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

Due to a system error, the data reported in v1 is not correct and has been removed from public view.

Summary
EudraCT number	2012-003990-24
Trial protocol	BE DE AT GB ES DK
Global end of trial date	25 Apr 2014

Results information
Results version number	v2(current)
This version publication date	13 Jul 2016
First version publication date	07 Aug 2015
Other versions	v1 (removed from public view)
Version creation reason	Correction of full data set Address EudraCT System related issues & verify data

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

VX12-809-104

ISRCTN number

US NCT number

NCT01807949

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

22 May 2014

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 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 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

11 Apr 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

Australia: 42

Country: Number of subjects enrolled

Austria: 9

Country: Number of subjects enrolled

Belgium: 36

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

Denmark: 10

Country: Number of subjects enrolled

France: 32

Country: Number of subjects enrolled

Germany: 48

Country: Number of subjects enrolled

Spain: 19

Country: Number of subjects enrolled

United Kingdom: 14

Country: Number of subjects enrolled

United States: 335

Worldwide total number of subjects

559

EEA total number of subjects

168

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)

132

Adults (18-64 years)

427

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 187, 187, and 189 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 187, 185, and 187 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 400 mg q12h/IVA 250 mg q12h

Arm description

LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (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.

LUM 600 mg qd/IVA 250 mg q12h

Arm description

LUM 600 mg plus IVA 250 mg supplied as 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.

Number of subjects in period 1	Placebo	LUM 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Started	187	187	185
Completed	185	180	180
Not completed	2	7	5
Consent withdrawn by subject	1	2	2
Non-Compliance	-	1	-
Undefined	-	2	1
Adverse Events	1	2	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 400 mg q12h/IVA 250 mg q12h

Reporting group description

LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and in the evening, 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 FDC tablets in the morning and IVA 250 mg film-coated tablet in the evening, up to Week 24.

Reporting group values	Placebo	LUM 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h	Total
Number of subjects	187	187	185	559
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	25.7 ± 10.02	25 ± 9.03	24.3 ± 8.31	-
Gender categorical
Units: Subjects
Female	97	98	96	291
Male	90	89	89	268

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 400 mg q12h/IVA 250 mg q12h

Reporting group description

LUM 400 milligram (mg) plus IVA 250 mg supplied as fixed-dose combination (FDC) tablets in the morning and in the evening, 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 FDC tablets in the morning and IVA 250 mg film-coated tablet 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 subject 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	183	180	181
Units: percent predicted of FEV1
least squares mean (standard error)	-0.15 ± 0.539	2.85 ± 0.54	2.46 ± 0.54

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 (<18 versus >=18 years old), and percent predicted FEV1 severity at Screening (<70 versus >=70).

Comparison groups

Placebo v LUM 600 mg qd/IVA 250 mg q12h

Number of subjects included in analysis

364

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Mixed-Effects Model for Repeated Measure

Parameter type

Least Squares (LS) Mean Difference

Point estimate

2.62

Confidence interval

level

95%

sides

2-sided

lower limit

1.18

upper limit

4.06

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.56

upper limit

4.44

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

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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	183	180	181
Units: percent change
least squares mean (standard error)	0 ± 0.96	5.25 ± 0.961	4.42 ± 0.961

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

364

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

4.42

Confidence interval

level

95%

sides

2-sided

lower limit

1.86

upper limit

6.98

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

5.25

Confidence interval

level

95%

sides

2-sided

lower limit

2.69

upper limit

7.81

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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	183	180	180
Units: kilogram per square meter (kg/m^2)
least squares mean (standard error)	0.07 ± 0.066	0.43 ± 0.066	0.48 ± 0.066

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.41

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.59

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.54

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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	185	179	180
Units: units on a scale
least squares mean (standard error)	2.81 ± 1.153	5.66 ± 1.169	5.02 ± 1.166

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

365

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1651

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

2.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.91

upper limit

5.33

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

364

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0736

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

2.85

Confidence interval

level

95%

sides

2-sided

lower limit

-0.27

upper limit

5.98

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. 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. Analysis was performed on FAS

End point type

Secondary

End point timeframe

Week 16 and 24

End point values	Placebo	LUM 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	187	187	185
Units: percentage of subjects
number (not applicable)	22.5	41.2	45.9

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

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.9568

Confidence interval

level

95%

sides

2-sided

lower limit

1.8829

upper limit

4.6431

Notes
[1] - 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

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

2.3834

Confidence interval

level

95%

sides

2-sided

lower limit

1.5234

upper limit

3.7286

Notes
[2] - 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	187	187	185
Units: pulmonary exacerbation events per year
number (not applicable)	1.18	0.67	0.82

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

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0116 ^[3]

Method

Negative Binomial Regression

Parameter type

Event Rate Ratio

Point estimate

0.6912

Confidence interval

level

95%

sides

2-sided

lower limit

0.5187

upper limit

0.9209

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

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority ^[4]

P-value

= 0.0002

Method

Negative Binomial Regression

Parameter type

Event Rate Ratio

Point estimate

0.5659

Confidence interval

level

95%

sides

2-sided

lower limit

0.4191

upper limit

0.7641

Notes
[4] - 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	183	180	180
Units: kilograms (kg)
least squares mean (standard error)	0.44 ± 0.187	1.38 ± 0.187	1.57 ± 0.188

