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Clinical Trial Results:
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

Summary
EudraCT number	2012-003989-40
Trial protocol	SE IT CZ DE IE GB NL
Global end of trial date	29 Apr 2014

Results information
Results version number	v1(current)
This version publication date	14 Jul 2016
First version publication date	07 Aug 2015
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

VX12-809-103

ISRCTN number

US NCT number

NCT01807923

WHO universal trial number (UTN)

Sponsor organisation name

Vertex Pharmaceuticals Incorporated

Sponsor organisation address

50 Northern Avenue, Boston, MA, United States, 02210-1862

Public contact

Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com

Scientific contact

Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 617-341-6777, medicalinfo@vrtx.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001582-PIP01-13

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

29 May 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Apr 2014

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy of lumacaftor in combination with ivacaftor at Week 24 in subjects aged 12 years and older with cystic fibrosis (CF) who are homozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene.

Protection of trial subjects

The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).

Background therapy

Evidence for comparator

Actual start date of recruitment

28 May 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Sweden: 8

Country: Number of subjects enrolled

Netherlands: 18

Country: Number of subjects enrolled

United Kingdom: 26

Country: Number of subjects enrolled

Czech Republic: 16

Country: Number of subjects enrolled

Germany: 32

Country: Number of subjects enrolled

Ireland: 13

Country: Number of subjects enrolled

Italy: 54

Country: Number of subjects enrolled

Australia: 49

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

France: 44

Country: Number of subjects enrolled

United States: 261

Worldwide total number of subjects

549

EEA total number of subjects

211

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

158

Adults (18-64 years)

391

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 187, 185, and 187 subjects were randomized in ‘Placebo’, ‘LUM 600 mg qd/IVA 250 mg q12h’, and ‘LUM 400 mg q12h/IVA 250 mg q12h’, respectively; of which 184, 183, and 182 subjects in respective groups received at least 1 dose of the study drug.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo matched to LUM and IVA tablet q12h, up to Week 24.

LUM 600 mg qd/IVA 250 mg q12h

Arm description

LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Arm type

Experimental

Investigational medicinal product name

Lumacaftor Plus Ivacaftor Combination

Investigational medicinal product code

VX-809+VX-770

Other name

LUM+IVA

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

LUM 600 mg plus IVA 250 mg supplied as FDC tablet in the morning up to week 24.

Investigational medicinal product name

Ivacaftor

Investigational medicinal product code

VX-770

Other name

IVA

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Ivacaftor 250 mg film-coated tablet in the evening up to Week 24.

LUM 400 mg q12h/IVA 250 mg q12h

Arm description

LUM 400 mg plus IVA 250 mg supplied as FDC tablets in the morning and in the evening, up to Week 24.

Arm type

Experimental

Investigational medicinal product name

Lumacaftor Plus Ivacaftor Combination

Investigational medicinal product code

VX-809+VX-770

Other name

LUM+IVA

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

LUM 400 mg plus IVA 250 mg supplied as FDC tablet in the morning and in the evening, up to Week 24.

Number of subjects in period 1	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Started	184	183	182
Completed	182	179	176
Not completed	2	4	6
Physician decision	-	-	1
Adverse Event	2	1	2
Not Eligible (Genotype)	-	-	1
Withdrawal of Consent (not due to AE)	-	3	2

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

Reporting group title

LUM 600 mg qd/IVA 250 mg q12h

Reporting group description

LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Reporting group title

LUM 400 mg q12h/IVA 250 mg q12h

Reporting group description

LUM 400 mg plus IVA 250 mg supplied as FDC tablets in the morning and in the evening, up to Week 24.

Reporting group values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h	Total
Number of subjects	184	183	182	549
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	25 ( 10.8 )	24.7 ( 9.71 )	25.5 ( 10.09 )	-
Gender categorical
Units: Subjects
Female	84	86	84	254
Male	100	97	98	295

End points

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Reporting group title

Placebo

Reporting group description

Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

Reporting group title

LUM 600 mg qd/IVA 250 mg q12h

Reporting group description

LUM 600 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Reporting group title

LUM 400 mg q12h/IVA 250 mg q12h

Reporting group description

LUM 400 mg plus IVA 250 mg supplied as FDC tablets in the morning and in the evening, up to Week 24.

Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24

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End point title

Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24

End point 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 subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 12 to 17 years and for female subjects aged 12 to 15 years. Analysis was performed on Full Analysis Set (FAS) included all randomized subjects who received any amount of study drug. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Primary

End point timeframe

Baseline, Week 16 and 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	180	176	172
Units: percent predicted of FEV1
least squares mean (standard error)	-0.44 ( 0.524 )	3.59 ( 0.525 )	2.16 ( 0.53 )

Statistical Analysis 1

Statistical analysis description

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).

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

Least Squares (LS) Mean Difference

Point estimate

4.03

Confidence interval

level

95%

sides

2-sided

lower limit

2.62

upper limit

5.44

Statistical Analysis 2

Statistical analysis description

Analysis was performed using MMRM model, as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

1.18

upper limit

4.01

Secondary: Relative Change From Baseline in Percent Predicted FEV1 at Week 24

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End point title

Relative Change From Baseline in Percent Predicted FEV1 at Week 24

End point description

Relative change from baseline at week 24 was assessed as the average treatment effect at Week 16 and at Week 24. FEV1 and percent predicted FEV1 are defined in primary endpoint. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 16 and 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	180	176	172
Units: percent change
least squares mean (standard error)	-0.34 ( 0.913 )	6.39 ( 0.914 )	3.99 ( 0.923 )

Statistical Analysis 1

Statistical analysis description

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).

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

6.73

Confidence interval

level

95%

sides

2-sided

lower limit

4.27

upper limit

9.19

Statistical Analysis 2

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0006

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

4.33

Confidence interval

level

95%

sides

2-sided

lower limit

1.86

upper limit

6.8

Notes
[1] - Analysis was performed using MMRM model, as described in Statistical Analysis 1.

