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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX 770 in Subjects with Cystic Fibrosis and the G551D Mutation

Summary
EudraCT number	2008-007416-15
Trial protocol	IE GB DE CZ FR
Global end of trial date	29 Nov 2012

Results information
Results version number	v1(current)
This version publication date	28 Jun 2016
First version publication date	07 Aug 2015
Other versions

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

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Trial information

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Sponsor protocol code

VX08-770-102

ISRCTN number

US NCT number

NCT00909532

WHO universal trial number (UTN)

Sponsor organisation name

Vertex Pharmaceuticals Incorporated

Sponsor organisation address

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

Public contact

Medical Monitor, Vertex, +1 617-444-6777, medicalinfo@vrtx.com

Scientific contact

Medical Monitor, Vertex, +1 617-444-6777, medicalinfo@vrtx.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-000335-PIP01-08

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

15 Mar 2013

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Nov 2012

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial was to evaluate the efficacy of VX-770 after 24 weeks of treatment in subjects with cystic fibrosis (CF) with G551D cystic fibrosis transmembrane conductance regulator (CFTR) mutation.

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

10 Jun 2009

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

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

United Kingdom: 9

Country: Number of subjects enrolled

Czech Republic: 4

Country: Number of subjects enrolled

France: 3

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Ireland: 14

Country: Number of subjects enrolled

Australia: 19

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

United States: 91

Worldwide total number of subjects

161

EEA total number of subjects

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)

Adults (18-64 years)

125

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study started on 10 June 2009 (signing of first informed consent). After obtaining consent and assent (where applicable), screening evaluations were completed during a period of 2 to 5 weeks (Day -35 to Day -15) before the first dose of study drug.

Screening details

A total of 167 subjects were randomized; 161 subjects received at least 1 dose of the study drug. A 2-week run-in period was included to establish the baseline assessments on Day 1 after ensuring that subjects were properly taking their cystic fibrosis (CF) medication regimens.

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, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

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-ivacaftor tablet orally q12h up to 48 weeks.

150 mg Ivacaftor q12h

Arm description

Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Ivacaftor

Investigational medicinal product code

VX770

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ivacaftor 150 mg tablet administered orally q12h for up to 48 weeks.

Number of subjects in period 1	Placebo	150 mg Ivacaftor q12h
Started	78	83
Completed Treatment Period, Week 24	71	80
Completed	68	77
Not completed	10	6
Physician decision	1	-
Consent withdrawn by subject	1	1
'Wrong Genotype '	1	-
Pregnancy	-	1
Adverse event	4	1
'Increased Lab Draws, Difficult Lab Stick '	1	-
Noncompliance with Study Requirements	-	2
Prohibited Medication	2	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

Reporting group title

150 mg Ivacaftor q12h

Reporting group description

Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.

Reporting group values	Placebo	150 mg Ivacaftor q12h	Total
Number of subjects	78	83	161
Age categorical
Units: Subjects
<=18 years	17	19	36
Between 18 and 65 years	61	64	125
>=65 years	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	24.7 ± 9.21	26.2 ± 9.85	-
Gender categorical
Units: Subjects
Female	40	44	84
Male	38	39	77
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0
Not Hispanic or Latino	77	81	158
Unknown or Not Reported	1	2	3
Race/Ethnicity, Customized
Units: Subjects
White	77	81	158
Not Allowed to Ask Per Local Regulations	1	2	3
Region of Enrollment
Units: Subjects
North America	50	50	100
Europe	19	23	42
Australia	9	10	19
Percent Predicted FEV1, Categorical
Units: Subjects
< 70% predicted FEV1	45	49	94
≥ 70% predicted FEV1	33	34	67
Percent Predicted Forced Expiratory Volume in 1 Second (FEV1), Continuous [1]
Units: percentage
arithmetic mean (standard deviation)	63.7 ± 16.83	63.5 ± 16.14	-
Weight
Units: kilograms
arithmetic mean (standard deviation)	61.2 ± 13.93	61.7 ± 14.26	-
Body Mass Index
Units: kilograms per square meter
arithmetic mean (standard deviation)	21.9 ± 3.49	21.7 ± 3.65	-
Sweat Chloride
Units: millimoles per liter (mmol/liter)
arithmetic mean (standard deviation)	100.1 ± 10.63	100.4 ± 10	-

End points

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Reporting group title

Placebo

Reporting group description

Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

Reporting group title

150 mg Ivacaftor q12h

Reporting group description

Ivacaftor 150 mg tablet orally q12h for up to 48 weeks.