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

1.13

Confidence interval

level

95%

sides

2-sided

lower limit

0.62

upper limit

1.64

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

363

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.43

upper limit

1.46

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 subject 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	53	58	54
Units: z-score
least squares mean (standard error)	-0.0674 ± 0.04706	0.1544 ± 0.04513	0.164 ± 0.04652

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

Placebo v LUM 600 mg qd/IVA 250 mg q12h

Number of subjects included in analysis

107

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.2313

Confidence interval

level

95%

sides

2-sided

lower limit

0.1037

upper limit

0.3589

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

111

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.2217

Confidence interval

level

95%

sides

2-sided

lower limit

0.0961

upper limit

0.3473

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. 99999 indicates median time was not reached as less than 50% of subjects had the event of interest. 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	187	187	185
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

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0384

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

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

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

End point type

Secondary

End point timeframe

Through Week 24

End point values	Placebo	LUM 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	187	187	185
Units: percentage of subjects
number (not applicable)	47.1	28.9	36.8

Statistical Analysis 1

Statistical analysis description

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

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0393

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.6373

Confidence interval

level

95%

sides

2-sided

lower limit

0.416

upper limit

0.9764

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

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

0.4429

Confidence interval

level

95%

sides

2-sided

lower limit

0.2863

upper limit

0.6851

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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	183	176	178
Units: units on a scale
least squares mean (standard error)	0.0117 ± 0.00673	0.0108 ± 0.00683	0.009 ± 0.00682

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 index score.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

361

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7679

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-0.0028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0211

upper limit

0.0156

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

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9214

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-0.0009

Confidence interval

level

95%

sides

2-sided

lower limit

-0.0192

upper limit

0.0174

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 subject's 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	182	177	177
Units: units on a scale
least squares mean (standard error)	3.3 ± 1.07	6.6 ± 1.08	5.7 ± 1.08

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

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1034

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

5.3

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

359

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0262

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.4

upper limit

6.2

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 subject's 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	187	187	185
Units: units on a scale
least squares mean (standard error)
Effectiveness (n = 159, 161, 161)	-8.49 ± 1.814	3.12 ± 1.793	0.15 ± 1.807
Side Effects (n = 157, 161, 159)	2.03 ± 1.144	-2.26 ± 1.121	-1.14 ± 1.137
Convenience (n = 158, 161, 160)	4.57 ± 1.525	4.88 ± 1.501	4.57 ± 1.523
Global Satisfaction (n= 158, 161, 160)	-9.62 ± 1.841	-2.46 ± 1.814	-4.98 ± 1.845

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 320.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

8.64

Confidence interval

level

95%

sides

2-sided

lower limit

3.77

upper limit

13.51

Statistical Analysis 2

Statistical analysis description

Effectiveness: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 320.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

11.61

Confidence interval

level

95%

sides

2-sided

lower limit

6.75

upper limit

16.48

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

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0403

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-3.18

Confidence interval

level

95%

sides

2-sided

lower limit

-6.21

upper limit

-0.14

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 318.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0054

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

-4.29

Confidence interval

level

95%

sides

2-sided

lower limit

-7.31

upper limit

-1.28

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 318.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 1

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.07

upper limit

4.07

Statistical Analysis 6

Statistical analysis description

Convenience: analysis was performed as described in Statistical Analysis 1. Actual number of subjects included in analysis were 319.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8777

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-3.74

upper limit

4.37

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 318.

Comparison groups

LUM 600 mg qd/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

372

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0668

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

4.64

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

9.61

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 319.

Comparison groups

LUM 400 mg q12h/IVA 250 mg q12h v Placebo

Number of subjects included in analysis

374

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0045

Method

MMRM

Parameter type

LS Mean Difference

Point estimate

7.16

Confidence interval

level

95%

sides

2-sided

lower limit

2.23

upper limit

12.08

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. Analysis done on Safety Set(SS) included all randomized subjects who received any amount of study drug. Subjects were analyzed as per actual treatment received. Any AE that increased in severity or newly developed at or after the initial dosing of study drug to 28 days after the last dose is TEAE.

End point type

Secondary

End point timeframe

Up to Week 28

End point values	Placebo	LUM 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	186	187	185 ^[5]
Units: subjects
number (not applicable)
Subjects With Treatment-Emergent AEs	181	177	181
Subjects With Treatment-Emergent SAEs	57	31	51

Notes
[5] - Actual Number of Subjects Analyzed as per Actual Treatment Received = 186