Secondary: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

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End point title

Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

End point description

BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2). Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	178	176
Units: kilogram per square meter (kg/m^2)
least squares mean (standard error)	0.19 ( 0.07 )	0.35 ( 0.07 )	0.32 ( 0.071 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

362

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1122

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.04

upper limit

0.35

Statistical Analysis 2

Statistical analysis description

Analysis was performed using MMRM model, as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1938

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

0.32

Secondary: Absolute Change From Baseline in (Cystic Fibrosis Questionnaire-Revised) CFQ R Respiratory Domain Score at Week 24

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End point title

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

End point description

The CFQ-R is a validated subject-reported outcome measuring health-related quality of life for subjects 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. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	176	172
Units: units on a scale
least squares mean (standard error)	1.1 ( 1.161 )	4.98 ( 1.178 )	2.6 ( 1.192 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0168 ^[2]

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

3.88

Confidence interval

level

95%

sides

2-sided

lower limit

0.7

upper limit

7.05

Notes
[2] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

Statistical Analysis 2

Statistical analysis description

Analysis was performed using MMRM model, as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

356

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3569

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-1.69

upper limit

4.69

Secondary: Percentage of subjects With Response Based on Percent Predicted FEV1

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End point title

Percentage of subjects With Response Based on Percent Predicted FEV1

End point description

A subject was considered as a responder if the subject 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 primary endpoint. Analysis was performed on FAS. A subject 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.

End point type

Secondary

End point timeframe

Week 16 and 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: percentage of subjects
number (not applicable)	22.3	46.4	36.8

Statistical Analysis 1

Statistical analysis description

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).

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.9378

Confidence interval

level

95%

sides

2-sided

lower limit

1.8786

upper limit

4.5941

Notes
[3] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

Placebo v LUM 400 mg q12h/IVA 250 mg q12h

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0023 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.0592

Confidence interval

level

95%

sides

2-sided

lower limit

1.292

upper limit

3.2819

Notes
[4] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

Secondary: Number of Pulmonary Exacerbation Events

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End point title

Number of Pulmonary Exacerbation Events

End point 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. Analysis was performed on FAS.

End point type

Secondary

End point timeframe

through Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: pulmonary exacerbation events per year
number (not applicable)	1.07	0.77	0.71

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0491

Method

Negative Binomial Regression

Parameter type

Event Rate Ratio

Point estimate

0.7186

Confidence interval

level

95%

sides

2-sided

lower limit

0.517

upper limit

0.9987

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0169 ^[5]

Method

Negative Binomial Regression

Parameter type

Event Rate Ratio

Point estimate

0.6643

Confidence interval

level

95%

sides

2-sided

lower limit

0.4749

upper limit

0.9291

Notes
[5] - This test is considered nominally significant because a hierarchical procedure was used and was broken prior to this test.

Secondary: Absolute Change From Baseline in Weight at Week 24

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End point title

Absolute Change From Baseline in Weight at Week 24

End point description

Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	178	176
Units: kilograms (kg)
least squares mean (standard error)	0.93 ( 0.202 )	1.34 ( 0.205 )	1.23 ( 0.205 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

362

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1565

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.96

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

360

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2992

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.86

Secondary: Absolute Change From Baseline in BMI-for-age Z-score at Week 24

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End point title

Absolute Change From Baseline in BMI-for-age Z-score at Week 24

End point 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. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint. Only subjects who were <20 years of age were analyzed.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	69	65	58
Units: z-score
least squares mean (standard error)	0.0153 ( 0.04886 )	0.1132 ( 0.05081 )	0.0933 ( 0.05431 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1539

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.098

Confidence interval

level

95%

sides

2-sided

lower limit

-0.037

upper limit

0.233

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2713

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.0781

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0615

upper limit

0.2176

Secondary: Time-to-First Pulmonary Exacerbation

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End point title

Time-to-First Pulmonary Exacerbation

End point description

Time to first pulmonary exacerbation was assessed using Cox Regression. For subjects who completed 24 weeks of treatment, subjects 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 subjects who prematurely discontinued study treatment, subjects without a pulmonary exacerbation through the Week 24 Visit were considered censored at the time of the Week 24 Visit. Analysis was performed on FAS. The number 99999 represents data not available because median time was not reached as less than 50% of subjects had the event of interest.

End point type

Secondary

End point timeframe

through Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: days
median (full range (min-max))	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Statistical Analysis 1

Statistical analysis description

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).

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0396

Method

Cox Proportional Hazard Regression

Confidence interval

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0385

Method

Cox Proportional Hazard Regression

Confidence interval

Secondary: Percentage of subjects With At Least 1 Pulmonary Exacerbation Event

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End point title

Percentage of subjects With At Least 1 Pulmonary Exacerbation Event

End point description

Analysis was performed on FAS.

End point type

Secondary

End point timeframe

through Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: percentage of subjects
number (not applicable)	39.7	30.1	30.2

Statistical Analysis 1

Statistical analysis description

OR and 95% confidence intervals (CIs) are Mantel-Haenszel estimates. P values are from a Cochran-Mante-lHaenszel 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).

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0552

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.6565

Confidence interval

level

95%

sides

2-sided

lower limit

0.4266

upper limit

1.0103

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0512

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.6438

Confidence interval

level

95%

sides

2-sided

lower limit

0.4142

upper limit

1.0005

Secondary: Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24

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End point title

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

End point description

EQ-5D-3L: subject 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. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	179	175	170
Units: units on a scale
least squares mean (standard error)	0.0006 ( 0.00739 )	0.0066 ( 0.00746 )	0.01 ( 0.00757 )

Statistical Analysis 1

Statistical analysis description

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 EQ5D3L index score.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

354

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5604

Method

MMRM

Parameter type

LS Mean Difference]

Point estimate

0.006

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0142

upper limit

0.0262

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

349

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3613

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.0095

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0109

upper limit

0.0298

Secondary: Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24

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End point title

Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24

End point description

The EQ-5D-3L VAS records the subjects self-rated health on a vertical, visual analogue scale where the best state a subject can imagine is marked 100 and the worst state a subject can imagine is marked 0, higher scores indicates a better health state. Analysis was performed on FAS. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	180	173	171
Units: units on a scale
least squares mean (standard error)	1.4 ( 1.03 )	3.5 ( 1.04 )	2.8 ( 1.04 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