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

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End point title

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

End point description

Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

End point type

Primary

End point timeframe

Baseline through 24 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	78	83
Units: percent of predicted volume (L)
least squares mean (standard error)	-0.2 ± 0.7	10.4 ± 0.7

Percent Predicted FEV1 Through Week 24

Statistical analysis description

The primary analysis for the primary efficacy variable was based on a Mixed-Effects Model for Repeated Measures (MMRM). The model included absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1) as the dependent variable, treatment (ivacaftor versus placebo) and visit (Day 15, Week 8, Week 16, and Week 24) as fixed effects, and subject as a random effect, with adjustment for the continuous baseline values of age and percent predicted FEV1.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[1]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

10.6

Confidence interval

level

95%

sides

2-sided

lower limit

8.6

upper limit

12.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[1] - The primary and key secondary endpoints were analyzed using Hochberg’s step-up procedure: test 1, primary (α=0.05); test 2, CFQ-R resp domain (Wk24) and sweat chloride (Wk24)(α=0.05).

Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

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End point title

Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

End point description

End point type

Secondary

End point timeframe

Baseline through 48 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	78	83
Units: percent of predicted volume (L)
least squares mean (standard error)	-0.4 ± 0.7	10.1 ± 0.7

Percent Predicted FEV1 Through Week 48

Statistical analysis description

Analysis of this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were obtained from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for the continuous baseline values of age and percent predicted forced expiratory volume in 1 second (FEV1),using unstructured covariance matrix.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

8.5

upper limit

12.5

Variability estimate

Standard error of the mean

Dispersion value

Notes
[2] - There was no adjustment for multiple comparisons. Denominator degrees of freedom were estimated using the Kenward-Roger approximation. No imputation of missing data was done.

Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

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End point title

Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

End point description

The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID). Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

End point type

Secondary

End point timeframe

Baseline through 24 weeks and 48 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	71	80
Units: score on a scale
least squares mean (standard error)
Change from Baseline Through Week 24	-2.1 ± 1.3	6 ± 1.2
Change from Baseline Through Week 48	-2.7 ± 1.2	6 ± 1.1

CFQ-R Score Through Week 24

Statistical analysis description

Through Week 24: Analysis for the respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, domain score, and percent predicted FEV1, using unstructured covariance matrix.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

8.1

Confidence interval

level

95%

sides

2-sided

lower limit

4.7

upper limit

11.4

Variability estimate

Standard error of the mean

Dispersion value

1.7

Notes
[3] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05).

CFQ-R Score Through Week 48

Statistical analysis description

Through Week 48: Analysis for the CFQ-R respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from MMRM with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age,sweat chloride, and percent predicted FEV1,using unstructured covariance matrix

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

8.6

Confidence interval

level

95%

sides

2-sided

lower limit

5.3

upper limit

11.9

Variability estimate

Standard error of the mean

Dispersion value

1.7

Notes
[4] - There was no adjustment for multiple comparisons.

Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

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End point title

Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

End point description

The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

End point type

Secondary

End point timeframe

Baseline through 24 weeks and 48 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	74	78
Units: millimoles per liter
least squares mean (standard error)
Change from Baseline Through Week 24	-0.8 ± 1.3	-48.7 ± 1.2
Change from Baseline Through Week 48	-0.6 ± 1.3	-48.7 ± 1.2

Sweat Chloride Concentration Through Week 24

Statistical analysis description

Through Week 24: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-47.9

Confidence interval

level

95%

sides

2-sided

lower limit

-51.3

upper limit

-44.5

Variability estimate

Standard error of the mean

Dispersion value

1.7

Notes
[5] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).

