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    Clinical Trial Results:
    A Phase 3, Rollover Study to Evaluate the Safety and Efficacy of Long-term Treatment With Lumacaftor in Combination With Ivacaftor in Subjects Aged 6 Years and Older With Cystic Fibrosis, Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    		 2015-001644-11
    Trial protocol
    		 SE   GB   BE   DK   DE   FR  
    Global end of trial date
    24 Apr 2020

    Results information
    Results version number
    		 v1
    This version publication date
    06 Nov 2020
    First version publication date
    06 Nov 2020
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    VX15-809-110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02544451
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, Massachusetts, United States,
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001582-PIP01-13
    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
    14 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long term safety and tolerability of lumacaftor (LUM) in combination with ivacaftor (IVA) in subjects aged 6 years and older with cystic fibrosis (CF), homozygous for the F508del CFTR mutation, who are in the Treatment Cohort.
    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
    13 Aug 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 143
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    Denmark: 7
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Australia: 28
    Worldwide total number of subjects
    246
    EEA total number of subjects
    54
    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)
    225
    Adolescents (12-17 years)
    21
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study consists of 2 Treatment Periods: Treatment Period 1 and Treatment Period 2. Treatment Period 1 had a Treatment Cohort and an Observational Cohort.

    Pre-assignment
    Screening details
    		 Subjects from Parent Studies 109 (NCT02514473) and 011B (NCT01897233) were enrolled in this study. A total of 240 subjects were enrolled in Treatment Cohort, out of which 1 subject was enrolled but never dosed. Subjects enrolled in the Observational Cohort were followed for safety endpoints only, no efficacy data were collected.

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LUM/IVA to LUM/IVA
    Arm description
    		 Subjects received LUM/IVA in parent studies (109, 011B) and continued to receive LUM/IVA for 96 weeks in the current study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM/IVA
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    lumacaftor/ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LUM/IVA twice daily for 96 weeks.

    Arm title
    		 PBO to LUM/IVA
    Arm description
    		 Subjects received placebo (PBO) in parent study (109) and then received LUM/IVA for 96 weeks in the current study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM/IVA
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    lumacaftor/ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LUM/IVA twice daily for 96 weeks.

    Arm title
    		 Observational Cohort
    Arm description
    		 Subjects completed a parent study (109, 011B) but were not eligible or elected to not receive LUM/IVA for 96 weeks in the current study.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1 [1]
    		LUM/IVA to LUM/IVA PBO to LUM/IVA Observational Cohort
    Started
    143
    96
    6
    Completed
    129
    84
    5
    Not completed
    14
    12
    1
         Physician decision
    4
    -
    -
         Adverse Event
    1
    6
    -
         Other
    4
    4
    -
         Withdrawal of consent
    -
    -
    1
         Lost to follow-up
    2
    -
    -
         Withdrawal of consent (not due to AE)
    3
    2
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 240 subjects were enrolled in Treatment Cohort of Treatment Period 1, out of which 1 subject was enrolled but never dosed.
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LUM/IVA
    Arm description
    		 Eligible subjects from Treatment Period 1 received LUM/IVA for up to approximately 168 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LUM/IVA
    Investigational medicinal product code
    VX-809/VX-770
    Other name
    lumacaftor/ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received LUM/IVA twice daily for 168 weeks.

    Number of subjects in period 2 [2]
    		LUM/IVA
    Started
    10
    Completed
    0
    Not completed
    10
         Commercial drug is available for subject
    10
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only eligible subjects from Treatment Period 1 received LUM/IVA during optional Treatment Period 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LUM/IVA to LUM/IVA
    Reporting group description
    		 Subjects received LUM/IVA in parent studies (109, 011B) and continued to receive LUM/IVA for 96 weeks in the current study.

    Reporting group title
    PBO to LUM/IVA
    Reporting group description
    		 Subjects received placebo (PBO) in parent study (109) and then received LUM/IVA for 96 weeks in the current study.

