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    Clinical Trial Results:
    A Phase 3, Double-blind, Parallel-group Study to Evaluate the Efficacy and Safety of Tezacaftor in Combination With Ivacaftor in Subjects Aged 6 Through 11 Years With Cystic Fibrosis, Homozygous or Heterozygous for the F508del-CFTR Mutation

    Summary
    EudraCT number
    		 2016-004479-35
    Trial protocol
    		 IE   DK   BE   DE   GB   PL   FR  
    Global end of trial date
    21 Dec 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Apr 2020
    First version publication date
    09 Jul 2019
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Update for Consistency with CT.gov results

    Trial information

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    Trial identification
    Sponsor protocol code
    VX16-661-115
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03559062
    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-001640-PIP01-14
    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
    01 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of tezacaftor (TEZ) in combination with ivacaftor (IVA) in subjects with cystic fibrosis (CF) aged 6 through 11 years, homozygous or heterozygous for F508del.
    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
    17 May 2018
    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
    Australia: 14
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Poland: 1
    Worldwide total number of subjects
    69
    EEA total number of subjects
    47
    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)
    69
    Adolescents (12-17 years)
    0
    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
    		 -

    Pre-assignment
    Screening details
    		 A total of 69 subjects were randomized, out of which 67 subjects received study drug and were included in subject disposition and baseline characteristics section.

    Period 1
    Period 1 title
    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 with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.
    Arm type
    		 Blinding arm

    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 once daily in the morning.

    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.

    Arm title
    		 TEZ/IVA
    Arm description
    		 Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TEZ/IVA
    Investigational medicinal product code
    VX-661/VX-770
    Other name
    Tezacaftor/Ivacaftor fixed dose combination
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received TEZ/IVA once daily in the morning.

    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 IVA once daily in the evening.

    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 morning.

    Arm title
    		 Ivacaftor
    Arm description
    		 Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.
    Arm type
    		 Blinding arm

    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 IVA every 12 hours.

    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 once daily in the morning.

    Number of subjects in period 1 [1]
    		Placebo TEZ/IVA Ivacaftor
    Started
    10
    54
    3
    Completed
    10
    53
    3
    Not completed
    0
    1
    0
         Other
    -
    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 69 subjects were randomized, out of which 67 subjects received study drug and were included in subject disposition and baseline characteristics section.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.

    Reporting group title
    Ivacaftor
    Reporting group description
    		 Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.

    Reporting group values
    		 Placebo TEZ/IVA Ivacaftor Total
    Number of subjects
    		 10 54 3 67
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.0 ± 1.7 8.5 ± 1.7 9.0 ± 1.7 -
    Gender categorical
    Units: Subjects
        Female
    		 6 29 2 37
        Male
    		 4 25 1 30
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 1
        Not Hispanic or Latino
    		 10 46 3 59
        Unknown or Not Reported
    		 0 7 0 7
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 1 0 1
        White
    		 10 51 3 64
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 2 0 2
    Lung Clearance Index 2.5 (LCI2.5)
    LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value.
    Units: Lung clearance index
        arithmetic mean (standard deviation)
    		 9.67 ± 1.65 9.56 ± 2.06 8.60 ± 1.40 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with genotype F/F received placebo matched to TEZ/IVA fixed dose combination (FDC) in the morning and placebo matched to IVA in the evening for 8 weeks.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.

    Reporting group title
    Ivacaftor
    Reporting group description
    		 Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.