Sweat Chloride Concentration Through Week 48

Statistical analysis description

Through Week 48: Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-48.1

Confidence interval

level

95%

sides

2-sided

lower limit

-51.5

upper limit

-44.7

Variability estimate

Standard error of the mean

Dispersion value

1.7

Notes
[6] - There was no adjustment for multiple comparisons.

Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

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End point title

Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

End point description

Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

End point type

Secondary

End point timeframe

Baseline through 24 weeks and 48 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	78	83
Units: proportion of event-free participants
number (confidence interval 95%)
0 to 15 Days	0.97 (0.9 to 0.99)	0.98 (0.91 to 0.99)
16 to 56 Days	0.87 (0.77 to 0.93)	0.89 (0.8 to 0.94)
57 to 112 Days	0.72 (0.61 to 0.81)	0.83 (0.73 to 0.9)
113 to 168 Days	0.53 (0.41 to 0.64)	0.78 (0.68 to 0.86)
169 to 224 Days	0.51 (0.39 to 0.61)	0.75 (0.64 to 0.83)
225 to 280 Days	0.44 (0.32 to 0.55)	0.7 (0.58 to 0.78)
281 to 336 Days	0.41 (0.29 to 0.52)	0.67 (0.55 to 0.76)

first Pulmonary Exacerbation Through Week 24

Statistical analysis description

Time to first pulmonary exacerbation through Week 24 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[7]

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

0.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.23

upper limit

0.71

Notes
[7] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).

first Pulmonary Exacerbation Through Week 48

Statistical analysis description

Time to first pulmonary exacerbation through Week 48 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012 ^[8]

Method

Regression, Cox

Parameter type

Cox proportional hazard

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

0.73

Notes
[8] - Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg’s step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg’s on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).

Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

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End point title

Absolute Change From Baseline in Weight at Week 24 and Week 48

End point description

As malnutrition is common in subjects with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status. Analysis population included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

End point type

Secondary

End point timeframe

Baseline to 24 weeks and 48 weeks

End point values	Placebo	150 mg Ivacaftor q12h
Number of subjects analysed	78	83
Units: kilograms
least squares mean (standard error)
At Week 24	0.2 ± 0.4	3 ± 0.4
At Week 48	0.4 ± 0.5	3.1 ± 0.5

Weight at Week 24

Statistical analysis description

At Week 24: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect, and intercept, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.8

upper limit

3.7

Variability estimate

Standard error of the mean

Dispersion value

0.5

Weight at Week 48

Statistical analysis description

At Week 48: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect and visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.

Comparison groups

Placebo v 150 mg Ivacaftor q12h

Number of subjects included in analysis

161

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

2.7

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

4.1

Variability estimate

Standard error of the mean

Dispersion value

0.7

Adverse events

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Timeframe for reporting adverse events

For enrolled subjects, adverse events were collected through the Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug).

Adverse event reporting additional description

For subjects who were screened but were not subsequently enrolled in the study, non-serious adverse event (AEs) were not collected, but serious adverse events (SAEs) were reported. For subjects who completed 48 weeks of study drug treatment and enrolled in the open-label extension study, adverse events were only collected through the Week 48 Visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Placebo

Reporting group description

Placebo-matched-to-ivacaftor tablet orally every 12 hours (q12h) up to 48 weeks.

Reporting group title

150 mg Ivacaftor q12h

Reporting group description

Ivacaftor 150 mg tablet orally every 12 hours (q12h) up to 48 weeks.