Placebo v LUM 600 mg qd/IVA 250 mg q12h

Number of subjects included in analysis

353

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1342

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

4.9

Statistical Analysis 2

Statistical analysis description

Analysis was performed as described in Statistical Analysis 1.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3071

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

4.2

Secondary: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24

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End point title

Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24

End point description

The TSQM is a 14-item self-administered questionnaire which measures subjects 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. Analysis was performed on FAS. Here, "n" signifies subjects who were evaluable for specified category for each arm, respectively.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: units on a scale
least squares mean (standard error)
Effectiveness (n = 163, 156, 144)	-5.3 ( 1.643 )	0.19 ( 1.666 )	0.5 ( 1.726 )
Side Effects (n = 162, 154, 143)	2.23 ( 1.119 )	-1.94 ( 1.141 )	-2.51 ( 1.179 )
Convenience (n = 163, 154, 144)	4.37 ( 1.504 )	4.98 ( 1.54 )	7.45 ( 1.579 )
Global Satisfaction (n= 163, 154, 144)	-10.49 ( 1.863 )	-5 ( 1.906 )	-3.77 ( 1.956 )

Statistical Analysis 1

Statistical analysis description

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. Actual number of subjects included in analysis were 319.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.016

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

5.49

Confidence interval

level

95%

sides

2-sided

lower limit

1.03

upper limit

9.96

Statistical Analysis 2

Statistical analysis description

Effectiveness: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 307.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0126

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.25

upper limit

10.35

Statistical Analysis 3

Statistical analysis description

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. Actual number of subjects included in analysis were 316.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0074

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-4.18

Confidence interval

level

95%

sides

2-sided

lower limit

-7.23

upper limit

-1.13

Statistical Analysis 4

Statistical analysis description

Side Effects: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 305.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0029

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-4.74

Confidence interval

level

95%

sides

2-sided

lower limit

-7.85

upper limit

-1.63

Statistical Analysis 5

Statistical analysis description

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. Actual number of subjects included in analysis were 317.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7721

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.61

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

4.71

Statistical Analysis 6

Statistical analysis description

Convenience: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 307.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1472

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

3.08

Confidence interval

level

95%

sides

2-sided

lower limit

-1.09

upper limit

7.25

Statistical Analysis 7

Statistical analysis description

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. Actual number of subjects included in analysis were 317.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

367

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0345

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

5.49

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

10.58

Statistical Analysis 8

Statistical analysis description

Global Satisfaction: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 307.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

366

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0109

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

6.72

Confidence interval

level

95%

sides

2-sided

lower limit

1.55

upper limit

11.89

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)

End point description

AE: any untoward medical occurrence in a subject 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. Safety Set (SS) included all randomized subjects who received any amount of study drug.

End point type

Secondary

End point timeframe

up to Week 28

End point values	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	184	183	182
Units: subjects
number (not applicable)
Subjects With Treatment-Emergent AEs	174	175	174
Subjects With Treatment-Emergent SAEs	49	33	33

No statistical analyses for this end point

Secondary: 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)

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End point 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) ^[6]

End point 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,ave is average of individual 3 to 6 hours post-dose observed concentrations across Day 15, and Weeks 4 and 8 and Ctrough,ave 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. Pharmacokinetic (PK) population included all randomized subjects who received at least one dose of study drug and had a PK assessment. Here, number of subjects analyzed signifies subjects who were evaluable for this endpoint and "n" signifies subjects evaluable for specified category for each arm, respectively.

End point type

Secondary

End point timeframe

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

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic (PK) analysis was not performed in subjects receiving placebo.

