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    Clinical Trial Results:
    Phase 3b, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Safety, Efficacy, and Tolerability of Tezacaftor/Ivacaftor (TEZ/IVA) in an Orkambi-experienced Population Who Are Homozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    		 2017-000540-18
    Trial protocol
    		 FR   DE  
    Global end of trial date
    09 Aug 2018

    Results information
    Results version number
    		 v1
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    VX16-661-114
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03150719
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vertex Pharmaceuticals Incorporated
    Sponsor organisation address
    50 Northern Avenue, Boston, United States,
    Public contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 8776348789, medicalinfo@vrtx.com
    Scientific contact
    Medical Monitor, Vertex Pharmaceuticals Incorporated, +1 8776348789, 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
    27 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the respiratory safety of Tezacaftor/Ivacaftor (TEZ/IVA) in subjects with Cystic Fibrosis homozygous for F508del mutation of the CFTR gene that previously discontinued Lumacaftor/Ivacaftor (LUM/IVA) due to treatment-related respiratory signs or symptoms
    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
    24 May 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    98
    EEA total number of subjects
    49
    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)
    97
    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 98 subjects were randomized: 47 in placebo group and 51 in TEZ/IVA group. One subject in TEZ/IVA group did not receive any study drug.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo (matched to TEZ/IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to TEZ/IVA FDC once daily in the morning for 56 days.

    Investigational medicinal product name
    Placebo (matched to IVA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to IVA once daily in the evening for 56 days.

    Arm title
    		 TEZ/IVA
    Arm description
    		 Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 100 milligram (mg) TEZ/ 150 mg IVA FDC once daily in the morning for 56 days.

    Investigational medicinal product name
    IVA
    Investigational medicinal product code
    VX-770
    Other name
    Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 150 mg IVA once daily in the evening for 56 days.

    Number of subjects in period 1 [1]
    		Placebo TEZ/IVA
    Started
    47
    50
    Completed
    46
    48
    Not completed
    1
    2
         Adverse Event
    -
    1
         Other
    1
    -
         Death
    -
    1
    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 98 subjects were randomized: 47 in placebo group and 51 in TEZ/IVA group. One subject in TEZ/IVA group did not receive any study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days.

    Reporting group values
    		 Placebo TEZ/IVA Total
    Number of subjects
    		 47 50 97
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.3 ± 10.0 34.3 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    		 30 31 61
        Male
    		 17 19 36

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days.

    Primary: Incidence of Respiratory Adverse Events of Special Interest (RAESIs)

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    End point title
    		 Incidence of Respiratory Adverse Events of Special Interest (RAESIs) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 56
    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: Only descriptive statistics were planned. No statistical comparisons were planned for primary safety endpoint.
    End point values
    		 Placebo TEZ/IVA
    Number of subjects analysed
    47
    50
    Units: Subjects
    10
    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 Day 84
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to TEZ/IVA fixed dose combination (FDC) once daily in the morning followed by placebo matched to IVA once daily in the evening for 56 days.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects received TEZ/IVA FDC once daily in the morning followed by IVA once daily in the evening for 56 days.

    Serious adverse events
    		 Placebo TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 47 (19.15%)
    5 / 50 (10.00%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleuritic pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (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
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    7 / 47 (14.89%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 47 (59.57%)
    30 / 50 (60.00%)
    Investigations
    Bacterial test positive
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 47 (14.89%)
    6 / 50 (12.00%)
         occurrences all number
    11
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 50 (4.00%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 47 (10.64%)
    4 / 50 (8.00%)
         occurrences all number
    9
    4
    Constipation
         subjects affected / exposed
    0 / 47 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    Nausea
         subjects affected / exposed
    2 / 47 (4.26%)
    4 / 50 (8.00%)
         occurrences all number
    2
    5
    Diarrhoea
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 47 (17.02%)
    9 / 50 (18.00%)
         occurrences all number
    8
    9
    Dyspnoea
         subjects affected / exposed
    5 / 47 (10.64%)
    5 / 50 (10.00%)
         occurrences all number
    5
    5
    Haemoptysis
         subjects affected / exposed
    2 / 47 (4.26%)
    3 / 50 (6.00%)
         occurrences all number
    2
    3
    Respiration abnormal
         subjects affected / exposed
    1 / 47 (2.13%)
    3 / 50 (6.00%)
         occurrences all number
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    Sputum increased
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 50 (4.00%)
         occurrences all number
    5
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 47 (0.00%)
    6 / 50 (12.00%)
         occurrences all number
    0
    6
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    9 / 47 (19.15%)
    4 / 50 (8.00%)
         occurrences all number
    10
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Apr 2017
    Revised sample size, and the time from Orkambi initiation to discontinuation; Additional safety measures added; Subjects who completed Day 56 Visit were given the opportunity to enroll in a long-term, open-label safety study of TEZ/IVA
    09 Jun 2017
    Added post-dose spirometry on Day 1 for additional safety; Clarified the visits for pulse oximetry and vital sign assessments; Removed restrictions on the concomitant use of corticosteroids

    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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