    Reporting group title
    Observational Cohort
    Reporting group description
    		 Subjects completed a parent study (109, 011B) but were not eligible or elected to not receive LUM/IVA for 96 weeks in the current study.

    Reporting group values
    		 LUM/IVA to LUM/IVA PBO to LUM/IVA Observational Cohort Total
    Number of subjects
    		 143 96 6 245
    Age categorical
    Units: Subjects
        Less than 9 Years
    		 58 38 5 101
        Greater than or equal to 9 years
    		 85 58 1 144
    Gender categorical
    Units: Subjects
        Female
    		 83 56 2 141
        Male
    		 60 40 4 104

    End points

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    End points reporting groups
    Reporting group title
    LUM/IVA to LUM/IVA
    Reporting group description
    		 Subjects received LUM/IVA in parent studies (109, 011B) and continued to receive LUM/IVA for 96 weeks in the current study.

    Reporting group title
    PBO to LUM/IVA
    Reporting group description
    		 Subjects received placebo (PBO) in parent study (109) and then received LUM/IVA for 96 weeks in the current study.

    Reporting group title
    Observational Cohort
    Reporting group description
    		 Subjects completed a parent study (109, 011B) but were not eligible or elected to not receive LUM/IVA for 96 weeks in the current study.
    Reporting group title
    LUM/IVA
    Reporting group description
    		 Eligible subjects from Treatment Period 1 received LUM/IVA for up to approximately 168 weeks.

    Primary: Treatment Period 1 (Treatment Cohort): Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Treatment Period 1 (Treatment Cohort): Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1] [2]
    End point description
    Safety set included all participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 100
    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: No statistical analyses were planned for this endpoint. Therefore, only descriptive data are provided.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was applicable for Treatment Period 1 Treatment cohort arms. Therefore, data are reported for these arms only.
    End point values
    		 LUM/IVA to LUM/IVA PBO to LUM/IVA
    Number of subjects analysed
    143
    96
    Units: subjects
        Subjects with any AEs
    142
    94
        Subjects with SAEs
    43
    29
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Period 1: Day 1 up to Week 100 Treatment Period 2: Day 1 up to Week 168
    Adverse event reporting additional description
    Only serious adverse events were collected for the observational cohort. Non-serious AEs were not collected and are not reported for the observational cohort.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0, 22.1
    Reporting groups
    Reporting group title
    Treatment Period 1: LUM/IVA to LUM/IVA
    Reporting group description
    		 Subjects received LUM/IVA in parent studies (109, 011B) and continued to receive LUM/IVA for 96 weeks in the current study.

    Reporting group title
    Treatment Period 1: PBO to LUM/IVA
    Reporting group description
    		 Subjects received placebo (PBO) in parent study (109) and then received LUM/IVA for 96 weeks in the current study.

    Reporting group title
    Observational Cohort
    Reporting group description
    		 Subjects completed a parent study (109, 011B) but were not eligible or elected to not receive LUM/IVA for 96 weeks in the current study.

    Reporting group title
    Treatment Period 2: LUM/IVA
    Reporting group description
    		 Eligible subjects from Treatment Period 1 received LUM/IVA for up to approximately 168 weeks.