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 endpoint was not planned to be assessed in Placebo arm. Analysis was performed on 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 400 mg q12h/IVA 250 mg q12h	LUM 600 mg qd/IVA 250 mg q12h
Number of subjects analysed	182	182
Units: microgram per milliliter (mcg/mL)
arithmetic mean (standard deviation)
LUM, Day 1: C3-6h (n = 180, 181)	20.2 ± 8.33	30.8 ± 12.6
LUM, Day 15: C3-6h (n = 176, 174)	23.9 ± 8.87	30.4 ± 11.2
LUM, Week 4: Ctrough (n = 179, 174)	13.2 ± 6.28	8.11 ± 5.21
LUM, Week 4: C3-6h (n = 168, 164)	24.5 ± 8.75	29.2 ± 12.1
LUM, Week 8: Ctrough (n = 177, 177)	12.4 ± 6.87	7.87 ± 5.71
LUM, Week 8: C3-6h (n = 170, 174)	24.9 ± 9.79	30.4 ± 11.6
LUM, Week 16: Ctrough (n = 173, 171)	12.2 ± 6.87	7.53 ± 6.05
M-28 LUM, Day 1: C3-6h (n = 180, 181)	0.181 ± 0.079	0.226 ± 0.103
M-28 LUM, Day 15: C3-6h (n = 176, 174)	1.39 ± 0.606	1.43 ± 0.588
M-28 LUM, Week 4: Ctrough (n = 179, 174)	1.42 ± 0.661	1.32 ± 0.68
M-28 LUM, Week 4: C3-6h (n = 168, 164)	1.45 ± 0.675	1.39 ± 0.657
M-28 LUM, Week 8: Ctrough (n = 177, 177)	1.44 ± 0.722	1.34 ± 0.714
M-28 LUM, Week 8: C3-6h (n = 170, 174)	1.48 ± 0.711	1.41 ± 0.702
M-28 LUM, Week 16: Ctrough (n = 173, 171)	1.43 ± 0.775	1.27 ± 0.763
IVA, Day 1: C3-6h (n = 180, 181)	1.36 ± 0.647	1.34 ± 0.643
IVA, Day 15: C3-6h (n = 176, 174)	0.469 ± 0.282	0.647 ± 0.492
IVA, Week 4: Ctrough (n = 179, 174)	0.108 ± 0.112	0.164 ± 0.207
IVA, Week 4: C3-6h (n = 168, 164)	0.473 ± 0.239	0.636 ± 0.38
IVA, Week 8: Ctrough (n = 177, 177)	0.102 ± 0.13	0.182 ± 0.293
IVA, Week 8: C3-6h (n = 170, 174)	0.513 ± 0.277	0.71 ± 0.567
IVA, Week 16: Ctrough (n = 173, 171)	0.113 ± 0.218	0.163 ± 0.237
M-1 IVA, Day 1: C3-6h (n = 180, 181)	2.65 ± 1.29	2.51 ± 1.3
M-1 IVA, Day 15: C3-6h (n = 176, 174)	1.85 ± 0.86	2.21 ± 1.08
M-1 IVA, Week 4: Ctrough (n = 179, 174)	0.501 ± 0.455	0.676 ± 0.612
M-1 IVA, Week 4: C3-6h (n = 168, 164)	1.88 ± 0.953	2.11 ± 1.12
M-1 IVA, Week 8: Ctrough (n = 177, 177)	0.463 ± 0.495	0.672 ± 0.704
M-1 IVA, Week 8: C3-6h (n = 170, 174)	1.91 ± 0.91	2.15 ± 1.19
M-1 IVA, Week 16: Ctrough (n = 173, 171)	0.465 ± 0.449	0.643 ± 0.594
M-6 IVA, Day 1: C3-6h (n = 180, 181)	0.996 ± 0.797	0.993 ± 0.82
M-6 IVA, Day 15: C3-6h (n = 176, 174)	2.99 ± 1.68	3.62 ± 2.18
M-6 IVA, Week 4: Ctrough (n = 179, 174)	1.64 ± 1.2	1.73 ± 1.34
M-6 IVA, Week 4: C3-6h (n = 168, 164)	2.64 ± 1.45	3.07 ± 1.84
M-6 IVA, Week 8: Ctrough (n = 177, 177)	1.47 ± 1.17	1.6 ± 1.22
M-6 IVA, Week 8: C3-6h (n = 170, 174)	2.56 ± 1.48	3 ± 2.01
M-6 IVA, Week 16: Ctrough (n = 173, 171)	1.42 ± 1.05	1.51 ± 1.29
LUM: Ctrough,ave (n = 182, 179)	12.7 ± 5.6	7.81 ± 4.26
LUM: C3-6h,ave (n = 181, 182)	24.3 ± 7.72	29.9 ± 9.19
M-28 LUM: Ctrough,ave (n = 182, 179)	1.42 ± 0.676	1.31 ± 0.672
M-28 LUM: C3-6h,ave (n = 181, 182)	1.43 ± 0.64	1.41 ± 0.62
IVA: Ctrough,ave (n = 182, 179)	0.11 ± 0.124	0.17 ± 0.196
IVA: C3-6h,ave (n = 181, 182)	0.484 ± 0.21	0.668 ± 0.392
M1-IVA: Ctrough,ave (n = 182, 179)	0.484 ± 0.391	0.66 ± 0.504
M1-IVA: C3-6h,ave (n = 181, 182)	1.87 ± 0.71	2.14 ± 0.951
M6-IVA: Ctrough,ave (n = 182, 179)	1.5 ± 0.897	1.6 ± 1.08
M6-IVA: C3-6h,ave (n = 181, 182)	2.7 ± 1.23	3.18 ± 1.65

