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    Clinical Trial Results:
    A Phase 3, Randomized, Double-blind, Controlled Study Evaluating the Efficacy and Safety of VX-121 Combination Therapy in Subjects With Cystic Fibrosis Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive CFTR Mutation and No F508del Mutation

    Summary
    EudraCT number
    		 2021-000694-85
    Trial protocol
    		 NO   SE   DE   DK   IE   IT   GR   BE   AT   NL   PL   HU  
    Global end of trial date
    30 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2024
    First version publication date
    01 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX20-121-103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05076149
    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-003052-PIP01-21
    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
    15 Dec 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in cystic fibrosis (CF) subjects who are homozygous for F508del, heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or have at least 1 other triple combination responsive (TCR) CFTR mutation and no F508del mutation
    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
    27 Oct 2021
    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
    Netherlands: 13
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 31
    Country: Number of subjects enrolled
    Denmark: 11
    Country: Number of subjects enrolled
    France: 50
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 18
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Canada: 29
    Country: Number of subjects enrolled
    New Zealand: 25
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    United States: 202
    Country: Number of subjects enrolled
    United Kingdom: 34
    Worldwide total number of subjects
    597
    EEA total number of subjects
    266
    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)
    82
    Adults (18-64 years)
    513
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in cystic fibrosis (CF) subjects aged 12 years or older. It was pre-specified in the protocol to combine the data from this study with study VX20-121-102 (NCT05033080) for selected endpoints.

    Pre-assignment
    Screening details
    		 A total of 597 subjects were enrolled in this study, of which 24 were included in the run-in period but were not dosed in treatment period. Therefore, results are presented for only 573 subjects dosed in the treatment period.

    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
    		 ELX/TEZ/IVA
    Arm description
    		 Following elexacftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) run-in period of 4 weeks, subjects received ELX 200 milligram (mg) once daily (qd) /TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 52 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ELX/TEZ/IVA
    Investigational medicinal product code
    VX-445/VX-661/VX-770
    Other name
    Elexacaftor/Tezacaftor/Ivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ELX/TEZ/IVA fixed-dose combination (FDC) 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.

    Arm title
    		 VX-121/TEZ/D-IVA
    Arm description
    		 Following ELX/TEZ/IVA run-in period of 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 250 mg qd in the treatment period for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VX-121/TEZ/D-IVA
    Investigational medicinal product code
    VX-121/VX-661/VX-561
    Other name
    VX-121/tezacaftor/deutivacaftor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received VX-121/TEZ/D-IVA fixed-dose combination (FDC) once daily in the morning.

    Number of subjects in period 1 [1]
    		ELX/TEZ/IVA VX-121/TEZ/D-IVA
    Started
    289
    284
    Completed
    279
    264
    Not completed
    10
    20
         Physician decision
    -
    1
         Other non compliance
    1
    1
         Adverse Event
    3
    9
         Other
    5
    4
         Lost to follow-up
    -
    1
         Withdrawal of consent (not due to AE)
    1
    3
         Commercial drug is available for subject
    -
    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 597 subjects were enrolled in the study, of which 24 were included in the run-in period but were not dosed in treatment period. Therefore, results are presented for only 573 subjects dosed in the treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following elexacftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) run-in period of 4 weeks, subjects received ELX 200 milligram (mg) once daily (qd) /TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 52 weeks.

    Reporting group title
    VX-121/TEZ/D-IVA
    Reporting group description
    		 Following ELX/TEZ/IVA run-in period of 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 250 mg qd in the treatment period for 52 weeks.

    Reporting group values
    		 ELX/TEZ/IVA VX-121/TEZ/D-IVA Total
    Number of subjects
    		 289 284 573
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.0 ( 12.4 ) 33.3 ( 12.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 145 135 280
        Male
    		 144 149 293
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 4 9
        Not Hispanic or Latino
    		 261 265 526
        Not Collected per Local Regulations
    		 23 15 38
    Race
    Units: Subjects
        White
    		 262 270 532
        Asian
    		 1 1 2
        American Indian or Alaska Native
    		 1 0 1
        Other
    		 1 1 2
        Not Collected per Local Regulations
    		 23 10 33
        More than one race
    		 1 2 3
    Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
    Units: Percentage points
        arithmetic mean (standard deviation)
    		 66.4 ( 14.9 ) 67.2 ( 14.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following elexacftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) run-in period of 4 weeks, subjects received ELX 200 milligram (mg) once daily (qd) /TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 52 weeks.

    Reporting group title
    VX-121/TEZ/D-IVA
    Reporting group description
    		 Following ELX/TEZ/IVA run-in period of 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 250 mg qd in the treatment period for 52 weeks.

    Subject analysis set title
    ELX/TEZ/IVA (pooled analysis with 121-102)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pooled Full Analysis Set (PFAS) included all randomized subjects from this study (VX20-121-103) and from Study VX20-121-102 who carried the intended CFTR mutation(s) and received at least 1 dose of study drug during the Treatment Period. The PFAS will be used only for pooled analysis of selected endpoints.