    Serious adverse events
    		 Treatment Period 1: LUM/IVA to LUM/IVA Treatment Period 1: PBO to LUM/IVA Observational Cohort Treatment Period 2: LUM/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    43 / 143 (30.07%)
    29 / 96 (30.21%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Pulmonary function test decreased
         subjects affected / exposed
    2 / 143 (1.40%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical mycobacterium test positive
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas test positive
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis hepatic disease
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystic fibrosis lung
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 143 (2.80%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus disorder
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    34 / 143 (23.78%)
    15 / 96 (15.63%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    1 / 48
    1 / 25
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical mycobacterial lower respiratory tract infection
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment Period 1: LUM/IVA to LUM/IVA Treatment Period 1: PBO to LUM/IVA Observational Cohort Treatment Period 2: LUM/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    141 / 143 (98.60%)
    93 / 96 (96.88%)
    0 / 6 (0.00%)
    9 / 10 (90.00%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    45 / 143 (31.47%)
    27 / 96 (28.13%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    64
    41
    0
    1
    Fatigue
         subjects affected / exposed
    10 / 143 (6.99%)
    11 / 96 (11.46%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    14
    12
    0
    0
    Chest pain
         subjects affected / exposed
    2 / 143 (1.40%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    8 / 143 (5.59%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    13
    6
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    91 / 143 (63.64%)
    64 / 96 (66.67%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    195
    166
    0
    3
    Nasal congestion
         subjects affected / exposed
    34 / 143 (23.78%)
    21 / 96 (21.88%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    60
    29
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    32 / 143 (22.38%)
    18 / 96 (18.75%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    59
    29
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    24 / 143 (16.78%)
    13 / 96 (13.54%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    39
    18
    0
    0
    Productive cough
         subjects affected / exposed
    19 / 143 (13.29%)
    15 / 96 (15.63%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    51
    26
    0
    0
    Sputum increased
         subjects affected / exposed
    18 / 143 (12.59%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    21
    7
    0
    0
    Sinus congestion
         subjects affected / exposed
    12 / 143 (8.39%)
    4 / 96 (4.17%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    16
    5
    0
    0
    Nasal polyps
         subjects affected / exposed
    9 / 143 (6.29%)
    3 / 96 (3.13%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    9
    4
    0
    0
    Haemoptysis
         subjects affected / exposed
    8 / 143 (5.59%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    10
    1
    0
    0
    Wheezing
         subjects affected / exposed
    8 / 143 (5.59%)
    4 / 96 (4.17%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    9
    6
    0
    1
    Respiration abnormal
         subjects affected / exposed
    7 / 143 (4.90%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    8
    0
    0
    Asthma
         subjects affected / exposed
    5 / 143 (3.50%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    5
    0
    0
    Dyspnoea
         subjects affected / exposed
    4 / 143 (2.80%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    6
    0
    0
    Bronchiectasis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Epistaxis
         subjects affected / exposed
    5 / 143 (3.50%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    5
    2
    0
    2
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    1
    Paranasal sinus hypersecretion
         subjects affected / exposed
    4 / 143 (2.80%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    2
    0
    2
    Rales
         subjects affected / exposed
    2 / 143 (1.40%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    1
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    4 / 143 (2.80%)
    4 / 96 (4.17%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    4
    0
    1
    Investigations
    Bacterial test positive
         subjects affected / exposed
    30 / 143 (20.98%)
    16 / 96 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    45
    46
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 143 (15.38%)
    21 / 96 (21.88%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    27
    26
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 143 (11.89%)
    13 / 96 (13.54%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    22
    16
    0
    0
    Pseudomonas test positive
         subjects affected / exposed
    10 / 143 (6.99%)
    3 / 96 (3.13%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    10
    6
    0
    0
    Pulmonary function test decreased
         subjects affected / exposed
    8 / 143 (5.59%)
    11 / 96 (11.46%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    9
    11
    0
    0
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    6 / 143 (4.20%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    6
    7
    0
    0
    Forced expiratory volume decreased
         subjects affected / exposed
    6 / 143 (4.20%)
    13 / 96 (13.54%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    8
    16
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    4 / 143 (2.80%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    6
    0
    0
    Prothrombin time prolonged