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 non-serious AEs.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.0

Reporting group title

Placebo

Reporting group description

Placebo matched to LUM and IVA tablet 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 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	57 / 186 (30.65%)	51 / 186 (27.42%)	31 / 187 (16.58%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events
Vascular disorders
Axillary vein thrombosis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Hypertension
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Deep vein thrombosis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Medical device complication
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (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
Pyrexia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Bronchospasm
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Haemoptysis
subjects affected / exposed	1 / 186 (0.54%)	4 / 186 (2.15%)	0 / 187 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary cavitation
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Psychiatric disorders
Suicide attempt
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Suicidal ideation
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Investigations
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial test positive
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram T wave inversion
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Injury, poisoning and procedural complications
Suture related complication
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Post procedural haematoma
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Nervous system disorders
Convulsion
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Distal intestinal obstruction syndrome
subjects affected / exposed	3 / 186 (1.61%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Colitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Ileus
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Hepatitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Renal and urinary disorders
Renal failure acute
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Proteinuria
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Nephrolithiasis
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	48 / 186 (25.81%)	36 / 186 (19.35%)	24 / 187 (12.83%)
occurrences causally related to treatment / all	6 / 60	0 / 39	1 / 27
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Bronchopulmonary aspergillosis allergic
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (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
Bronchopneumonia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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 viral
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Conjunctivitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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 infection pseudomonal
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Influenza
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Respiratory tract infection fungal
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (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
Viraemia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
Viral infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (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
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
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	181 / 186 (97.31%)	179 / 186 (96.24%)	175 / 187 (93.58%)
Vascular disorders
Flushing
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Hot flush
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	0	0	2
Orthostatic hypotension
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hypertension
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Peripheral coldness
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Phlebitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Subclavian vein thrombosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Venous thrombosis limb
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	22 / 186 (11.83%)	22 / 186 (11.83%)	16 / 187 (8.56%)
occurrences all number	27	25	20
Fatigue
subjects affected / exposed	10 / 186 (5.38%)	13 / 186 (6.99%)	17 / 187 (9.09%)
occurrences all number	11	14	20
Chest discomfort
subjects affected / exposed	4 / 186 (2.15%)	4 / 186 (2.15%)	4 / 187 (2.14%)
occurrences all number	4	4	4
Pain
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	5 / 187 (2.67%)
occurrences all number	2	1	5
Malaise
subjects affected / exposed	1 / 186 (0.54%)	4 / 186 (2.15%)	2 / 187 (1.07%)
occurrences all number	1	6	2
Chills
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	3 / 187 (1.60%)
occurrences all number	2	1	3
Chest pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	3 / 187 (1.60%)
occurrences all number	1	0	3
Medical device pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	1	0	2
Influenza like illness
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	2	0	1
Thirst
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	0	2	2
Application site pruritus
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Sensation of foreign body
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Application site rash
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Asthenia
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Device occlusion
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Energy increased
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Infusion site pain
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Feeling jittery
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Local swelling
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Oedema peripheral
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Vessel puncture site bruise
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Application site irritation
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Adverse drug reaction
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Application site reaction
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Discomfort
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Device leakage
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Device malfunction
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Infusion site bruising
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Injection site erythema
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Feeling hot
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Injection site warmth
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Medical device complication
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Injection site pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Thrombosis in device
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Vessel puncture site pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Immune system disorders
Seasonal allergy
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Drug hypersensitivity
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Food allergy
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	3 / 187 (1.60%)
occurrences all number	0	2	3
Metrorrhagia
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	4	2	1
Polymenorrhoea
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Menstruation irregular
subjects affected / exposed	0 / 186 (0.00%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	0	3	4
Menorrhagia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Amenorrhoea
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Endometriosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Haemorrhagic ovarian cyst
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Breast tenderness
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Uterine spasm
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Oligomenorrhoea
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Vaginal haemorrhage
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Vulvovaginal pruritus
