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

    Summary
    EudraCT number
    		 2017-002968-40
    Trial protocol
    		 GB   IE   BE   DE   FR   DK   PL  
    Global end of trial date
    29 Sep 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Apr 2024
    First version publication date
    13 Apr 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX17-661-116
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03537651
    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
    25 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2023
    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 TEZ/IVA in subjects with CF aged 6 years and older, who are homozygous or heterozygous for F508del in Part A
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki and the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Apr 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 67 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 14
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    130
    EEA total number of subjects
    38
    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)
    130
    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
    		 This study was conducted in cystic fibrosis (CF) subjects aged 6 years or older who participated in parent Studies VX15-661-113 Part B (Study 113B; NCT02953314) or VX16-661-115 (Study 115; NCT03559062). Eligible subjects from parent studies were enrolled in Study 116.

    Period 1
    Period 1 title
    Part A
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part A: TEZ/IVA
    Arm description
    		 Subjects weighing less than (<)40 kilograms (kg) at Day 1 received tezacaftor (TEZ) 50 milligrams (mg) once daily (qd)/ivacaftor (IVA) 75 mg every 12 hours (q12h) and the subjects weighing greater than or equals to (>=) 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.
    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 TEZ/IVA fixed-dose combination 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.

    Number of subjects in period 1
    		Part A: TEZ/IVA
    Started
    130
    113B/116 FAS
    64 [1]
    113B/116 LCI FAS
    30 [2]
    115/116 FAS
    66 [3]
    115/116 FAS (TEZ/IVA Group)
    53 [4]
    Completed
    69
    Not completed
    61
         Adverse Event
    2
         Other
    1
         Commercial Drug is Available for Participant
    56
         Withdrawal of Consent (not due to AE)
    2
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All enrolled subjects from parent Study 113B who received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All enrolled subjects who participated in the LCI sub study in parent Study 113B and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All enrolled subjects who were randomized to either TEZ/IVA, IVA or placebo treatment group in parent Study 115 and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All enrolled subjects who were randomized to the TEZ/IVA treatment group in parent Study 115 and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
    Period 2
    Period 2 title
    Part B
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Part B: TEZ/IVA
    Arm description
    		 Subjects weighing <30 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the subjects weighing >=30 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks. Doses were adjusted upward for changes in body weight and/or age.
    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 TEZ/IVA fixed-dose combination 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.

    Number of subjects in period 2 [5]
    		Part B: TEZ/IVA
    Started
    62
    113B/116 FAS
    9
    115/116 FAS
    53
    Completed
    3
    Not completed
    59
         Adverse Event
    1
         Other
    1
         Commercial Drug is available for Subject
    56
         Withdrawal of Consent (not due to AE)
    1
    Notes
    [5] - 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: A total of 130 subjects were enrolled in the parent study on Part A. However, only 62 subjects rolled over to Part B from Part A of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: TEZ/IVA
    Reporting group description
    		 Subjects weighing less than (<)40 kilograms (kg) at Day 1 received tezacaftor (TEZ) 50 milligrams (mg) once daily (qd)/ivacaftor (IVA) 75 mg every 12 hours (q12h) and the subjects weighing greater than or equals to (>=) 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.

    Reporting group values
    		 Part A: TEZ/IVA Total
    Number of subjects
    		 130 130
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.3 ( 1.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 67 67
        Male
    		 63 63
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 4
        Not Hispanic or Latino
    		 119 119
        Not Collected per Local Regulations
    		 7 7
    Race
    Units: Subjects
        White
    		 125 125
        Black or African American
    		 1 1
        Asian
    		 1 1
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Not Collected per Local Regulations
    		 2 2
        Other
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    Part A: TEZ/IVA
    Reporting group description
    		 Subjects weighing less than (<)40 kilograms (kg) at Day 1 received tezacaftor (TEZ) 50 milligrams (mg) once daily (qd)/ivacaftor (IVA) 75 mg every 12 hours (q12h) and the subjects weighing greater than or equals to (>=) 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.
    Reporting group title
    Part B: TEZ/IVA
    Reporting group description
    		 Subjects weighing <30 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the subjects weighing >=30 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks. Doses were adjusted upward for changes in body weight and/or age.