    Subject analysis set title
    VX-121/TEZ/D-IVA (pooled analysis with 121-102)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The Pooled Full Analysis Set (PFAS) included all randomized subjects from this study (VX20-121-103) and from Study VX20-121-102 who carried the intended CFTR mutation(s) and received at least 1 dose of study drug during the Treatment Period. The PFAS will be used only for pooled analysis of selected endpoints.

    Primary: Absolute Change in Percent Predicted Forced Expiratory Volume in 1second (ppFEV1)

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    End point title
    		 Absolute Change in Percent Predicted Forced Expiratory Volume in 1second (ppFEV1)
    End point description
    FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. The Full Analysis Set (FAS) all randomized subjects who carried the intended CFTR mutation(s) and received at least 1 dose of study drug during the Treatment Period. Here “ Number of Subjects Analyzed” signifies those subjects who were evaluated for this specific end point.
    End point type
    Primary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 ELX/TEZ/IVA VX-121/TEZ/D-IVA
    Number of subjects analysed
    276
    268
    Units: percentage points
        least squares mean (confidence interval 95%)
    0.0 (-0.5 to 0.5)
    0.2 (-0.3 to 0.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ELX/TEZ/IVA v VX-121/TEZ/D-IVA
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.0001
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 LS Mean difference
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.9

    Secondary: Absolute Change in Sweat Chloride (SwCl)

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    End point title
    		 Absolute Change in Sweat Chloride (SwCl)
    End point description
    Sweat samples were collected using an approved collection device. FAS.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 ELX/TEZ/IVA VX-121/TEZ/D-IVA
    Number of subjects analysed
    276
    270
    Units: millimole per liter (mmol/L)
        least squares mean (confidence interval 95%)
    -2.3 (-3.6 to -0.9)
    -5.1 (-6.4 to -3.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ELX/TEZ/IVA v VX-121/TEZ/D-IVA
    Number of subjects included in analysis
    546
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0034
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 LS Mean difference
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7
         upper limit
    		 -0.9

    Secondary: Percentage of subjects with SwCl <60 mmol/L (pooled with data from Study VX20-121-102)

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    End point title
    		 Percentage of subjects with SwCl <60 mmol/L (pooled with data from Study VX20-121-102)
    End point description
    The Pooled Full Analysis Set (PFAS) included all randomized subjects from this study (VX20-121-103) and from Study VX20-121-102 who carried the intended CFTR mutation(s) and received at least 1 dose of study drug during the Treatment Period. The PFAS will be used only for pooled analysis of selected endpoints. Here “ Number of Subjects Analyzed” signifies those subjects who were evaluated for this specific end point.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 ELX/TEZ/IVA (pooled analysis with 121-102) VX-121/TEZ/D-IVA (pooled analysis with 121-102)
    Number of subjects analysed
    479
    465
    Units: percentage of subjects
        number (not applicable)
    76.6
    85.8
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ELX/TEZ/IVA (pooled analysis with 121-102) v VX-121/TEZ/D-IVA (pooled analysis with 121-102)
    Number of subjects included in analysis
    944
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Generalized Estimated Equation Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.55
         upper limit
    		 3.15

    Secondary: Percentage of subjects with SwCl <30 mmol/L (pooled with data from Study VX20-121-102)

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    End point title
    		 Percentage of subjects with SwCl <30 mmol/L (pooled with data from Study VX20-121-102)
    End point description
    PFAS. The PFAS will be used only for pooled analysis of selected endpoints. Here “ Number of Subjects Analyzed” signifies those subjects who were evaluated for this specific end point.
    End point type
    Secondary
    End point timeframe
    From Baseline Through Week 24
    End point values
    		 ELX/TEZ/IVA (pooled analysis with 121-102) VX-121/TEZ/D-IVA (pooled analysis with 121-102)
    Number of subjects analysed
    479
    465
    Units: percentage of subjects
        number (not applicable)
    22.5
    30.5
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ELX/TEZ/IVA (pooled analysis with 121-102) v VX-121/TEZ/D-IVA (pooled analysis with 121-102)
    Number of subjects included in analysis
    944
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Generalized Estimated Equation Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 4.12

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Safety follow-up (up to 52 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    		 Following ELX/TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 52 weeks

    Reporting group title
    VX-121/TEZ/D-IVA
    Reporting group description
    		 Following ELX/TEZ/IVA run-in period of 4 weeks, subjects received VX-121 20 mg qd/TEZ 100 mg qd/D-IVA 250 mg qd in the treatment period for 52 weeks.