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Vulvovaginal pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	82 / 186 (44.09%)	69 / 186 (37.10%)	56 / 187 (29.95%)
occurrences all number	116	89	85
Sputum increased
subjects affected / exposed	47 / 186 (25.27%)	40 / 186 (21.51%)	29 / 187 (15.51%)
occurrences all number	51	45	36
Dyspnoea
subjects affected / exposed	15 / 186 (8.06%)	32 / 186 (17.20%)	31 / 187 (16.58%)
occurrences all number	19	35	35
Nasal congestion
subjects affected / exposed	19 / 186 (10.22%)	24 / 186 (12.90%)	13 / 187 (6.95%)
occurrences all number	21	27	18
Haemoptysis
subjects affected / exposed	26 / 186 (13.98%)	28 / 186 (15.05%)	20 / 187 (10.70%)
occurrences all number	32	48	22
Oropharyngeal pain
subjects affected / exposed	20 / 186 (10.75%)	20 / 186 (10.75%)	13 / 187 (6.95%)
occurrences all number	23	20	13
Rhinorrhoea
subjects affected / exposed	10 / 186 (5.38%)	11 / 186 (5.91%)	11 / 187 (5.88%)
occurrences all number	11	12	13
Respiration abnormal
subjects affected / exposed	13 / 186 (6.99%)	14 / 186 (7.53%)	18 / 187 (9.63%)
occurrences all number	16	18	21
Productive cough
subjects affected / exposed	14 / 186 (7.53%)	11 / 186 (5.91%)	5 / 187 (2.67%)
occurrences all number	15	13	9
Sinus congestion
subjects affected / exposed	11 / 186 (5.91%)	8 / 186 (4.30%)	8 / 187 (4.28%)
occurrences all number	11	10	9
Wheezing
subjects affected / exposed	9 / 186 (4.84%)	7 / 186 (3.76%)	6 / 187 (3.21%)
occurrences all number	10	9	6
Respiratory tract congestion
subjects affected / exposed	6 / 186 (3.23%)	8 / 186 (4.30%)	9 / 187 (4.81%)
occurrences all number	6	10	9
Sputum discoloured
subjects affected / exposed	6 / 186 (3.23%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	6	4	3
Dysphonia
subjects affected / exposed	4 / 186 (2.15%)	3 / 186 (1.61%)	7 / 187 (3.74%)
occurrences all number	4	3	8
Paranasal sinus hypersecretion
subjects affected / exposed	5 / 186 (2.69%)	8 / 186 (4.30%)	6 / 187 (3.21%)
occurrences all number	5	8	7
Rales
subjects affected / exposed	6 / 186 (3.23%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	7	2	2
Asthma
subjects affected / exposed	2 / 186 (1.08%)	4 / 186 (2.15%)	2 / 187 (1.07%)
occurrences all number	2	6	2
Epistaxis
subjects affected / exposed	2 / 186 (1.08%)	5 / 186 (2.69%)	1 / 187 (0.53%)
occurrences all number	2	5	1
Upper-airway cough syndrome
subjects affected / exposed	2 / 186 (1.08%)	2 / 186 (1.08%)	3 / 187 (1.60%)
occurrences all number	2	2	3
Bronchial obstruction
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	2	1	2
Increased viscosity of bronchial secretion
subjects affected / exposed	3 / 186 (1.61%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	4	0	0
Painful respiration
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	3 / 187 (1.60%)
occurrences all number	1	0	4
Throat irritation
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Nasal discharge discolouration
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	2	2
Sneezing
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Pleuritic pain
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Rhinitis allergic
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	2	1	0
Bronchospasm
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Dyspnoea exertional
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Nasal polyps
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Bronchial hyperreactivity
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Sputum decreased
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Hiccups
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Bronchial secretion retention
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Hyperventilation
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Increased bronchial secretion
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Lung disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Nasal discomfort
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Lung hyperinflation
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Pharyngeal exudate
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Pharyngeal erythema
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Pneumonitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pleurisy
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Pharyngeal oedema
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Respiratory disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Respiratory gas exchange disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Sinus disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Pulmonary pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Respiratory tract irritation
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Rhonchi
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Upper respiratory tract congestion
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Upper respiratory tract inflammation
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	7 / 186 (3.76%)	5 / 186 (2.69%)	2 / 187 (1.07%)
occurrences all number	7	5	2
Depression
subjects affected / exposed	3 / 186 (1.61%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	3	1	1
Anxiety
subjects affected / exposed	2 / 186 (1.08%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	2	2	2
Libido decreased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Mental disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Mood altered
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Nervousness
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Sleep disorder
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Nightmare
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	5 / 186 (2.69%)	3 / 186 (1.61%)	5 / 187 (2.67%)
occurrences all number	5	3	5
Blood creatine phosphokinase increased
subjects affected / exposed	10 / 186 (5.38%)	4 / 186 (2.15%)	12 / 187 (6.42%)
occurrences all number	11	4	17
Pulmonary function test decreased
subjects affected / exposed	14 / 186 (7.53%)	5 / 186 (2.69%)	3 / 187 (1.60%)
occurrences all number	16	5	3
Bacterial test positive
subjects affected / exposed	1 / 186 (0.54%)	4 / 186 (2.15%)	7 / 187 (3.74%)
occurrences all number	1	4	7
Alanine aminotransferase increased
subjects affected / exposed	4 / 186 (2.15%)	2 / 186 (1.08%)	4 / 187 (2.14%)
occurrences all number	4	2	4
Forced expiratory volume decreased
subjects affected / exposed	4 / 186 (2.15%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	4	0	2
Weight decreased
subjects affected / exposed	2 / 186 (1.08%)	3 / 186 (1.61%)	2 / 187 (1.07%)
occurrences all number	2	3	3
Hepatic enzyme increased
subjects affected / exposed	0 / 186 (0.00%)	4 / 186 (2.15%)	2 / 187 (1.07%)
occurrences all number	0	4	3
Sputum abnormal
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	2	0	2
Blood glucose increased
subjects affected / exposed	1 / 186 (0.54%)	3 / 186 (1.61%)	1 / 187 (0.53%)
occurrences all number	1	3	1
Blood creatinine increased
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	2	0	1
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Body temperature increased
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	0	3	1
Blood glucose decreased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	3
Eosinophil count increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Atypical mycobacterium test positive
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Fungal test positive
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Blood bicarbonate decreased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Haemoglobin decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Blood immunoglobulin E increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Blood iron decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Blood calcium increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Blood pressure increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Blood sodium decreased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Breath sounds abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Blood urine present
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Blood sodium increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