    Primary: Part A: 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
    		 Part A: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Safety Set included all subjects who were enrolled and received at least 1 dose of TEZ/IVA in Part A of Study 116.
    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: Only descriptive statistics were planned. No statistical comparisons were planned for the safety endpoint.
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    130
    Units: Subjects
        Subjects with TEAEs
    129
        Subjects with SAEs
    31
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in Lung Clearance Index 2.5 (LCI2.5) for 115/116 FAS (TEZ/IVA Group)

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    End point title
    		 Part A: Absolute Change in Lung Clearance Index 2.5 (LCI2.5) for 115/116 FAS (TEZ/IVA Group)
    End point description
    The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry. 115/116 Full analysis set (FAS) (TEZ/IVA group) included all enrolled participants who were randomized to the TEZ/IVA treatment group in parent Study 115 and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype. As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
    End point type
    Secondary
    End point timeframe
    From Parent Study 115 Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    53
    Units: Index
        least squares mean (confidence interval 95%)
    -0.95 (-1.38 to -0.52)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in LCI2.5 for 113B/116 LCI FAS

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    End point title
    		 Part A: Absolute Change in LCI2.5 for 113B/116 LCI FAS
    End point description
    The LCI2.5 index is the number of lung turnovers required to reduce the end tidal inert gas concentration to 1/40th of its starting values and is calculated by dividing the sum of exhaled tidal breaths (cumulative exhaled volume (CEV)) by simultaneously measured functional residual capacity (FRC). An LCI of 7.5 and below is normal; values greater than 7.5 are abnormal. LCI is able to detect abnormalities in lung function earlier than more traditional modalities such as spirometry. 13B/116 LCI FAS included all enrolled participants who participated in the LCI sub study in parent Study 113B and received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype. As pre-specified in the SAP, only descriptive summary statistics were planned to be reported for the 113B/116 LCI FAS.
    End point type
    Secondary
    End point timeframe
    From Parent Study 113B Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    30
    Units: Index
        arithmetic mean (standard deviation)
    -2.04 ( 1.73 )
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in Sweat Chloride (SwCl) for 115/116 FAS (TEZ/IVA Group)

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    End point title
    		 Part A: Absolute Change in Sweat Chloride (SwCl) for 115/116 FAS (TEZ/IVA Group)
    End point description
    Sweat samples were collected using an approved collection device.115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
    End point type
    Secondary
    End point timeframe
    From Parent Study 115 Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    53
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    -13.8 (-17.7 to -9.9)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in SwCl for 113B/116 FAS

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    End point title
    		 Part A: Absolute Change in SwCl for 113B/116 FAS
    End point description
    Sweat samples were collected using an approved collection device.113B/116 FAS included all enrolled subjects from parent Study 113B who received at least 1 dose of TEZ/IVA in Study 116 and had an eligible genotype.
    End point type
    Secondary
    End point timeframe
    From Parent Study 113B Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    64
    Units: mmol/L
        least squares mean (confidence interval 95%)
    -16.2 (-21.9 to -10.5)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 115/116 FAS (TEZ/IVA Group)

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    End point title
    		 Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 115/116 FAS (TEZ/IVA Group)
    End point description
    The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
    End point type
    Secondary
    End point timeframe
    From Parent Study 115 Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    53
    Units: units on a scale
        least squares mean (confidence interval 95%)
    6.4 (3.5 to 9.3)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in CFQ-R Respiratory Domain Score for 113B/116 FAS

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    End point title
    		 Part A: Absolute Change in CFQ-R Respiratory Domain Score for 113B/116 FAS
    End point description
    The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with CF. Respiratory domain assessed respiratory symptoms, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life.113B/116 FAS.
    End point type
    Secondary
    End point timeframe
    From Parent Study 113B Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    64
    Units: units on a scale
        least squares mean (confidence interval 95%)
    6.0 (1.1 to 10.8)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in Body Mass Index (BMI) for 115/116 FAS (TEZ/IVA Group)

