiccups	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Hyperventilation	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Increased bronchial secretion	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Lung disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Lung hyperinflation	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Nasal discomfort	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Pharyngeal erythema	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Pharyngeal exudate	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Pharyngeal oedema	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pleurisy	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Pneumonitis	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Pulmonary pain	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Respiratory disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Respiratory gas exchange disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Respiratory tract irritation	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Rhonchi	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Sinus disorder	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Upper respiratory tract congestion	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Upper respiratory tract inflammation	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Skin and subcutaneous tissue disorders
Rash	5/186 (2.7%)		8/186 (4.3%)		18/187 (9.6%)
Acne	4/186 (2.2%)		8/186 (4.3%)		1/187 (0.5%)
Hyperhidrosis	2/186 (1.1%)		5/186 (2.7%)		3/187 (1.6%)
Pruritus	3/186 (1.6%)		2/186 (1.1%)		2/187 (1.1%)
Alopecia	1/186 (0.5%)		1/186 (0.5%)		3/187 (1.6%)
Night sweats	1/186 (0.5%)		1/186 (0.5%)		2/187 (1.1%)
Urticaria	2/186 (1.1%)		2/186 (1.1%)		0/187 (0%)
Eczema	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Dry skin	1/186 (0.5%)		0/186 (0%)		1/187 (0.5%)
Erythema	1/186 (0.5%)		1/186 (0.5%)		0/187 (0%)
Onychoclasis	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Rash pruritic	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Red man syndrome	2/186 (1.1%)		0/186 (0%)		0/187 (0%)
Skin odour abnormal	0/186 (0%)		1/186 (0.5%)		1/187 (0.5%)
Blister	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Cutaneous lupus erythematosus	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Dermatitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Drug eruption	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hair texture abnormal	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hyperkeratosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Ingrowing nail	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Lividity	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Papule	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Pruritus allergic	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Pruritus generalised	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Rash erythematous	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Rash macular	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Rash papular	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Skin lesion	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Swelling face	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Vascular disorders
Flushing	1/186 (0.5%)		2/186 (1.1%)		0/187 (0%)
Hot flush	0/186 (0%)		0/186 (0%)		2/187 (1.1%)
Deep vein thrombosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Hypertension	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Orthostatic hypotension	1/186 (0.5%)		0/186 (0%)		0/187 (0%)
Peripheral coldness	0/186 (0%)		0/186 (0%)		1/187 (0.5%)
Phlebitis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Subclavian vein thrombosis	0/186 (0%)		1/186 (0.5%)		0/187 (0%)
Venous thrombosis limb	1/186 (0.5%)		0/186 (0%)		0/187 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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