    Serious adverse events
    		 ELX/TEZ/IVA VX-121/TEZ/D-IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 289 (13.84%)
    40 / 284 (14.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal cyst
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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 / 289 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute stress disorder
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 289 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 289 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 289 (0.00%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fractured base
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-traumatic headache
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in attention
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatic cyst
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    2 / 289 (0.69%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flatulence
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Fatty liver alcoholic
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    2 / 289 (0.69%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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
    Metapneumovirus pneumonia
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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
    2 / 289 (0.69%)
    4 / 284 (1.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    12 / 289 (4.15%)
    18 / 284 (6.34%)
         occurrences causally related to treatment / all
    0 / 13
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 289 (0.35%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 289 (2.08%)
    2 / 284 (0.70%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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
    Type 3 diabetes mellitus
         subjects affected / exposed
    0 / 289 (0.00%)
    1 / 284 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 289 (0.35%)
    0 / 284 (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
    		 ELX/TEZ/IVA VX-121/TEZ/D-IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    253 / 289 (87.54%)
    252 / 284 (88.73%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    17 / 289 (5.88%)
    24 / 284 (8.45%)
         occurrences all number
    18
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 289 (6.23%)
    19 / 284 (6.69%)
         occurrences all number
    20
    20
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 289 (6.23%)
    24 / 284 (8.45%)
         occurrences all number
    22
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    41 / 289 (14.19%)
    51 / 284 (17.96%)
         occurrences all number
    98
    60
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    29 / 289 (10.03%)
    28 / 284 (9.86%)
         occurrences all number
    38
    43
    Fatigue
         subjects affected / exposed
    30 / 289 (10.38%)
    33 / 284 (11.62%)
         occurrences all number
    40
    38
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    23 / 289 (7.96%)
    15 / 284 (5.28%)
         occurrences all number
    30
    18
    Constipation
         subjects affected / exposed
    19 / 289 (6.57%)
    15 / 284 (5.28%)
         occurrences all number
    23
    18
    Diarrhoea
         subjects affected / exposed
    44 / 289 (15.22%)
    37 / 284 (13.03%)
         occurrences all number
    49
    46
    Vomiting
         subjects affected / exposed
    19 / 289 (6.57%)
    12 / 284 (4.23%)
         occurrences all number
    24
    14
    Nausea
         subjects affected / exposed
    13 / 289 (4.50%)
    22 / 284 (7.75%)
         occurrences all number
    14
    23
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    37 / 289 (12.80%)
    45 / 284 (15.85%)
         occurrences all number
    50
    58
    Productive cough
         subjects affected / exposed
    19 / 289 (6.57%)
    16 / 284 (5.63%)
         occurrences all number
    24
    24
    Rhinorrhoea
         subjects affected / exposed
    22 / 289 (7.61%)
    16 / 284 (5.63%)
         occurrences all number
    25
    19
    Sinus congestion
         subjects affected / exposed
    10 / 289 (3.46%)
    18 / 284 (6.34%)
         occurrences all number
    10
    25
    Sputum increased
         subjects affected / exposed
    29 / 289 (10.03%)
    27 / 284 (9.51%)
         occurrences all number
    38
    30
    Nasal congestion
         subjects affected / exposed
    23 / 289 (7.96%)
    29 / 284 (10.21%)
         occurrences all number
    29
    36
    Haemoptysis
         subjects affected / exposed
    22 / 289 (7.61%)
    16 / 284 (5.63%)
         occurrences all number
    36
    23
    Dyspnoea
         subjects affected / exposed
    21 / 289 (7.27%)
    11 / 284 (3.87%)
         occurrences all number
    21
    14
    Cough
         subjects affected / exposed
    60 / 289 (20.76%)
    63 / 284 (22.18%)
         occurrences all number
    88
    94
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 289 (4.50%)
    25 / 284 (8.80%)
         occurrences all number
    15
    30
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 289 (2.08%)
    16 / 284 (5.63%)
         occurrences all number
    7
    17
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 289 (8.65%)
    14 / 284 (4.93%)
         occurrences all number
    26
    15
    Back pain
         subjects affected / exposed
    15 / 289 (5.19%)
    16 / 284 (5.63%)
         occurrences all number
    15
    20
    Infections and infestations
    COVID-19
         subjects affected / exposed
    72 / 289 (24.91%)
    57 / 284 (20.07%)
         occurrences all number
    79
    60
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    85 / 289 (29.41%)
    70 / 284 (24.65%)
         occurrences all number
    125
    109
    Influenza
         subjects affected / exposed
    14 / 289 (4.84%)
    29 / 284 (10.21%)
         occurrences all number
    14
    30
    Nasopharyngitis
         subjects affected / exposed
    60 / 289 (20.76%)
    57 / 284 (20.07%)
         occurrences all number
    119
    84
    Viral upper respiratory tract infection
         subjects affected / exposed
    17 / 289 (5.88%)
    20 / 284 (7.04%)
         occurrences all number
    19
    26
    Upper respiratory tract infection
         subjects affected / exposed
    40 / 289 (13.84%)
    55 / 284 (19.37%)
         occurrences all number
    59
    71
    Sinusitis
         subjects affected / exposed
    26 / 289 (9.00%)
    9 / 284 (3.17%)
         occurrences all number
    31
    11

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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
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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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