Serious adverse events	Placebo	150 mg Ivacaftor q12h
Total subjects affected by serious adverse events
subjects affected / exposed	33 / 78 (42.31%)	20 / 83 (24.10%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Catheter Related Complication
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Testicular torsion
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	4 / 78 (5.13%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Cystic fibrosis lung
subjects affected / exposed	26 / 78 (33.33%)	11 / 83 (13.25%)
occurrences causally related to treatment / all	4 / 37	3 / 22
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrioventricular block complete
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic pseudocyst
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting1
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IgA nephropathy
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Implant site infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection pseudomonal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myringitis bullous
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	150 mg Ivacaftor q12h
Total subjects affected by non serious adverse events
subjects affected / exposed	78 / 78 (100.00%)	82 / 83 (98.80%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Haematoma
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Hot flush
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hypotension
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Peripheral Coldness
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Poor peripheral circulation
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	9 / 78 (11.54%)	10 / 83 (12.05%)
occurrences all number	11	13
Fatigue
subjects affected / exposed	7 / 78 (8.97%)	7 / 83 (8.43%)
occurrences all number	9	8
Non-cardiac chest pain
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	4	3
Chest discomfort
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Chills
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Malaise
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Pain
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Application site burn
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Application site dermatitis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Application site scar
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Asthenia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Axillary pain
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Catheter Related Complication
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Catheter Thrombosis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Chest pain
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Exercise tolerance decreased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Influenza like illness
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Oedema peripheral
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Food allergy
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Seasonal allergy
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Balanitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Breast inflammation
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Breast Mass
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Epididymitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Gynaecomastia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Nipple disorder
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Nipple pain
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Oligomenorrhoea
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Ovarian cyst
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Prostatitis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	33 / 78 (42.31%)	27 / 83 (32.53%)
occurrences all number	59	38
Oropharyngeal pain
subjects affected / exposed	15 / 78 (19.23%)	17 / 83 (20.48%)
occurrences all number	23	25
Nasal congestion
subjects affected / exposed	12 / 78 (15.38%)	17 / 83 (20.48%)
occurrences all number	17	22
Haemoptysis
subjects affected / exposed	15 / 78 (19.23%)	9 / 83 (10.84%)
occurrences all number	21	17
Productive cough
subjects affected / exposed	11 / 78 (14.10%)	12 / 83 (14.46%)
occurrences all number	19	15
Rales
subjects affected / exposed	8 / 78 (10.26%)	9 / 83 (10.84%)
occurrences all number	14	17
Respiratory tract congestion
subjects affected / exposed	6 / 78 (7.69%)	6 / 83 (7.23%)
occurrences all number	9	7
Sinus congestion
subjects affected / exposed	4 / 78 (5.13%)	8 / 83 (9.64%)
occurrences all number	4	9
Rhinorrhoea
subjects affected / exposed	6 / 78 (7.69%)	4 / 83 (4.82%)
occurrences all number	6	4
Paranasal sinus hypersecretion
subjects affected / exposed	6 / 78 (7.69%)	3 / 83 (3.61%)
occurrences all number	7	3
Wheezing
subjects affected / exposed	3 / 78 (3.85%)	5 / 83 (6.02%)
occurrences all number	3	8
Dyspnoea
subjects affected / exposed	5 / 78 (6.41%)	2 / 83 (2.41%)
occurrences all number	5	2
Pleuritic pain
subjects affected / exposed	2 / 78 (2.56%)	5 / 83 (6.02%)
occurrences all number	2	7
Dysphonia
subjects affected / exposed	3 / 78 (3.85%)	3 / 83 (3.61%)
occurrences all number	3	3
Respiration abnormal
subjects affected / exposed	4 / 78 (5.13%)	2 / 83 (2.41%)
occurrences all number	5	2
Epistaxis
subjects affected / exposed	1 / 78 (1.28%)	3 / 83 (3.61%)
occurrences all number	1	4
Lung hyperinflation
subjects affected / exposed	2 / 78 (2.56%)	2 / 83 (2.41%)
occurrences all number	3	3
Nasal mucosal disorder
subjects affected / exposed	2 / 78 (2.56%)	2 / 83 (2.41%)
occurrences all number	2	2
Increased viscosity of bronchial secretion
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Nasal inflammation
subjects affected / exposed	0 / 78 (0.00%)	3 / 83 (3.61%)
occurrences all number	0	3
Nasal turbinate abnormality
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	2	2
Pharyngeal erythema
subjects affected / exposed	0 / 78 (0.00%)	3 / 83 (3.61%)
occurrences all number	0	3
Rhinitis allergic
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Rhonchi
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	4
Asthma
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Postnasal Drip
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Pulmonary congestion
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Sinus disorder
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Sputum discoloured
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	3	0
Sputum retention
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Throat irritation
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Upper respiratory tract congestion
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Bronchial secretion retention