    Primary: Absolute Change in Lung Clearance Index 2.5

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    End point title
    		 Absolute Change in Lung Clearance Index 2.5 [1] [2]
    End point description
    LCI2.5 represents the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting value. Full Analysis Set: all subjects who were randomized, received at least 1 dose of study drug and had an eligible genotype. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of primary efficacy analysis.
    End point type
    Primary
    End point timeframe
    From baseline through Week 8
    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: The study was designed to perform within treatment group comparison. Because single group within treatment comparisons cannot be reported in the EudraCT database, no statistical analyses are reported.
    [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 is applicable for only TEZ/IVA.
    End point values
    		 TEZ/IVA
    Number of subjects analysed
    54
    Units: Lung clearance index
        least squares mean (standard error)
    -0.51 ± 0.11
    No statistical analyses for this end point

    Secondary: Absolute Change in Sweat Chloride At Week 8

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    End point title
    		 Absolute Change in Sweat Chloride At Week 8 [3]
    End point description
    Sweat samples were collected using an approved collection device. FAS. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of secondary efficacy analysis.
    End point type
    Secondary
    End point timeframe
    From baseline at Week 8
    Notes
    [3] - 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 is applicable for only TEZ/IVA.
    End point values
    		 TEZ/IVA
    Number of subjects analysed
    54
    Units: millimole per liter (mmol/L)
        least squares mean (standard error)
    -12.3 ± 1.5
    No statistical analyses for this end point

    Secondary: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8

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    End point title
    		 Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8 [4]
    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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. FAS. As per the pre-specified analysis, efficacy was only planned to be assessed for TEZ/IVA group. Placebo or IVA groups were used for blinding purposes only and were not applicable for the purpose of secondary efficacy analysis.
    End point type
    Secondary
    End point timeframe
    From baseline through Week 8
    Notes
    [4] - 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 is applicable for only TEZ/IVA.
    End point values
    		 TEZ/IVA
    Number of subjects analysed
    54
    Units: units on a scale
        least squares mean (standard error)
    2.3 ± 1.2
    No statistical analyses for this end point

    Secondary: Safety and Tolerability as Assessed Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit

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    End point title
    		 Safety and Tolerability as Assessed Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) up to Safety Follow-up Visit
    End point description
    Safety set included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to safety follow-up visit (up to Week 12)
    End point values
    		 Placebo TEZ/IVA Ivacaftor
    Number of subjects analysed
    10
    54
    3
    Units: subjects
        Subjects with AEs
    8
    41
    2
        Subjects with SAEs
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to safety follow-up visit (up to Week 12)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with genotype F/F received placebo matched to TEZ/IVA FDC in the morning and placebo matched to IVA in the evening for 8 weeks.

    Reporting group title
    TEZ/IVA
    Reporting group description
    		 Subjects with genotype F/F received TEZ/IVA FDC in the morning and IVA in the evening for 8 weeks. Subjects with genotype F/RF received TEZ/IVA FDC and placebo matched to IVA in the morning and IVA in the evening for 8 weeks.

    Reporting group title
    Ivacaftor
    Reporting group description
    		 Subjects with genotype F/RF received placebo matched to TEZ/IVA FDC in the morning and IVA in morning and evening for 8 weeks.

    Serious adverse events
    		 Placebo TEZ/IVA Ivacaftor
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo TEZ/IVA Ivacaftor
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    31 / 54 (57.41%)
    2 / 3 (66.67%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Thermal burn
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    8 / 54 (14.81%)
    0 / 3 (0.00%)
         occurrences all number
    1
    11
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 54 (7.41%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 54 (5.56%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    9 / 54 (16.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    10
    0
    Sputum increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 54 (5.56%)
    1 / 3 (33.33%)
         occurrences all number
    0
    4
    1
    Productive cough
         subjects affected / exposed
    1 / 10 (10.00%)
    7 / 54 (12.96%)
    0 / 3 (0.00%)
         occurrences all number
    1
    9
    0
    Nasal congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 54 (5.56%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Throat irritation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Blister
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 54 (5.56%)
    0 / 3 (0.00%)
         occurrences all number
    4
    3
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 54 (7.41%)
    0 / 3 (0.00%)
         occurrences all number
    0
    5
    0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 54 (9.26%)
    0 / 3 (0.00%)
         occurrences all number
    1
    5
    0
    Otitis media
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 54 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Impetigo
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 54 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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