End point values	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/IVA 250 mg q12h
Number of subjects analysed	180	181
Units: microgram per milliliter (mcg/mL)
arithmetic mean (standard deviation)
LUM, Day 1: C3-6h (n = 180, 175)	27.5 ( 12.5 )	18.4 ( 8.55 )
LUM, Day 15: Ctrough (n = 172, 175)	7.56 ( 5.33 )	14.1 ( 6.99 )
LUM, Day 15: C3-6 (n = 167, 171)	26.1 ( 11.5 )	23.6 ( 8.54 )
LUM, Week 4: Ctrough (n = 172, 178)	7.75 ( 5.05 )	13.4 ( 6.7 )
LUM, Week 4: C3-6 (n = 170, 171)	28.4 ( 11.2 )	24.2 ( 8.66 )
LUM, Week 8: Ctrough (n = 173, 174)	7.43 ( 5.6 )	13.4 ( 6.68 )
LUM, Week 8: C3-6 (n = 165, 171)	28.2 ( 11.2 )	24.4 ( 8.8 )
LUM, Week 16: Ctrough (n = 165, 164)	6.95 ( 4.99 )	13.5 ( 7.49 )
M-28 LUM, Day 1: C3-6h (n = 180, 175)	0.22 ( 0.107 )	0.179 ( 0.0811 )
M-28 LUM, Day 15: Ctrough (n = 172, 175)	1.25 ( 0.614 )	1.48 ( 0.59 )
M-28 LUM, Day 15: C3-6 (n = 167, 171)	1.37 ( 0.606 )	1.49 ( 0.576 )
M-28 LUM, Week 4: Ctrough (n = 172, 178)	1.31 ( 0.646 )	1.48 ( 0.642 )
M-28 LUM, Week 4: C3-6 (n = 170, 171)	1.39 ( 0.635 )	1.49 ( 0.615 )
M-28 LUM, Week 8: Ctrough (n = 173, 174)	1.32 ( 0.684 )	1.53 ( 0.674 )
M-28 LUM, Week 8: C3-6 (n = 165, 171)	1.42 ( 0.658 )	1.56 ( 0.669 )
M-28 LUM, Week 16: Ctrough (n = 165, 164)	1.3 ( 0.769 )	1.57 ( 0.757 )
IVA, Day 1: C3-6h (n = 180, 175)	1.29 ( 0.624 )	1.24 ( 0.63 )
IVA, Day 15: Ctrough (n = 172, 176)	0.151 ( 0.123 )	0.115 ( 0.123 )
IVA, Day 15: C3-6 (n = 167, 171)	0.557 ( 0.311 )	0.413 ( 0.199 )
IVA, Week 4: Ctrough (n = 172, 178)	0.142 ( 0.107 )	0.105 ( 0.083 )
IVA, Week 4: C3-6 (n = 170, 171)	0.638 ( 0.325 )	0.456 ( 0.235 )
IVA, Week 8: Ctrough (n = 173, 174)	0.13 ( 0.101 )	0.0894 ( 0.0726 )
IVA, Week 8: C3-6 (n = 165, 171)	0.648 ( 0.364 )	0.47 ( 0.295 )
IVA, Week 16: Ctrough (n = 165, 164)	0.133 ( 0.131 )	0.0834 ( 0.0622 )
M-1 IVA, Day 1: C3-6h (n = 180, 175)	2.46 ( 1.29 )	2.41 ( 1.35 )
M-1 IVA, Day 15: Ctrough (n = 172, 176)	0.665 ( 0.578 )	0.511 ( 0.53 )
M-1 IVA, Day 15: C3-6 (n = 167, 171)	1.94 ( 0.981 )	1.71 ( 0.867 )
M-1 IVA, Week 4: Ctrough (n = 172, 178)	0.628 ( 0.492 )	0.45 ( 0.345 )
M-1 IVA, Week 4: C3-6 (n = 170, 171)	2.21 ( 1.01 )	1.76 ( 0.932 )
M-1 IVA, Week 8: Ctrough (n = 173, 174)	0.584 ( 0.451 )	0.404 ( 0.381 )
M-1 IVA, Week 8: C3-6 (n = 165, 171)	2.17 ( 1.06 )	1.78 ( 0.975 )
M-1 IVA, Week 16: Ctrough (n = 165, 164)	0.589 ( 0.519 )	0.396 ( 0.319 )
M-6 IVA, Day 1: C3-6h (n = 180, 175)	0.976 ( 0.877 )	0.927 ( 0.875 )
M-6 IVA, Day 15: Ctrough (n = 172, 176)	1.68 ( 1.31 )	1.67 ( 1.4 )
M-6 IVA, Day 15: C3-6 (n = 167, 171)	3.03 ( 1.96 )	2.87 ( 1.81 )
M-6 IVA, Week 4: Ctrough (n = 172, 178)	1.66 ( 1.36 )	1.46 ( 0.938 )
M-6 IVA, Week 4: C3-6 (n = 170, 171)	3.07 ( 1.92 )	2.49 ( 1.53 )
M-6 IVA, Week 8: Ctrough (n = 173, 174)	1.52 ( 1.12 )	1.31 ( 0.946 )
M-6 IVA, Week 8: C3-6 (n = 165, 171)	2.96 ( 1.86 )	2.36 ( 1.57 )
M-6 IVA, Week 16: Ctrough (n = 165, 164)	1.4 ( 1.11 )	1.33 ( 1.02 )
LUM: Ctrough,ave (n = 179, 181)	7.49 ( 3.93 )	13.5 ( 5.52 )
LUM: C3-6h, ave (n = 179, 181)	27.7 ( 8.63 )	24 ( 7.29 )
M-28 LUM: Ctrough,ave (n = 179, 181)	1.31 ( 0.628 )	1.51 ( 0.614 )
M-28 LUM: C3-6h, ave (n = 179, 181)	1.39 ( 0.596 )	1.51 ( 0.585 )
IVA: Ctrough,ave (n = 179, 181)	0.137 ( 0.0773 )	0.0989 ( 0.0644 )
IVA: C3-6h, ave (n = 179, 181)	0.614 ( 0.271 )	0.445 ( 0.193 )
M1-IVA: Ctrough,ave (n = 179, 181)	0.606 ( 0.35 )	0.441 ( 0.293 )
M1-IVA: C3-6h, ave (n = 179, 181)	2.11 ( 0.817 )	1.74 ( 0.726 )
M6-IVA: Ctrough,ave (n = 179, 181)	1.57 ( 0.992 )	1.44 ( 0.861 )
M6-IVA: C3-6h, ave (n = 179, 181)	3.04 ( 1.55 )	2.57 ( 1.34 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

up to Week 28

Adverse event reporting additional description

Subjects were analyzed as per actual treatment received. Other adverse events includes only nonserious AEs.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo

Reporting group description

Placebo matched to lumacaftor (LUM, VX-809) and ivacaftor (IVA, VX-770) tablet every 12 hours (q12h), up to Week 24.

Reporting group title

LUM 600 mg qd/IVA 250 mg q12h

Reporting group description

LUM 600 mg plus IVA 250 mg supplied as fixed-dose combination (FDC) tablet in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Reporting group title

LUM 400 mg q12h/ IVA 250 mg q12h

Reporting group description

LUM 400 mg plus IVA 250 mg supplied as FDC tablet in the morning and in the evening, up to Week 24.

