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    Clinical Trial Results:
    A Phase 3b, Open-Label Study to Evaluate Lumacaftor and Ivacaftor Combination Therapy in Subjects 12 Years and Older With Cystic Fibrosis and Advanced Lung Disease, Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    2017-001309-34
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    03 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Aug 2017
    First version publication date
    10 Aug 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX14-809-106
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02390219
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States, 022101862
    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
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of lumacaftor/ivacaftor (LUM/IVA) combination therapy in subjects 12 years and older with cystic fibrosis (CF) and advanced lung disease and 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 Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    45
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 46 subjects were enrolled and treated in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    LUM/IVA
    Arm description
    Subjects received LUM 400 milligram (mg) in combination with IVA 250 mg as fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.
    Arm type
    Experimental

    Investigational medicinal product name
    Lumacaftor Plus Ivacaftor Combination
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    LUM 400 mg in combination with IVA 250 mg as FDC tablet q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet q12h was also permitted.

    Number of subjects in period 1
    LUM/IVA
    Started
    46
    Completed
    33
    Not completed
    13
         Death
    1
         Physician decision
    1
         Adverse event
    6
         Unspecified
    2
         Consent withdrawn by subject
    1
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LUM/IVA
    Reporting group description
    Subjects received LUM 400 milligram (mg) in combination with IVA 250 mg as fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.

    Reporting group values
    LUM/IVA Total
    Number of subjects
    46 46
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32.1 ± 9 -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    30 30

    End points

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    End points reporting groups
    Reporting group title
    LUM/IVA
    Reporting group description
    Subjects received LUM 400 milligram (mg) in combination with IVA 250 mg as fixed-dose combination (FDC) tablet orally every 12 hours (q12h) for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.

    Primary: Number of Subjects With Treatment Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Treatment Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) [1]
    End point description
    AE: any untoward medical occurrence in a subject during the study; event does not necessarily have a causal relationship with treatment. This includes any newly occurring event/previous condition that has increased in severity/frequency after informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event, which falls into any of the following categories, regardless of its relationship to study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. TEAEs: AEs that started/ worsened on/after the start of study drug through the Safety Follow up Visit (4 weeks after the last dose of study drug). Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. Safety Set: all subjects who were exposed to any amount of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    LUM/IVA
    Number of subjects analysed
    46
    Units: subjects
        Subjects with AEs
    43
        Subjects with SAEs
    18
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24

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    End point title
    Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
    End point description
    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, 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. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. Full Analysis Set (FAS) included all subjects who were enrolled and administered any amount of study drug. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Up to Week 24
    End point values
    LUM/IVA
    Number of subjects analysed
    32
    Units: Percent predicted of FEV1
        least squares mean (standard error)
    -0.4 ± 0.7
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24

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    End point title
    Absolute Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Up to Week 24
    End point description
    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 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. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. FAS included all subjects who were enrolled and administered any amount of study drug. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Up to Week 24
    End point values
    LUM/IVA
    Number of subjects analysed
    32
    Units: Litre (L)
        least squares mean (standard error)
    -0.02 ± 0.03
    No statistical analyses for this end point

    Secondary: Duration For Which Subjects Received Intravenous (IV) Antibiotics

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    End point title
    Duration For Which Subjects Received Intravenous (IV) Antibiotics
    End point description
    The duration for which subjects received IV antibiotics for sinopulmonary signs and symptoms were reported. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. FAS included all subjects who were enrolled and administered any amount of study drug. Here “Number of subjects analyzed” signifies those subjects who received at least one IV antibiotic for sinopulmonary signs and symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 24
    End point values
    LUM/IVA
    Number of subjects analysed
    22
    Units: Days
        arithmetic mean (standard deviation)
    11.38 ± 18.15
    No statistical analyses for this end point

    Secondary: Number of Hospitalizations

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    End point title
    Number of Hospitalizations
    End point description
    Number of hospitalizations (all causes) through Week 24 was summarized. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. FAS included all subjects who were enrolled and administered any amount of study drug. Here “Number of subjects analyzed” analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 24
    End point values
    LUM/IVA
    Number of subjects analysed
    16
    Units: hospitalizations
        number (not applicable)
    23
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4