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Dyspnoea exertional
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hypoventilation
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Nasal oedema
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Nasal polyps
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Painful respiration
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Prolonged expiration
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Sneezing
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Stridor
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Tonsillar hypertrophy
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 78 (1.28%)	3 / 83 (3.61%)
occurrences all number	1	3
Abnormal dreams
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Libido decreased
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Sleep disorder
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Affect lability
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Affective disorder
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Anxiety
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Depression
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Panic attack
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Tobacco withdrawal symptoms
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Investigations
Pulmonary function test decreased
subjects affected / exposed	11 / 78 (14.10%)	3 / 83 (3.61%)
occurrences all number	14	3
Alanine aminotransferase increased
subjects affected / exposed	5 / 78 (6.41%)	5 / 83 (6.02%)
occurrences all number	6	9
C-reactive protein increased
subjects affected / exposed	5 / 78 (6.41%)	4 / 83 (4.82%)
occurrences all number	6	4
Blood glucose increased
subjects affected / exposed	3 / 78 (3.85%)	5 / 83 (6.02%)
occurrences all number	3	6
Aspartate aminotransferase increased
subjects affected / exposed	2 / 78 (2.56%)	5 / 83 (6.02%)
occurrences all number	2	7
Bacteria Sputum Identified
subjects affected / exposed	1 / 78 (1.28%)	6 / 83 (7.23%)
occurrences all number	1	7
Hepatic enzyme increased
subjects affected / exposed	3 / 78 (3.85%)	4 / 83 (4.82%)
occurrences all number	4	4
Blood alkaline phosphatase increased
subjects affected / exposed	3 / 78 (3.85%)	3 / 83 (3.61%)
occurrences all number	4	6
Breath sounds abnormal
subjects affected / exposed	4 / 78 (5.13%)	2 / 83 (2.41%)
occurrences all number	5	2
Weight decreased
subjects affected / exposed	4 / 78 (5.13%)	2 / 83 (2.41%)
occurrences all number	4	2
Gamma-glutamyltransferase increased
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	4	5
Sputum abnormal
subjects affected / exposed	2 / 78 (2.56%)	3 / 83 (3.61%)
occurrences all number	2	3
Urine leukocyte esterase positive
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	3	2
Blood glucose decreased
subjects affected / exposed	3 / 78 (3.85%)	1 / 83 (1.20%)
occurrences all number	4	1
Blood urine present
subjects affected / exposed	2 / 78 (2.56%)	2 / 83 (2.41%)
occurrences all number	3	2
Prothrombin time prolonged
subjects affected / exposed	1 / 78 (1.28%)	3 / 83 (3.61%)
occurrences all number	1	3
Activated partial thromboplastin time prolonged
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	3
Blood bilirubin increased
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	3
Forced expiratory volume decreased
subjects affected / exposed	3 / 78 (3.85%)	0 / 83 (0.00%)
occurrences all number	4	0
International normalised ratio increased
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	1
Vitamin D decreased
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
White blood cell count increased
subjects affected / exposed	3 / 78 (3.85%)	0 / 83 (0.00%)
occurrences all number	4	0
Blood glucose fluctuation
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Blood immunoglobulin E increased
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Glucose urine present
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Neutrophil count increased
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	6	0
Bacterial Antibody Positive
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Blood immunoglobulin G increased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Blood urea increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Full blood count abnormal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Fungus Sputum Test Positive
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Gastrointestinal examination abnormal
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Haemoglobin decreased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Liver function test abnormal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Liver palpable subcostal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Lymphocyte count decreased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Monocyte count increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	2	0
Platelet count decreased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Protein urine present
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Specific gravity urine increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Spirometry abnormal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Transaminases increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Weight increased
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
White blood cell count decreased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
ELECTROCARDIOGRAM ST-T CHANGE
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Injury, poisoning and procedural complications
Joint Sprain
subjects affected / exposed	4 / 78 (5.13%)	0 / 83 (0.00%)
occurrences all number	5	0
Contusion
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Limb injury
subjects affected / exposed	0 / 78 (0.00%)	3 / 83 (3.61%)
occurrences all number	0	3
Procedural pain
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	3	2
Excoriation
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Hand fracture
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Arthropod bite
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	2	0
Burns second degree
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Concussion
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Foot fracture
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Joint dislocation
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Joint injury
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Medication error
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Muscle strain
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Rib fracture
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Skeletal injury