Serious adverse events	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 184 (26.63%)	33 / 183 (18.03%)	33 / 182 (18.13%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer metastatic
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seminoma
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Implant site thrombosis
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	5 / 182 (2.75%)
occurrences causally related to treatment / all	1 / 2	0 / 0	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchospasm
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Forced expiratory volume decreased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alanine aminotransferase increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Post procedural haematoma
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Pericarditis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Epilepsy
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Distal intestinal obstruction syndrome
subjects affected / exposed	2 / 184 (1.09%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences causally related to treatment / all	0 / 3	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal adhesions
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatitis cholestatic
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	41 / 184 (22.28%)	19 / 183 (10.38%)	17 / 182 (9.34%)
occurrences causally related to treatment / all	1 / 51	0 / 22	0 / 18
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site cellulitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of bronchiectasis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection viral
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Placebo	LUM 600 mg qd/IVA 250 mg q12h	LUM 400 mg q12h/ IVA 250 mg q12h
Total subjects affected by non serious adverse events
subjects affected / exposed	173 / 184 (94.02%)	175 / 183 (95.63%)	172 / 182 (94.51%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	0	2	2
Flushing
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Hot flush
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	0	0	2
Deep vein thrombosis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Hypotension
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Poor venous access
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	19 / 184 (10.33%)	17 / 183 (9.29%)	17 / 182 (9.34%)
occurrences all number	20	17	18
Pyrexia
subjects affected / exposed	12 / 184 (6.52%)	12 / 183 (6.56%)	17 / 182 (9.34%)
occurrences all number	14	14	19
Asthenia
subjects affected / exposed	3 / 184 (1.63%)	5 / 183 (2.73%)	3 / 182 (1.65%)
occurrences all number	3	5	3
Pain
subjects affected / exposed	2 / 184 (1.09%)	4 / 183 (2.19%)	3 / 182 (1.65%)
occurrences all number	2	4	3
Chest discomfort
subjects affected / exposed	1 / 184 (0.54%)	3 / 183 (1.64%)	3 / 182 (1.65%)
occurrences all number	1	4	3
Malaise
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	1	4	3
Chills
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	1	0	2
Drug intolerance
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	0	0	3
Chest pain
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Influenza like illness
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Drug interaction
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Exercise tolerance decreased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Feeling abnormal
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Feeling cold
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Feeling hot
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Hyperthermia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Implant site thrombosis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Local swelling
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Medical device pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Oedema peripheral
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Seasonal allergy
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Anaphylactic reaction
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Hypersensitivity
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Milk allergy
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	2	3	3
Metrorrhagia
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	0	3	3
Amenorrhoea
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	0	0	4
Menorrhagia
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	0	2	1
Menstruation irregular
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	0	3	1
Polymenorrhoea
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Erectile dysfunction
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Gynaecomastia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Penile erythema
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Testicular pain
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	66 / 184 (35.87%)	52 / 183 (28.42%)	47 / 182 (25.82%)
occurrences all number	93	63	60
Haemoptysis
subjects affected / exposed	23 / 184 (12.50%)	22 / 183 (12.02%)	26 / 182 (14.29%)
occurrences all number	29	27	34
Sputum increased
subjects affected / exposed	23 / 184 (12.50%)	15 / 183 (8.20%)	25 / 182 (13.74%)
occurrences all number	25	16	27
Dyspnoea
subjects affected / exposed	14 / 184 (7.61%)	21 / 183 (11.48%)	17 / 182 (9.34%)
occurrences all number	15	29	23
Respiration abnormal
subjects affected / exposed	9 / 184 (4.89%)	26 / 183 (14.21%)	14 / 182 (7.69%)
occurrences all number	10	32	16
Nasal congestion
subjects affected / exposed	25 / 184 (13.59%)	9 / 183 (4.92%)	11 / 182 (6.04%)
occurrences all number	29	9	12
Oropharyngeal pain
subjects affected / exposed	10 / 184 (5.43%)	24 / 183 (13.11%)	11 / 182 (6.04%)
occurrences all number	14	26	12
Rhinorrhoea
subjects affected / exposed	5 / 184 (2.72%)	6 / 183 (3.28%)	10 / 182 (5.49%)
occurrences all number	6	6	10
Wheezing
subjects affected / exposed	6 / 184 (3.26%)	5 / 183 (2.73%)	5 / 182 (2.75%)
occurrences all number	6	7	8
Rales
subjects affected / exposed	7 / 184 (3.80%)	4 / 183 (2.19%)	4 / 182 (2.20%)
occurrences all number	7	5	5
Productive cough
subjects affected / exposed	1 / 184 (0.54%)	6 / 183 (3.28%)	7 / 182 (3.85%)
occurrences all number	1	8	7
Respiratory tract congestion
subjects affected / exposed	5 / 184 (2.72%)	3 / 183 (1.64%)	4 / 182 (2.20%)
occurrences all number	6	3	5
Epistaxis
subjects affected / exposed	4 / 184 (2.17%)	4 / 183 (2.19%)	2 / 182 (1.10%)
occurrences all number	5	11	2
Asthma
subjects affected / exposed	3 / 184 (1.63%)	0 / 183 (0.00%)	6 / 182 (3.30%)
occurrences all number	4	0	6
Bronchospasm
subjects affected / exposed	1 / 184 (0.54%)	3 / 183 (1.64%)	5 / 182 (2.75%)
occurrences all number	1	3	6
Sinus congestion
subjects affected / exposed	1 / 184 (0.54%)	7 / 183 (3.83%)	1 / 182 (0.55%)
occurrences all number	1	7	1
Paranasal sinus hypersecretion
subjects affected / exposed	1 / 184 (0.54%)	4 / 183 (2.19%)	3 / 182 (1.65%)
occurrences all number	1	4	3
Sputum discoloured
subjects affected / exposed	3 / 184 (1.63%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	3	2	1
Nasal inflammation
subjects affected / exposed	1 / 184 (0.54%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	1	3	1
Rhinitis allergic
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	2	1	2
Rhonchi
subjects affected / exposed	2 / 184 (1.09%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	2	2	1
Upper-airway cough syndrome
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	3	1	2
Dysphonia
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	2	1	1
Dyspnoea exertional
subjects affected / exposed	0 / 184 (0.00%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	0	3	1
Increased upper airway secretion
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Increased viscosity of bronchial secretion
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	2	0	2
Painful respiration
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	2	1	1
Pharyngeal erythema
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	1	2	1
Pleuritic pain
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	2	0	2
Lung hyperinflation
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	1	2	1
Throat irritation
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	3	0	1
Bronchial hyperreactivity
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Nasal polyps
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Obstructive airways disorder
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Paranasal cyst
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Pulmonary congestion
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Allergic cough
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Bronchial obstruction
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Bronchiectasis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Hypoxia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Nasal obstruction
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Nasal oedema
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Nasal septum deviation
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Pharyngeal exudate
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Prolonged expiration
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Pulmonary pain
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Respiratory failure
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Respiratory tract irritation
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Rhinalgia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Sneezing
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Throat tightness
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Upper respiratory tract inflammation
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Psychiatric disorders
Insomnia
subjects affected / exposed	6 / 184 (3.26%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	8	2	3
Anxiety
subjects affected / exposed	2 / 184 (1.09%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	2	2	2
Depression
subjects affected / exposed	4 / 184 (2.17%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	4	1	1
Depressed mood
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	0	0	3
Irritability
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Attention deficit/hyperactivity disorder
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Bradyphrenia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Depressive symptom
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Disorientation
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Disturbance in social behaviour
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Emotional disorder
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Libido decreased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Middle insomnia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Sleep disorder
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Suicidal ideation
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	10 / 184 (5.43%)	10 / 183 (5.46%)	13 / 182 (7.14%)
occurrences all number	11	12	14
Bacterial test positive
subjects affected / exposed	9 / 184 (4.89%)	4 / 183 (2.19%)	7 / 182 (3.85%)
occurrences all number	13	6	9
Alanine aminotransferase increased
subjects affected / exposed	5 / 184 (2.72%)	4 / 183 (2.19%)	3 / 182 (1.65%)
occurrences all number	5	4	4
Forced expiratory volume decreased
subjects affected / exposed	7 / 184 (3.80%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	7	3	1
Weight decreased
subjects affected / exposed	5 / 184 (2.72%)	2 / 183 (1.09%)	4 / 182 (2.20%)
occurrences all number	5	2	4