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    End point title
    Absolute Change From Baseline in Sweat Chloride at Average of Day 15 and Week 4
    End point description
    Sweat samples were collected using an approved collection device. Baseline was defined as the average of the measurements at screening and on Day 1 pre-dose. The average absolute change from baseline in sweat chloride was derived as: (Average of Day 15 and Week 4 value) minus Baseline value. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. FAS included all subjects who were enrolled and administered any amount of study drug. Here “Number of subjects analyzed” analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15 and Week 4
    End point values
    LUM/IVA
    Number of subjects analysed
    41
    Units: Millimoles per litre (mmol/L)
        least squares mean (standard error)
    -16.4 ± 1.3
    No statistical analyses for this end point

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

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    End point title
    Absolute Change From Baseline in Cystic Fibrosis Questionnaire – Revised (CFQ-R) Respiratory Domain Score Through 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. Results were reported as planned, as a combined single LUM/IVA arm irrespective of permitted dose modification. FAS included all subjects who were enrolled and administered any amount of study drug. Here, "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Through Week 24
    End point values
    LUM/IVA
    Number of subjects analysed
    44
    Units: Units on a scale
        least squares mean (standard error)
    2.5 ± 1.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 28
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    LUM/IVA
    Reporting group description
    Subjects received LUM 400 mg in combination with IVA 250 mg as FDC tablet orally q12h for 24 weeks. A reduced initial dose of LUM 200 mg in combination with IVA 125 mg FDC tablet orally q12h was permitted.

    Serious adverse events
    LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 46 (39.13%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiration abnormal
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neuralgia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    16 / 46 (34.78%)
         occurrences causally related to treatment / all
    2 / 27
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 46 (93.48%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Drug hypersensitivity
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 46 (15.22%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    5
    Pain
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    4
    Asthenia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Affect lability
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Irritability
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Menorrhagia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Pulmonary function test decreased
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Blood glucose increased
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Blood glucose decreased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Blood immunoglobulin E increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Forced expiratory volume decreased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Fungal test positive
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Oxygen consumption increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Sputum abnormal
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Weight decreased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    2
    Tachycardia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Respiration abnormal
         subjects affected / exposed
    25 / 46 (54.35%)
         occurrences all number
    39
    Cough
         subjects affected / exposed
    21 / 46 (45.65%)
         occurrences all number
    32
    Dyspnoea
         subjects affected / exposed
    20 / 46 (43.48%)
         occurrences all number
    28
    Sputum increased
         subjects affected / exposed
    13 / 46 (28.26%)
         occurrences all number
    18
    Oropharyngeal pain
         subjects affected / exposed
    9 / 46 (19.57%)
         occurrences all number
    9
    Haemoptysis
         subjects affected / exposed
    7 / 46 (15.22%)
         occurrences all number
    10
    Nasal congestion
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    6
    Wheezing
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    7
    Respiratory tract congestion
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    4
    Upper respiratory tract congestion
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Productive cough
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    3
    Rhinorrhoea
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Asthma
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Painful respiration
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Paranasal sinus discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Sinus congestion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    2
    Sputum retention
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 46 (15.22%)
         occurrences all number
    9
    Lethargy
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    3
    Transient ischaemic attack
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Eye disorders
    Lacrimation increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    7
    Nausea
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    Abdominal pain
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Flatulence
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Abdominal discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Dysphagia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Gastrointestinal tract mucosal discolouration
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Renal and urinary disorders
    Nephrocalcinosis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Rash
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Acne
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Alopecia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Eczema
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Night sweats
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Rash macular
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Muscle spasms
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Arthralgia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    Dehydration
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    20 / 46 (43.48%)
         occurrences all number
    26
    Nasopharyngitis
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Gastroenteritis viral
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    2
    Vulvovaginal mycotic infection
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences all number
    3
    Chronic sinusitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Labyrinthitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Sinusitis bacterial
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Jan 2015
    1. Modified eligibility criteria; 2. The Patient Health Questionnaire (PHQ) was changed from PHQ-9 to PHQ-8.
    29 Apr 2015
    1. Included additional safety precautions; 2. Text was added to reflect the option for dose modification
    14 Jul 2015
    1. Clarified that enrollment was no longer limited to subjects with ppFEV1 values greater than or equal to (>= )30 to less than (<) 40 at Screening and >=30 on Day 1.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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