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Stress fracture
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Sunburn
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Congenital, familial and genetic disorders
Cystic fibrosis lung
subjects affected / exposed	39 / 78 (50.00%)	29 / 83 (34.94%)
occurrences all number	77	47
Cystic fibrosis related diabetes
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Cardiac disorders
Palpitations
subjects affected / exposed	0 / 78 (0.00%)	3 / 83 (3.61%)
occurrences all number	0	3
Tachycardia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Extrasystoles
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Left ventricular dysfunction
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Nervous system disorders
Headache
subjects affected / exposed	13 / 78 (16.67%)	19 / 83 (22.89%)
occurrences all number	31	39
Dizziness
subjects affected / exposed	1 / 78 (1.28%)	10 / 83 (12.05%)
occurrences all number	1	11
Sinus headache
subjects affected / exposed	4 / 78 (5.13%)	6 / 83 (7.23%)
occurrences all number	4	6
Migraine
subjects affected / exposed	2 / 78 (2.56%)	3 / 83 (3.61%)
occurrences all number	3	3
Lethargy
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Aphonia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Cognitive disorder
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Dizziness postural
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Hemicephalalgia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hyposmia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Memory impairment
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Paraesthesia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Presyncope
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Sciatica
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Syncope
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	2 / 78 (2.56%)	3 / 83 (3.61%)
occurrences all number	2	3
Anaemia
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Eosinophilia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Iron deficiency anaemia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Lymph node pain
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Lymphadenitis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 78 (0.00%)	4 / 83 (4.82%)
occurrences all number	0	4
Ear pain
subjects affected / exposed	1 / 78 (1.28%)	3 / 83 (3.61%)
occurrences all number	1	3
Deafness
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Tinnitus
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Ear congestion
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Ear pruritus
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Middle ear effusion
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Tympanic membrane hyperaemia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Vestibular disorder
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Eye disorders
Conjunctival hyperaemia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	2	2
Dry eye
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Lacrimation increased
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	10 / 78 (12.82%)	13 / 83 (15.66%)
occurrences all number	13	14
Nausea
subjects affected / exposed	9 / 78 (11.54%)	13 / 83 (15.66%)
occurrences all number	12	22
Diarrhoea
subjects affected / exposed	10 / 78 (12.82%)	11 / 83 (13.25%)
occurrences all number	12	12
Vomiting
subjects affected / exposed	10 / 78 (12.82%)	9 / 83 (10.84%)
occurrences all number	10	13
Abdominal pain upper
subjects affected / exposed	6 / 78 (7.69%)	4 / 83 (4.82%)
occurrences all number	7	5
Constipation
subjects affected / exposed	5 / 78 (6.41%)	1 / 83 (1.20%)
occurrences all number	5	1
Flatulence
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	5	2
Abdominal discomfort
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	1
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	1
Toothache
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Abdominal distension
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	6	1
Abdominal pain lower
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Faeces pale
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Gastritis
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Haemorrhoids
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Abdominal tenderness
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Distal intestinal obstruction syndrome
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
DRY MOUTH
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Dyspepsia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Frequent bowel movements
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Gastrointestinal motility disorder
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Inguinal hernia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Pancreatitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Post-tussive vomiting
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Steatorrhoea
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Tooth impacted
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hepatobiliary disorders
Cytolytic Hepatitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 78 (5.13%)	12 / 83 (14.46%)
occurrences all number	4	22
Acne
subjects affected / exposed	3 / 78 (3.85%)	6 / 83 (7.23%)
occurrences all number	3	6
Pruritus
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	3	2
Dry skin
subjects affected / exposed	3 / 78 (3.85%)	1 / 83 (1.20%)
occurrences all number	3	1
Erythema
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Night sweats
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Rash erythematous
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Rash macular
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	1
Alopecia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Eczema
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	4	0
Rash maculo-papular
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Dermatitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Dermatitis acneiform
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Dermatitis contact
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Drug eruption
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Ecchymosis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Hair texture abnormal
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Heat Rash
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hyperhidrosis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Hypoaesthesia Facial
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Photosensitivity Allergic Reaction
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	2	0