Liver function test abnormal
subjects affected / exposed	6 / 184 (3.26%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	7	3	1
Pulmonary function test decreased
subjects affected / exposed	6 / 184 (3.26%)	4 / 183 (2.19%)	0 / 182 (0.00%)
occurrences all number	7	4	0
Aspartate aminotransferase increased
subjects affected / exposed	3 / 184 (1.63%)	3 / 183 (1.64%)	3 / 182 (1.65%)
occurrences all number	3	3	4
Blood creatinine increased
subjects affected / exposed	4 / 184 (2.17%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	4	3	1
White blood cell count increased
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	1	2	2
Blood glucose decreased
subjects affected / exposed	3 / 184 (1.63%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	3	0	1
Hepatic enzyme increased
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	0	2	2
Vitamin D decreased
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Breath sounds abnormal
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Fungal test positive
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	1	1	1
Staphylococcus test positive
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	0	1	2
Transaminases increased
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	1	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Blood glucose increased
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Blood immunoglobulin E increased
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Blood phosphorus increased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Body temperature increased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Atypical mycobacterium test positive
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Blood bicarbonate decreased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Blood calcium increased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Blood phosphorus abnormal
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Blood potassium increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Blood sodium decreased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Blood urea increased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
C-reactive protein increased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Chest X-ray abnormal
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Forced expiratory volume increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Glucose tolerance test abnormal
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Glucose urine present
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Haemoglobin increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Heart rate increased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Neutrophil count increased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Platelet count decreased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Pseudomonas test positive
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Red blood cell count increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Sputum abnormal
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Urine calcium increased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Vitamin E decreased
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
White blood cell count decreased
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
White blood cells urine positive
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Muscle strain
subjects affected / exposed	0 / 184 (0.00%)	3 / 183 (1.64%)	2 / 182 (1.10%)
occurrences all number	0	4	2
Joint injury
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Ligament sprain
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	0	1	2
Procedural pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	1	0	2
Concussion
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	0	0	2
Excoriation
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	3	0	0
Facial bones fracture
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Stoma site pain
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	3	0
Sunburn
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Arthropod bite
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Back injury
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Contusion
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Fall
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Foot fracture
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Foreign body in eye
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Laceration
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Meniscus injury
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Muscle rupture
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Post procedural complication
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Radius fracture
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Respiratory fume inhalation disorder
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Skeletal injury
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Stoma site erythema
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Vaccination complication
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Vascular procedure complication
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Atrial fibrillation
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Atrioventricular block second degree
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Defect conduction intraventricular
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Pericarditis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Tachycardia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Nervous system disorders
Headache
subjects affected / exposed	25 / 184 (13.59%)	28 / 183 (15.30%)	29 / 182 (15.93%)
occurrences all number	29	42	35
Dizziness
subjects affected / exposed	5 / 184 (2.72%)	5 / 183 (2.73%)	5 / 182 (2.75%)
occurrences all number	6	5	6
Sinus headache
subjects affected / exposed	2 / 184 (1.09%)	3 / 183 (1.64%)	3 / 182 (1.65%)
occurrences all number	2	5	3
Migraine
subjects affected / exposed	3 / 184 (1.63%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	3	0	4
Lethargy
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	1	2	2
Dysgeusia
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	2	0	2
Poor quality sleep
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	0	0	3
Dysarthria
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Paraesthesia
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Syncope
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Tremor
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	0	0	5
Amnesia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Ataxia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Cognitive disorder
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Dysaesthesia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Epilepsy
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Hypoaesthesia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Memory impairment
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Neuropathy peripheral
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Presyncope
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Sciatica
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Somnolence
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Tension headache
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Eosinophilia
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Lymphadenopathy
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Lymph node pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Neutropenia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Thrombocytosis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 184 (0.54%)	4 / 183 (2.19%)	0 / 182 (0.00%)
occurrences all number	1	5	0
Ear pain
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	1	2	1
Cerumen impaction
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Tympanic membrane disorder
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Tympanic membrane hyperaemia
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Ear canal erythema
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Ear congestion
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Asthenopia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Blepharospasm
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Astigmatism
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Conjunctivitis allergic
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Eye disorder
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Eye pruritus
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Visual acuity reduced
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	13 / 184 (7.07%)	16 / 183 (8.74%)	24 / 182 (13.19%)
occurrences all number	14	19	34
Abdominal pain
subjects affected / exposed	12 / 184 (6.52%)	11 / 183 (6.01%)	23 / 182 (12.64%)
occurrences all number	15	17	31
Nausea
subjects affected / exposed	11 / 184 (5.98%)	9 / 183 (4.92%)	14 / 182 (7.69%)
occurrences all number	12	11	18
Constipation
subjects affected / exposed	11 / 184 (5.98%)	6 / 183 (3.28%)	7 / 182 (3.85%)
occurrences all number	11	7	7
Abdominal pain upper
subjects affected / exposed	10 / 184 (5.43%)	7 / 183 (3.83%)	5 / 182 (2.75%)
occurrences all number	11	8	8
Flatulence
subjects affected / exposed	1 / 184 (0.54%)	9 / 183 (4.92%)	11 / 182 (6.04%)
occurrences all number	1	11	11
Vomiting
subjects affected / exposed	2 / 184 (1.09%)	8 / 183 (4.37%)	7 / 182 (3.85%)
occurrences all number	2	9	8
Abdominal distension
subjects affected / exposed	4 / 184 (2.17%)	2 / 183 (1.09%)	5 / 182 (2.75%)
occurrences all number	4	3	6
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 184 (1.09%)	3 / 183 (1.64%)	6 / 182 (3.30%)
occurrences all number	2	3	6
Dyspepsia
subjects affected / exposed	2 / 184 (1.09%)	3 / 183 (1.64%)	4 / 182 (2.20%)
occurrences all number	2	4	4
Abdominal discomfort
subjects affected / exposed	1 / 184 (0.54%)	3 / 183 (1.64%)	3 / 182 (1.65%)
occurrences all number	1	3	3
Enteritis
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	3 / 182 (1.65%)
occurrences all number	2	0	3
Steatorrhoea
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	3 / 182 (1.65%)
occurrences all number	0	1	3
Dry mouth
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	1	1	1
Frequent bowel movements
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	1	1	1
Toothache
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	1	0	2
Abdominal pain lower
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Distal intestinal obstruction syndrome
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Faeces soft
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Gastrointestinal motility disorder
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Malabsorption
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Abdominal tenderness
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Anal fissure
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Chapped lips
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Colonic haematoma
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Defaecation urgency
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Faecaloma
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Gastric dilatation
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Gastritis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Gastrointestinal pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Gingival swelling
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Gingivitis ulcerative