C-reactive protein increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Coagulation test abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Electrocardiogram T wave abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Crystal urine present
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Electrocardiogram PR shortened
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Haemophilus test positive
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Glycosylated haemoglobin increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Lymphocyte count decreased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	2
Liver function test abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Mean cell volume increased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Mean cell haemoglobin decreased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Oxygen saturation decreased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Neutrophil count increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	2
Red blood cell count decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Serum ferritin decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Vitamin D decreased
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Transaminases increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Weight increased
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
White blood cell count decreased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
White blood cell count increased
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Injury, poisoning and procedural complications
Ligament sprain
subjects affected / exposed	2 / 186 (1.08%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	2	3	3
Muscle strain
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	3 / 187 (1.60%)
occurrences all number	2	1	3
Procedural pain
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	1	1	2
Laceration
subjects affected / exposed	1 / 186 (0.54%)	3 / 186 (1.61%)	1 / 187 (0.53%)
occurrences all number	1	3	1
Joint injury
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Arthropod bite
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Sunburn
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Concussion
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Alcohol poisoning
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Vaccination complication
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	2	0	1
Arthropod sting
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Limb injury
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Animal bite
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Ankle fracture
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Iliotibial band syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Contusion
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Foreign body
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Ligament injury
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Joint dislocation
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Rib fracture
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Splinter
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Stoma site irritation
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Road traffic accident
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Traumatic haematoma
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Thermal burn
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Congenital, familial and genetic disorders
Cystic fibrosis related diabetes
subjects affected / exposed	5 / 186 (2.69%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	5	0	2
Talipes
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Tachycardia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Atrioventricular block first degree
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Sinus arrhythmia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Cyanosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Sinus bradycardia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Ventricular extrasystoles
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Nervous system disorders
Sinus headache
subjects affected / exposed	7 / 186 (3.76%)	15 / 186 (8.06%)	7 / 187 (3.74%)
occurrences all number	8	16	11
Headache
subjects affected / exposed	33 / 186 (17.74%)	30 / 186 (16.13%)	29 / 187 (15.51%)
occurrences all number	37	39	36
Dizziness
subjects affected / exposed	5 / 186 (2.69%)	7 / 186 (3.76%)	3 / 187 (1.60%)
occurrences all number	5	7	3
Lethargy
subjects affected / exposed	3 / 186 (1.61%)	3 / 186 (1.61%)	2 / 187 (1.07%)
occurrences all number	3	3	2
Dysgeusia
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Migraine
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	2	1	1
Amnesia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Hypoaesthesia
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Tremor
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Paraesthesia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Intercostal neuralgia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Parosmia
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Convulsion
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Cervicogenic headache
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Ageusia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Coordination abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Disturbance in attention
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hyperaesthesia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Epilepsy
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hypertonia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hyposmia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Nerve compression
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Muscle contractions involuntary
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Loss of consciousness
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Presyncope
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Syncope
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Blood and lymphatic system disorders
Increased tendency to bruise
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	3	0	0
Leukopenia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Eosinophilia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Lymphadenopathy
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Neutropenia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	3 / 187 (1.60%)
occurrences all number	1	1	3
Ear pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	3 / 187 (1.60%)
occurrences all number	0	1	3
Tympanic membrane disorder
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Ear discomfort
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	1	1	1
Vertigo
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Vertigo positional
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Middle ear effusion
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Eye disorders
Blepharospasm
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	0	0	2
Vision blurred
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Blindness transient
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Conjunctival hyperaemia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Eye pruritus
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Eye irritation
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Eye pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Eye swelling
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Periorbital oedema
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Visual acuity reduced
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Photopsia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	19 / 186 (10.22%)	15 / 186 (8.06%)	10 / 187 (5.35%)
occurrences all number	21	24	12
Diarrhoea
subjects affected / exposed	18 / 186 (9.68%)	20 / 186 (10.75%)	21 / 187 (11.23%)
occurrences all number	19	28	24
Nausea
subjects affected / exposed	17 / 186 (9.14%)	20 / 186 (10.75%)	32 / 187 (17.11%)
occurrences all number	18	22	39
Flatulence
subjects affected / exposed	10 / 186 (5.38%)	11 / 186 (5.91%)	13 / 187 (6.95%)
occurrences all number	10	13	13
Abdominal pain upper