Rash generalised
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Rosacea
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Skin irritation
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Dysuria
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Haematuria
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Anuria
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Calculus ureteric
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Pollakiuria
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Polyuria
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	5 / 78 (6.41%)	7 / 83 (8.43%)
occurrences all number	5	11
Back pain
subjects affected / exposed	5 / 78 (6.41%)	5 / 83 (6.02%)
occurrences all number	7	5
Myalgia
subjects affected / exposed	3 / 78 (3.85%)	4 / 83 (4.82%)
occurrences all number	3	5
Pain in extremity
subjects affected / exposed	3 / 78 (3.85%)	4 / 83 (4.82%)
occurrences all number	5	4
Musculoskeletal chest pain
subjects affected / exposed	2 / 78 (2.56%)	4 / 83 (4.82%)
occurrences all number	2	5
Musculoskeletal pain
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Arthritis
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Fibromyalgia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Flank pain
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Neck pain
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Bone pain
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Epiphyseal disorder
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Finger deformity
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Jaw disorder
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Muscle atrophy
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Muscle spasms
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Muscle tightness
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Synovial cyst
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Torticollis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	12 / 78 (15.38%)	19 / 83 (22.89%)
occurrences all number	16	26
Nasopharyngitis
subjects affected / exposed	10 / 78 (12.82%)	10 / 83 (12.05%)
occurrences all number	14	13
Sinusitis
subjects affected / exposed	7 / 78 (8.97%)	6 / 83 (7.23%)
occurrences all number	12	8
Rhinitis
subjects affected / exposed	4 / 78 (5.13%)	6 / 83 (7.23%)
occurrences all number	4	6
Viral infection
subjects affected / exposed	5 / 78 (6.41%)	2 / 83 (2.41%)
occurrences all number	5	2
Influenza
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	3	2
Pharyngitis
subjects affected / exposed	3 / 78 (3.85%)	2 / 83 (2.41%)
occurrences all number	3	2
Urinary tract infection
subjects affected / exposed	1 / 78 (1.28%)	4 / 83 (4.82%)
occurrences all number	1	5
Oral candidiasis
subjects affected / exposed	1 / 78 (1.28%)	3 / 83 (3.61%)
occurrences all number	1	4
Ear infection
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Pharyngitis streptococcal
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	2
Tooth infection
subjects affected / exposed	3 / 78 (3.85%)	0 / 83 (0.00%)
occurrences all number	3	0
Vulvovaginal mycotic infection
subjects affected / exposed	1 / 78 (1.28%)	2 / 83 (2.41%)
occurrences all number	1	2
Acute sinusitis
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Bacterial disease carrier
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Gastroenteritis
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	2
Laryngitis
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Lung infection
subjects affected / exposed	0 / 78 (0.00%)	2 / 83 (2.41%)
occurrences all number	0	6
Respiratory tract infection viral
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Tooth abscess
subjects affected / exposed	2 / 78 (2.56%)	0 / 83 (0.00%)
occurrences all number	2	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	2
Abscess
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Bacterial infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Bronchiectasis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Bronchopulmonary aspergillosis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Bronchopulmonary aspergillosis allergic
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Cellulitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Conjunctivitis viral
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Cystitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Dacryocystitis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Diverticulitis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Gastroenteritis viral
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Implant site infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Infection
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Labyrinthitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Lice infestation
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Lower respiratory tract infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Onychomycosis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Oral herpes
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Pancreas infection
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Paronychia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Pneumonia bacterial
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Pulpitis dental
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Rhinovirus infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Skin infection
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Sputum purulent
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Staphylococcal infection
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Vaginal infection
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Viral pharyngitis
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Vulvovaginal candidiasis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Metabolism and nutrition disorders
Hypoglycaemia
subjects affected / exposed	4 / 78 (5.13%)	3 / 83 (3.61%)
occurrences all number	4	3
Decreased appetite
subjects affected / exposed	2 / 78 (2.56%)	2 / 83 (2.41%)
occurrences all number	2	2
Dehydration
subjects affected / exposed	2 / 78 (2.56%)	1 / 83 (1.20%)
occurrences all number	2	2
Hyperglycaemia
subjects affected / exposed	1 / 78 (1.28%)	1 / 83 (1.20%)
occurrences all number	1	1
Anorexia
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Gout
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Hypovitaminosis
subjects affected / exposed	1 / 78 (1.28%)	0 / 83 (0.00%)
occurrences all number	1	0
Polydipsia
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1
Vitamin D deficiency
subjects affected / exposed	0 / 78 (0.00%)	1 / 83 (1.20%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