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    End point title
    		 Part A: Absolute Change in Body Mass Index (BMI) for 115/116 FAS (TEZ/IVA Group)
    End point description
    BMI was defined as weight in kilograms (kg) divided by squared height in meters (m^2).115/116 FAS (TEZ/IVA group). As pre-specified in the SAP, model-based efficacy analysis for participants from parent Study 115 was planned only for the TEZ/IVA treatment group.
    End point type
    Secondary
    End point timeframe
    From Parent Study 115 Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    53
    Units: kilogram per meter square (kg/m^2)
        least squares mean (confidence interval 95%)
    1.25 (1.00 to 1.49)
    No statistical analyses for this end point

    Secondary: Part A: Absolute Change in BMI for 113B/116 FAS

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    End point title
    		 Part A: Absolute Change in BMI for 113B/116 FAS
    End point description
    BMI was defined as weight in kg divided by m^2.113B/116 FAS.
    End point type
    Secondary
    End point timeframe
    From Parent Study 113B Baseline at Week 96 (Study 116)
    End point values
    		 Part A: TEZ/IVA
    Number of subjects analysed
    64
    Units: kg/m^2
        least squares mean (confidence interval 95%)
    1.19 (0.74 to 1.64)
    No statistical analyses for this end point

    Secondary: Part B: 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
    		 Part B: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Safety Set included all subjects who were enrolled and received at least 1 dose of TEZ/IVA in Part B of Study 116.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 192
    End point values
    		 Part B: TEZ/IVA
    Number of subjects analysed
    62
    Units: Subjects
        Subjects With TEAEs
    53
        Subjects With SAEs
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 Through Safety Follow-up Visit (up to Week 100 for Part A, and up to Week 192 for Part B)
    Adverse event reporting additional description
    Safety Set included all subjects who were enrolled and received at least 1 dose of TEZ/IVA in Study 116.MedDRA version 23.1 applied for Part A, MedDRA version 26.1 applied for Part B.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1,26.1
    Reporting groups
    Reporting group title
    Part A: TEZ/IVA
    Reporting group description
    		 Subjects weighing <40 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the subjects weighing >= 40 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks. Doses were adjusted upward for changes in body weight and/or age.

    Reporting group title
    Part B: TEZ/IVA
    Reporting group description
    		 Subjects weighing <30 kg at Day 1 received TEZ 50 mg qd/IVA 75 mg q12h and the subjects weighing >=30 kg at Day 1 received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 192 weeks. Doses were adjusted upward for changes in body weight and/or age.