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Haemorrhoids
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Oesophagitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Rectal tenesmus
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Tongue coated
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Hepatitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	2 / 184 (1.09%)	8 / 183 (4.37%)	6 / 182 (3.30%)
occurrences all number	2	8	6
Pruritus
subjects affected / exposed	1 / 184 (0.54%)	5 / 183 (2.73%)	4 / 182 (2.20%)
occurrences all number	1	6	5
Acne
subjects affected / exposed	5 / 184 (2.72%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	5	1	1
Hyperhidrosis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	0	1	2
Night sweats
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	0	3	1
Urticaria
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	2	1	0
Alopecia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Dermatitis allergic
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Photosensitivity reaction
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	0	0	2
Pruritus allergic
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Pruritus generalised
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Rash macular
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Chloasma
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Cold sweat
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Drug eruption
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Dry skin
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Eczema
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Erythema
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Erythema nodosum
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Macule
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Rash generalised
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Rash maculo-papular
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Red man syndrome
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Swelling face
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Urine odour abnormal
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Calculus urinary
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Haematuria
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Leukocyturia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Nephropathy
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Nephropathy toxic
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Pollakiuria
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Renal failure acute
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Urine abnormality
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	6 / 184 (3.26%)	7 / 183 (3.83%)	3 / 182 (1.65%)
occurrences all number	6	7	3
Myalgia
subjects affected / exposed	4 / 184 (2.17%)	3 / 183 (1.64%)	7 / 182 (3.85%)
occurrences all number	5	3	7
Back pain
subjects affected / exposed	5 / 184 (2.72%)	3 / 183 (1.64%)	5 / 182 (2.75%)
occurrences all number	6	3	6
Arthralgia
subjects affected / exposed	4 / 184 (2.17%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	4	1	2
Pain in extremity
subjects affected / exposed	4 / 184 (2.17%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	4	0	1
Musculoskeletal pain
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	3 / 182 (1.65%)
occurrences all number	0	1	3
Flank pain
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	0	2	1
Muscle spasms
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	2	1	0
Joint swelling
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Tendon pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Arthropathy
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Intervertebral disc protrusion
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Musculoskeletal discomfort
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Neck pain
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Tendon disorder
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Tendonitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	58 / 184 (31.52%)	57 / 183 (31.15%)	54 / 182 (29.67%)
occurrences all number	86	79	75
Nasopharyngitis
subjects affected / exposed	20 / 184 (10.87%)	9 / 183 (4.92%)	26 / 182 (14.29%)
occurrences all number	23	13	33
Upper respiratory tract infection
subjects affected / exposed	10 / 184 (5.43%)	16 / 183 (8.74%)	17 / 182 (9.34%)
occurrences all number	13	21	21
Rhinitis
subjects affected / exposed	12 / 184 (6.52%)	16 / 183 (8.74%)	8 / 182 (4.40%)
occurrences all number	17	18	8
Sinusitis
subjects affected / exposed	12 / 184 (6.52%)	7 / 183 (3.83%)	5 / 182 (2.75%)
occurrences all number	15	7	5
Influenza
subjects affected / exposed	3 / 184 (1.63%)	8 / 183 (4.37%)	8 / 182 (4.40%)
occurrences all number	3	8	8
Bronchitis
subjects affected / exposed	7 / 184 (3.80%)	9 / 183 (4.92%)	2 / 182 (1.10%)
occurrences all number	11	11	4
Respiratory tract infection
subjects affected / exposed	3 / 184 (1.63%)	2 / 183 (1.09%)	6 / 182 (3.30%)
occurrences all number	5	2	7
Pharyngitis
subjects affected / exposed	2 / 184 (1.09%)	4 / 183 (2.19%)	4 / 182 (2.20%)
occurrences all number	2	4	4
Vulvovaginal mycotic infection
subjects affected / exposed	4 / 184 (2.17%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	4	2	5
Oral candidiasis
subjects affected / exposed	3 / 184 (1.63%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	3	3	3
Urinary tract infection
subjects affected / exposed	3 / 184 (1.63%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	3	2	3
Upper respiratory tract infection bacterial
subjects affected / exposed	2 / 184 (1.09%)	2 / 183 (1.09%)	3 / 182 (1.65%)
occurrences all number	3	3	3
Viral infection
subjects affected / exposed	4 / 184 (2.17%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	4	2	1
Gastroenteritis viral
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	1	2	2
Lower respiratory tract infection bacterial
subjects affected / exposed	3 / 184 (1.63%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	3	1	1
Respiratory tract infection viral
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	2 / 182 (1.10%)
occurrences all number	1	2	2
Gastroenteritis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	3 / 182 (1.65%)
occurrences all number	0	1	3
H1N1 influenza
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Oral herpes
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	2 / 182 (1.10%)
occurrences all number	1	1	2
Otitis media
subjects affected / exposed	0 / 184 (0.00%)	3 / 183 (1.64%)	1 / 182 (0.55%)
occurrences all number	0	3	1
Acute sinusitis
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	2	1	1
Bronchopulmonary aspergillosis allergic
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Fungal skin infection
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	2	1	0
Laryngitis
subjects affected / exposed	1 / 184 (0.54%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	1	2	0
Sputum purulent
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	1 / 182 (0.55%)
occurrences all number	0	2	1
Bacterial disease carrier
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Chronic sinusitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	2	1
Clostridium difficile colitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Herpes zoster
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Lower respiratory tract infection viral
subjects affected / exposed	0 / 184 (0.00%)	2 / 183 (1.09%)	0 / 182 (0.00%)
occurrences all number	0	3	0
Mycobacterium abscessus infection
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Pharyngitis streptococcal
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Tonsillitis
subjects affected / exposed	1 / 184 (0.54%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	1	1	0
Vulvovaginal candidiasis
subjects affected / exposed	2 / 184 (1.09%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	2	0	0
Acute tonsillitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Body tinea
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Conjunctivitis bacterial
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Ear infection
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Eye infection
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Folliculitis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Genital infection fungal
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Giardiasis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Herpes dermatitis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Herpes simplex
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Lower respiratory tract infection
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Lung infection
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Lung infection pseudomonal
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Oral fungal infection
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Oropharyngeal candidiasis
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	2
Otitis externa
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Overgrowth bacterial
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Pseudomonas bronchitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	2	0
Soft tissue infection
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Stoma site infection
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Subcutaneous abscess
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Tinea pedis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Tinea versicolour
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Tooth infection
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Tracheitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Vestibular neuronitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Viral rhinitis
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Viral tonsillitis
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Viral upper respiratory tract infection
subjects affected / exposed	12 / 184 (6.52%)	15 / 183 (8.20%)	13 / 182 (7.14%)
occurrences all number	15	19	19
Bronchitis bacterial
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	0	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 184 (2.17%)	6 / 183 (3.28%)	6 / 182 (3.30%)
occurrences all number	4	6	6
Hypoglycaemia
subjects affected / exposed	3 / 184 (1.63%)	6 / 183 (3.28%)	2 / 182 (1.10%)
occurrences all number	3	6	3
Dehydration
subjects affected / exposed	3 / 184 (1.63%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	3	0	1
Hyperglycaemia
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	1 / 182 (0.55%)
occurrences all number	2	1	1
Gout
subjects affected / exposed	2 / 184 (1.09%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	2	1	0
Diabetes mellitus
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	1	0	1
Hyponatraemia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	2 / 182 (1.10%)
occurrences all number	0	0	2
Glucose tolerance impaired
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0
Hyperkalaemia
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Hypokalaemia
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Iron deficiency
subjects affected / exposed	1 / 184 (0.54%)	0 / 183 (0.00%)	0 / 182 (0.00%)
occurrences all number	1	0	0
Magnesium deficiency
subjects affected / exposed	0 / 184 (0.00%)	0 / 183 (0.00%)	1 / 182 (0.55%)
occurrences all number	0	0	1
Vitamin K deficiency
subjects affected / exposed	0 / 184 (0.00%)	1 / 183 (0.55%)	0 / 182 (0.00%)
occurrences all number	0	1	0