17 Apr 2009

Addition of a 24-week Extension Period for a total treatment duration of 48 weeks. Change to the secondary objective to evaluate the safety of VX-770 after both 24 weeks (original objective) and 48 weeks (newly added) of treatment. Addition of a secondary objective “To evaluate the efficacy of VX-770 after 48 weeks of treatment in subjects with CF who have the G551D-CFTR mutation on at least 1 allele”. Addition of a secondary endpoint of “Absolute change from baseline in percent predicted FEV1 through Week 48”. Addition of analysis of secondary and tertiary endpoints at Week 48. Addition of the option for subjects who complete 48 weeks of treatment to enroll in Study VX08-770-105.

10 Sep 2009

Addition of the tertiary endpoint of “Pulmonary exacerbations through Weeks 24 and 48”. Changed few of the inclusion/exclusion criteria. Updated the version of the CTCAE used in the study for the grading of adverse events from Version 3.0 to Version 4.0.

12 Apr 2010

Changes in study procedures regarding liver function testing and considerations for study drug interruption and discontinuation to ensure the continued safety of subjects in this study. Updated the name of the safety department at Vertex from “Pharmacovigilance” to “Global Patient Safety” (throughout the protocol). Updated contact information.

09 Jul 2010

Based on feedback from the US Food and Drug Administration (FDA), an additional criterion for removal of subjects in the study was added to protocol: total bilirubin >2 ULN and/or clinical jaundice, in association with elevation of ALT or AST >3 ULN. Additional clarification of the intended analysis were 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

http://www.ncbi.nlm.nih.gov/pubmed/22047557

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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 VX 770 in Subjects with Cystic Fibrosis and the G551D Mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Greece
Hungary
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Italy
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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 VX 770 in Subjects with Cystic Fibrosis and the G551D Mutation

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Secondary: Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48

Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Secondary: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)

Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Secondary: Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48

Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Secondary: Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48

Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

Secondary: Absolute Change From Baseline in Weight at Week 24 and Week 48

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX 770 in Subjects with Cystic Fibrosis and the G551D Mutation