    Serious adverse events
    		 Part A: TEZ/IVA Part B: TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 130 (23.85%)
    8 / 62 (12.90%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial test positive
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stenotrophomonas test positive
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary function test decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas test positive
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cystic fibrosis related diabetes
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (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
    Asthenia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus disorder
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Personality change
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (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
    Chronic sinusitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial disease carrier
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    15 / 130 (11.54%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 21
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Weight gain poor
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 62 (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
    		 Part A: TEZ/IVA Part B: TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    128 / 130 (98.46%)
    49 / 62 (79.03%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 130 (9.23%)
    2 / 62 (3.23%)
         occurrences all number
    15
    3
    Forced expiratory volume decreased
         subjects affected / exposed
    7 / 130 (5.38%)
    7 / 62 (11.29%)
         occurrences all number
    8
    7
    Pseudomonas test positive
         subjects affected / exposed
    11 / 130 (8.46%)
    2 / 62 (3.23%)
         occurrences all number
    12
    5
    Staphylococcus test positive
         subjects affected / exposed
    3 / 130 (2.31%)
    4 / 62 (6.45%)
         occurrences all number
    3
    4
    Bacterial test positive
         subjects affected / exposed
    19 / 130 (14.62%)
    8 / 62 (12.90%)
         occurrences all number
    23
    13
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 130 (6.15%)
    2 / 62 (3.23%)
         occurrences all number
    9
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 130 (15.38%)
    8 / 62 (12.90%)
         occurrences all number
    35
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 130 (5.38%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    Pyrexia
         subjects affected / exposed
    26 / 130 (20.00%)
    3 / 62 (4.84%)
         occurrences all number
    42
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    8 / 130 (6.15%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 130 (7.69%)
    4 / 62 (6.45%)
         occurrences all number
    11
    6
    Abdominal pain upper
         subjects affected / exposed
    8 / 130 (6.15%)
    1 / 62 (1.61%)
         occurrences all number
    11
    1
    Abdominal pain
         subjects affected / exposed
    20 / 130 (15.38%)
    6 / 62 (9.68%)
         occurrences all number
    27
    10
    Diarrhoea
         subjects affected / exposed
    8 / 130 (6.15%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Nausea
         subjects affected / exposed
    8 / 130 (6.15%)
    3 / 62 (4.84%)
         occurrences all number
    9
    5
    Vomiting
         subjects affected / exposed
    21 / 130 (16.15%)
    5 / 62 (8.06%)
         occurrences all number
    24
    6
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    14 / 130 (10.77%)
    3 / 62 (4.84%)
         occurrences all number
    20
    3
    Cough
         subjects affected / exposed
    73 / 130 (56.15%)
    15 / 62 (24.19%)
         occurrences all number
    157
    25
    Epistaxis
         subjects affected / exposed
    4 / 130 (3.08%)
    4 / 62 (6.45%)
         occurrences all number
    5
    5
    Nasal congestion
         subjects affected / exposed
    24 / 130 (18.46%)
    2 / 62 (3.23%)
         occurrences all number
    43
    2
    Nasal polyps
         subjects affected / exposed
    7 / 130 (5.38%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Oropharyngeal pain
         subjects affected / exposed
    24 / 130 (18.46%)
    6 / 62 (9.68%)
         occurrences all number
    35
    8
    Productive cough
         subjects affected / exposed
    22 / 130 (16.92%)
    6 / 62 (9.68%)
         occurrences all number
    29
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 130 (5.38%)
    0 / 62 (0.00%)
         occurrences all number
    9
    0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    8 / 130 (6.15%)
    4 / 62 (6.45%)
         occurrences all number
    13
    4
    Nasopharyngitis
         subjects affected / exposed
    24 / 130 (18.46%)
    10 / 62 (16.13%)
         occurrences all number
    62
    15
    Influenza
         subjects affected / exposed
    13 / 130 (10.00%)
    0 / 62 (0.00%)
         occurrences all number
    13
    0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    57 / 130 (43.85%)
    10 / 62 (16.13%)
         occurrences all number
    97
    13
    Gastroenteritis
         subjects affected / exposed
    9 / 130 (6.92%)
    2 / 62 (3.23%)
         occurrences all number
    15
    2
    Ear infection
         subjects affected / exposed
    8 / 130 (6.15%)
    2 / 62 (3.23%)
         occurrences all number
    9
    2
    COVID-19
         subjects affected / exposed
    0 / 130 (0.00%)
    15 / 62 (24.19%)
         occurrences all number
    0
    17
    Bacterial disease carrier
         subjects affected / exposed
    7 / 130 (5.38%)
    6 / 62 (9.68%)
         occurrences all number
    10
    8
    Rhinitis
         subjects affected / exposed
    11 / 130 (8.46%)
    4 / 62 (6.45%)
         occurrences all number
    18
    5
    Pharyngitis streptococcal
         subjects affected / exposed
    8 / 130 (6.15%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Pharyngitis
         subjects affected / exposed
    8 / 130 (6.15%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    10 / 130 (7.69%)
    3 / 62 (4.84%)
         occurrences all number
    19
    6
    Upper respiratory tract infection
         subjects affected / exposed
    31 / 130 (23.85%)
    10 / 62 (16.13%)
         occurrences all number
    54
    13
    Tonsillitis
         subjects affected / exposed
    2 / 130 (1.54%)
    4 / 62 (6.45%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2019
    Amended to add an additional 96 weeks of treatment (Part B). The dose cutoff for weight-based dosing was revised.
    13 Oct 2021
    Amended to add an additional 96 weeks of TEZ/IVA treatment to Part B to further evaluate the long-term safety and tolerability of TEZ/IVA in subjects enrolled in Study VX17-661-116 Part B.

    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
    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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