         subjects affected / exposed
    3 / 143 (2.10%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    7
    0
    0
    Weight decreased
         subjects affected / exposed
    1 / 143 (0.70%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    5
    0
    1
    Pulmonary imaging procedure abnormal
         subjects affected / exposed
    0 / 143 (0.00%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    4 / 143 (2.80%)
    2 / 96 (2.08%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    4
    2
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 143 (20.28%)
    26 / 96 (27.08%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    43
    36
    0
    1
    Dizziness
         subjects affected / exposed
    6 / 143 (4.20%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    7
    6
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    12 / 143 (8.39%)
    4 / 96 (4.17%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    17
    5
    0
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    0 / 143 (0.00%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    30 / 143 (20.98%)
    15 / 96 (15.63%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    36
    18
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    22 / 143 (15.38%)
    20 / 96 (20.83%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    38
    30
    0
    0
    Abdominal pain
         subjects affected / exposed
    17 / 143 (11.89%)
    19 / 96 (19.79%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    23
    24
    0
    2
    Diarrhoea
         subjects affected / exposed
    16 / 143 (11.19%)
    8 / 96 (8.33%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    16
    10
    0
    2
    Nausea
         subjects affected / exposed
    13 / 143 (9.09%)
    11 / 96 (11.46%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    15
    15
    0
    1
    Constipation
         subjects affected / exposed
    11 / 143 (7.69%)
    11 / 96 (11.46%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    13
    14
    0
    1
    Flatulence
         subjects affected / exposed
    4 / 143 (2.80%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    4
    8
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Gastritis
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 143 (6.99%)
    10 / 96 (10.42%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    12
    11
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 143 (3.50%)
    5 / 96 (5.21%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    6
    5
    0
    1
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    59 / 143 (41.26%)
    34 / 96 (35.42%)
    0 / 6 (0.00%)
    4 / 10 (40.00%)
         occurrences all number
    115
    70
    0
    6
    Upper respiratory tract infection
         subjects affected / exposed
    36 / 143 (25.17%)
    13 / 96 (13.54%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    52
    21
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    21 / 143 (14.69%)
    16 / 96 (16.67%)
    0 / 6 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    34
    29
    0
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    21 / 143 (14.69%)
    14 / 96 (14.58%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    28
    20
    0
    0
    Sinusitis
         subjects affected / exposed
    17 / 143 (11.89%)
    8 / 96 (8.33%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    19
    9
    0
    0
    Otitis media
         subjects affected / exposed
    13 / 143 (9.09%)
    8 / 96 (8.33%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    13
    10
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    12 / 143 (8.39%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    23
    6
    0
    0
    Bacterial disease carrier
         subjects affected / exposed
    11 / 143 (7.69%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    15
    8
    0
    2
    Influenza
         subjects affected / exposed
    11 / 143 (7.69%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    16
    7
    0
    0
    Ear infection
         subjects affected / exposed
    9 / 143 (6.29%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    10
    10
    0
    1
    Rhinitis
         subjects affected / exposed
    9 / 143 (6.29%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    6 / 10 (60.00%)
         occurrences all number
    19
    10
    0
    11
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    8 / 143 (5.59%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    9
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    7 / 143 (4.90%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    10
    9
    0
    2
    Pharyngitis
         subjects affected / exposed
    5 / 143 (3.50%)
    7 / 96 (7.29%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    12
    0
    0
    Gastroenteritis
         subjects affected / exposed
    7 / 143 (4.90%)
    4 / 96 (4.17%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    8
    4
    0
    1
    Oral fungal infection
         subjects affected / exposed
    2 / 143 (1.40%)
    0 / 96 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    0
    1
    Respiratory tract infection bacterial
         subjects affected / exposed
    3 / 143 (2.10%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    5
    1
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 143 (2.10%)
    6 / 96 (6.25%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    6
    0
    0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 96 (1.04%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2015
    Amended to assess post-dose spirometry.
    30 Nov 2017
    Amended to add Treatment Period 2 to assess long-term safety of LUM/IVA in subjects who completed 96 weeks of LUM/IVA treatment in Treatment Period 1.
    16 May 2019
    Amended to extend Treatment Cohort Period 2 for up to an additional 96 weeks (up to a total of 264 weeks of treatment).

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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