subjects affected / exposed	8 / 186 (4.30%)	15 / 186 (8.06%)	7 / 187 (3.74%)
occurrences all number	8	16	7
Vomiting
subjects affected / exposed	9 / 186 (4.84%)	12 / 186 (6.45%)	9 / 187 (4.81%)
occurrences all number	9	14	9
Abdominal distension
subjects affected / exposed	2 / 186 (1.08%)	6 / 186 (3.23%)	5 / 187 (2.67%)
occurrences all number	2	6	6
Constipation
subjects affected / exposed	8 / 186 (4.30%)	5 / 186 (2.69%)	6 / 187 (3.21%)
occurrences all number	8	5	6
Dyspepsia
subjects affected / exposed	1 / 186 (0.54%)	3 / 186 (1.61%)	5 / 187 (2.67%)
occurrences all number	1	3	5
Frequent bowel movements
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	7 / 187 (3.74%)
occurrences all number	2	1	7
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	6 / 187 (3.21%)
occurrences all number	1	1	6
Abdominal discomfort
subjects affected / exposed	0 / 186 (0.00%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	0	4	3
Steatorrhoea
subjects affected / exposed	2 / 186 (1.08%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	2	2	2
Eructation
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	1	1	3
Mouth ulceration
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Abdominal pain lower
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Post-tussive vomiting
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Abdominal tenderness
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Distal intestinal obstruction syndrome
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Abnormal faeces
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Aerophagia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Epigastric discomfort
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Faecaloma
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Dry mouth
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Faeces discoloured
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Faeces soft
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Food poisoning
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Gastritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Gastrointestinal disorder
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Gastrointestinal motility disorder
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Gastrointestinal pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Gastrointestinal sounds abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Gastrointestinal tract irritation
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Haematochezia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Haemorrhoids
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Lip pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Lip ulceration
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Retching
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Odynophagia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Oral pain
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Oesophageal pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Tongue discolouration
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Tongue disorder
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Tooth development disorder
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Umbilical hernia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Tooth impacted
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Hepatic pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Cholecystitis acute
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	5 / 186 (2.69%)	8 / 186 (4.30%)	18 / 187 (9.63%)
occurrences all number	5	8	19
Acne
subjects affected / exposed	4 / 186 (2.15%)	8 / 186 (4.30%)	1 / 187 (0.53%)
occurrences all number	4	8	1
Hyperhidrosis
subjects affected / exposed	2 / 186 (1.08%)	5 / 186 (2.69%)	3 / 187 (1.60%)
occurrences all number	2	5	3
Pruritus
subjects affected / exposed	3 / 186 (1.61%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	3	2	2
Alopecia
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	3 / 187 (1.60%)
occurrences all number	1	1	3
Night sweats
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	1	1	2
Urticaria
subjects affected / exposed	2 / 186 (1.08%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	2	2	0
Eczema
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	2	2	0
Erythema
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Onychoclasis
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Dry skin
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Red man syndrome
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Skin odour abnormal
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Rash pruritic
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Cutaneous lupus erythematosus
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Blister
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Dermatitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hyperkeratosis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hair texture abnormal
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Drug eruption
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Lividity
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Ingrowing nail
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Papule
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Pruritus allergic
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Rash erythematous
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pruritus generalised
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Rash papular
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Rash macular
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Skin lesion
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Swelling face
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	1	2	1
Calculus ureteric
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Pollakiuria
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Proteinuria
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Haematuria
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Renal colic
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Urine odour abnormal
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Endocrine disorders
Cushingoid
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Early menarche
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	6 / 186 (3.23%)	5 / 186 (2.69%)	9 / 187 (4.81%)
occurrences all number	7	6	10
Myalgia
subjects affected / exposed	8 / 186 (4.30%)	6 / 186 (3.23%)	3 / 187 (1.60%)
occurrences all number	8	6	4
Arthralgia
subjects affected / exposed	7 / 186 (3.76%)	2 / 186 (1.08%)	6 / 187 (3.21%)
occurrences all number	8	3	6
Flank pain
subjects affected / exposed	2 / 186 (1.08%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	2	4	3
Musculoskeletal chest pain
subjects affected / exposed	1 / 186 (0.54%)	8 / 186 (4.30%)	1 / 187 (0.53%)
occurrences all number	1	8	1
Musculoskeletal pain
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	3 / 187 (1.60%)
occurrences all number	1	2	3
Pain in extremity
subjects affected / exposed	2 / 186 (1.08%)	3 / 186 (1.61%)	2 / 187 (1.07%)
occurrences all number	2	3	2
Neck pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Muscle spasms
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	2	1	0
Muscle twitching
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	0	1	2
Muscle tightness
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Tendonitis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Joint swelling
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Arthropathy
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	2
Arthritis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Bone cyst
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Foot deformity
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hypermobility syndrome
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Chondritis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Intervertebral disc protrusion
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Muscle contracture
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Muscular weakness
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Musculoskeletal discomfort