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Were there any global substantial amendments to the protocol? Yes

25 Jul 2013

Modified primary endpoint and selected secondary endpoint.

05 Feb 2014

Order of primary and key secondary endpoints was revised.

24 Feb 2014

Clarification on which subjects were required to complete the Safety Follow-up Visit was provided.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: 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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24

Primary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) at Week 24

Secondary: Relative Change From Baseline in Percent Predicted FEV1 at Week 24

Secondary: Relative Change From Baseline in Percent Predicted FEV1 at Week 24

Secondary: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

Secondary: Absolute Change From Baseline in Body Mass Index (BMI) at Week 24

Secondary: Absolute Change From Baseline in (Cystic Fibrosis Questionnaire-Revised) CFQ R Respiratory Domain Score at Week 24

Secondary: Absolute Change From Baseline in (Cystic Fibrosis Questionnaire-Revised) CFQ R Respiratory Domain Score at Week 24

Secondary: Percentage of subjects With Response Based on Percent Predicted FEV1

Secondary: Percentage of subjects With Response Based on Percent Predicted FEV1

Secondary: Number of Pulmonary Exacerbation Events

Secondary: Number of Pulmonary Exacerbation Events

Secondary: Absolute Change From Baseline in Weight at Week 24

Secondary: Absolute Change From Baseline in Weight at Week 24

Secondary: Absolute Change From Baseline in BMI-for-age Z-score at Week 24

Secondary: Absolute Change From Baseline in BMI-for-age Z-score at Week 24

Secondary: Time-to-First Pulmonary Exacerbation

Secondary: Time-to-First Pulmonary Exacerbation

Secondary: Percentage of subjects With At Least 1 Pulmonary Exacerbation Event

Secondary: Percentage of subjects With At Least 1 Pulmonary Exacerbation Event

Secondary: Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24

Secondary: Absolute Change From Baseline in Euro Quality of Life Scale (EuroQol) 5-Dimension-3 Level (EQ-5D-3L) Index Score at Week 24

Secondary: Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24

Secondary: Absolute Change From Baseline in EQ-5D-3L VAS Score at Week 24

Secondary: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24

Secondary: Absolute Change From Baseline in Treatment Satisfaction Questionnaire for Medication (TSQM) Domain Scores at Week 24

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious Adverse Events (SAEs)

Secondary: 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)

Secondary: 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)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
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