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pubic pain
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Temporomandibular joint syndrome
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Tendon pain
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Rhabdomyolysis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis
subjects affected / exposed	74 / 186 (39.78%)	58 / 186 (31.18%)	50 / 187 (26.74%)
occurrences all number	101	77	65
Viral upper respiratory tract infection
subjects affected / exposed	13 / 186 (6.99%)	13 / 186 (6.99%)	10 / 187 (5.35%)
occurrences all number	15	15	11
Nasopharyngitis
subjects affected / exposed	20 / 186 (10.75%)	14 / 186 (7.53%)	22 / 187 (11.76%)
occurrences all number	23	15	26
Sinusitis
subjects affected / exposed	7 / 186 (3.76%)	17 / 186 (9.14%)	11 / 187 (5.88%)
occurrences all number	8	19	12
Upper respiratory tract infection
subjects affected / exposed	10 / 186 (5.38%)	8 / 186 (4.30%)	20 / 187 (10.70%)
occurrences all number	12	9	26
Rhinitis
subjects affected / exposed	6 / 186 (3.23%)	14 / 186 (7.53%)	8 / 187 (4.28%)
occurrences all number	8	21	11
Pharyngitis
subjects affected / exposed	4 / 186 (2.15%)	3 / 186 (1.61%)	3 / 187 (1.60%)
occurrences all number	4	3	3
Influenza
subjects affected / exposed	3 / 186 (1.61%)	6 / 186 (3.23%)	11 / 187 (5.88%)
occurrences all number	3	6	11
Gastroenteritis
subjects affected / exposed	5 / 186 (2.69%)	4 / 186 (2.15%)	4 / 187 (2.14%)
occurrences all number	5	4	4
Respiratory tract infection viral
subjects affected / exposed	1 / 186 (0.54%)	3 / 186 (1.61%)	2 / 187 (1.07%)
occurrences all number	1	4	2
Viral infection
subjects affected / exposed	4 / 186 (2.15%)	4 / 186 (2.15%)	0 / 187 (0.00%)
occurrences all number	5	4	0
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 186 (0.00%)	5 / 186 (2.69%)	3 / 187 (1.60%)
occurrences all number	0	6	3
Bronchitis
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	1	2	3
Ear infection
subjects affected / exposed	3 / 186 (1.61%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	3	1	1
Oral candidiasis
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	2 / 187 (1.07%)
occurrences all number	1	2	2
Respiratory tract infection bacterial
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	3 / 187 (1.60%)
occurrences all number	0	2	3
Gastroenteritis viral
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	2 / 187 (1.07%)
occurrences all number	1	1	2
Respiratory tract infection
subjects affected / exposed	2 / 186 (1.08%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	2	2	1
Urinary tract infection
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	1	2	1
Upper respiratory tract infection bacterial
subjects affected / exposed	0 / 186 (0.00%)	3 / 186 (1.61%)	1 / 187 (0.53%)
occurrences all number	0	6	1
Vulvovaginal candidiasis
subjects affected / exposed	2 / 186 (1.08%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	2	1	3
Bronchopulmonary aspergillosis allergic
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Acute sinusitis
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	3	0	2
Lower respiratory tract infection bacterial
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Laryngitis
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	1 / 187 (0.53%)
occurrences all number	0	2	1
Bronchopulmonary aspergillosis
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Gingivitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Clostridium difficile infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	2 / 187 (1.07%)
occurrences all number	0	0	4
Conjunctivitis
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Oral fungal infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Oral herpes
subjects affected / exposed	1 / 186 (0.54%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	1	1	0
Infectious mononucleosis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Rash pustular
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	1	0	1
Otitis externa
subjects affected / exposed	2 / 186 (1.08%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	2	0	0
Acarodermatitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Asymptomatic bacteriuria
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Chronic sinusitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Bacterial disease carrier
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Bronchitis viral
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Cellulitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Clostridium difficile colitis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Device related infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Cystitis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Eye infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Eyelid infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Epididymitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Gynaecological chlamydia infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Fungal infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Genital herpes
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Herpes simplex
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hordeolum
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Herpes zoster
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Infected bites
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Infusion site infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Localised infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Lower respiratory tract infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Lower respiratory tract infection viral
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Lung infection
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Otitis media
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Lung infection pseudomonal
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Nipple infection
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pharyngitis bacterial
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pneumonia
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Pseudomonas bronchitis
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Tonsillitis
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Tooth abscess
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Tinea versicolour
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Vaginitis bacterial
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Tooth infection
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	5 / 186 (2.69%)	4 / 186 (2.15%)	2 / 187 (1.07%)
occurrences all number	5	4	2
Decreased appetite
subjects affected / exposed	5 / 186 (2.69%)	7 / 186 (3.76%)	12 / 187 (6.42%)
occurrences all number	5	8	13
Hyperglycaemia
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	3 / 187 (1.60%)
occurrences all number	1	2	3
Dehydration
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	1 / 187 (0.53%)
occurrences all number	0	1	1
Gout
subjects affected / exposed	1 / 186 (0.54%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	1	2	0
Vitamin D deficiency
subjects affected / exposed	0 / 186 (0.00%)	2 / 186 (1.08%)	0 / 187 (0.00%)
occurrences all number	0	2	0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Glucose tolerance impaired
subjects affected / exposed	0 / 186 (0.00%)	0 / 186 (0.00%)	1 / 187 (0.53%)
occurrences all number	0	0	1
Hypomagnesaemia
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Hypokalaemia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Hyponatraemia
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0
Vitamin A deficiency
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Vitamin E deficiency
subjects affected / exposed	0 / 186 (0.00%)	1 / 186 (0.54%)	0 / 187 (0.00%)
occurrences all number	0	1	0
Increased appetite
subjects affected / exposed	1 / 186 (0.54%)	0 / 186 (0.00%)	0 / 187 (0.00%)
occurrences all number	1	0	0

More information

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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 Followup 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

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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