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    Clinical Trial Results:
    A Phase 3, Open-label Study Evaluating the Long-term Safety of VX-445 Combination Therapy in Subjects With Cystic Fibrosis

    Summary
    EudraCT number
    		 2018-004652-38
    Trial protocol
    		 IE   GB   DE   DK   PL  
    Global end of trial date
    14 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jun 2023
    First version publication date
    30 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VX18-445-113
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04043806
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Dec 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2022
    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 elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA)
    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
    09 Aug 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 34 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    United States: 243
    Country: Number of subjects enrolled
    Australia: 46
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    Ireland: 23
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    458
    EEA total number of subjects
    101
    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)
    83
    Adults (18-64 years)
    375
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted as a single part study (Part A) in countries including United States (US) with commercially available ELX/TEZ/IVA. The regional protocol for countries without commercially available ELX/TEZ/IVA was amended so that subjects in these countries had the opportunity to participate for up to an additional 48 weeks in Part B.

    Pre-assignment
    Screening details
    		 A total of 458 subjects were enrolled from the parent study VX17-659-105 (NCT03447262). One subject was enrolled but did not receive any dose in this study.

    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: ELX/TEZ/IVA
    Arm description
    		 Subjects received ELX (elexacaftor) 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 96 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    IVA
    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 [1]
    		Part A: ELX/TEZ/IVA
    Started
    457
    Completed
    412
    Not completed
    45
         Commercial drug is available for subjects
    13
         Physician decision
    2
         Other
    12
         Adverse event
    2
         Lost to follow-up
    6
         Other non-compliance
    2
         Withdrawal of Consent (not due to AE)
    8
    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 458 subjects were enrolled from the parent studies. One subject in enrolled but not dosed in this study. Therefore, data for 457 subjects are reported in the subject disposition and baseline characteristics sections.
    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: ELX/TEZ/IVA
    Arm description
    		 Subjects from certain countries participated in Part B and continued to receive ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 48 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Ivacaftor
    Investigational medicinal product code
    VX-770
    Other name
    IVA
    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 [2]
    		Part B: ELX/TEZ/IVA
    Started
    66
    Completed
    8
    Not completed
    58
         Commercial drug is available for subjects
    51
         Other
    6
         Adverse event
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 458 subjects were enrolled in the parent studies on Part A. However, only 66 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
    Reporting group description
    		 Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks.

    Reporting group values
    		 Part A Total
    Number of subjects
    		 457 457
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.5 ( 9.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 202 202
        Male
    		 255 255
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 14 14
        Not Hispanic or Latino
    		 437 437
        Not collected per local regulations
    		 6 6
    Race
    Units: Subjects
        White
    		 445 445
        Black or African American
    		 3 3
        Asian
    		 0 0
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Not collected per local regulations
    		 5 5
        Multiple
    		 4 4

    End points

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    End points reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX (elexacaftor) 200 milligram (mg) once daily (qd)/TEZ 100 mg qd/IVA 150 mg every 12 hours (q12h) in the treatment period for 96 weeks.
    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects from certain countries participated in Part B and continued to receive ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 48 weeks.

    Primary: Part A: Safety and Tolerability as Assessed by Number of Subjects With Treatment Emergent Adverse Events (TEAEs) 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 (TEAEs) and Serious Adverse Events (SAEs) [1]
    End point description
    Safety set included all subjects who received at least 1 dose of study drug in the treatment period.
    End point type
    Primary
    End point timeframe
    From Baseline through 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 this endpoint.
    End point values
    		 Part A: ELX/TEZ/IVA
    Number of subjects analysed
    457
    Units: Subjects
        Subjects with TEAEs
    435
        Subjects with SAEs
    75
    No statistical analyses for this end point

    Primary: Part B: Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) 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 (TEAEs) and Serious Adverse Events (SAEs) [2]
    End point description
    Safety set included all subjects who received at least 1 dose of study drug in the treatment period.
    End point type
    Primary
    End point timeframe
    From Baseline through Week 52
    Notes
    [2] - 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 this endpoint.
    End point values
    		 Part B: ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: Subjects
        Subjects with TEAEs
    50
        Subjects with SAEs
    4
    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 (up to Week 100 for Part A and up to Week 52 for Part B)
    Adverse event reporting additional description
    MedDRA 25.0 for Part A and MedDRA 25.1 for Part B
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0,25.1
    Reporting groups
    Reporting group title
    Part A: ELX/TEZ/IVA
    Reporting group description
    		 Subjects received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 96 weeks.

    Reporting group title
    Part B: ELX/TEZ/IVA
    Reporting group description
    		 Subjects from certain countries participated in Part B and continued to receive ELX 200 mg qd /TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 48 weeks.

    Serious adverse events
    		 Part A: ELX/TEZ/IVA Part B: ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    75 / 457 (16.41%)
    4 / 66 (6.06%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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
    Hypothermia
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device occlusion
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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
    3 / 457 (0.66%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Generalised anxiety disorder
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Substance-induced mood disorder
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 457 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    0 / 457 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 457 (0.00%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 457 (0.22%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site discharge
         subjects affected / exposed
    0 / 457 (0.00%)
    1 / 66 (1.52%)
         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
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Piriformis syndrome
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Distal intestinal obstruction syndrome
         subjects affected / exposed
    3 / 457 (0.66%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint instability
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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
    Abdominal abscess
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex pharyngitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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 / 457 (0.44%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 457 (1.53%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    31 / 457 (6.78%)
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 49
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abnormal loss of weight
         subjects affected / exposed
    1 / 457 (0.22%)
    0 / 66 (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: ELX/TEZ/IVA Part B: ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    404 / 457 (88.40%)
    45 / 66 (68.18%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    39 / 457 (8.53%)
    0 / 66 (0.00%)
         occurrences all number
    42
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 457 (8.53%)
    3 / 66 (4.55%)
         occurrences all number
    47
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    31 / 457 (6.78%)
    3 / 66 (4.55%)
         occurrences all number
    38
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    92 / 457 (20.13%)
    5 / 66 (7.58%)
         occurrences all number
    145
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    63 / 457 (13.79%)
    1 / 66 (1.52%)
         occurrences all number
    102
    1
    Pain
         subjects affected / exposed
    24 / 457 (5.25%)
    0 / 66 (0.00%)
         occurrences all number
    34
    0
    Fatigue
         subjects affected / exposed
    46 / 457 (10.07%)
    4 / 66 (6.06%)
         occurrences all number
    60
    4
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    42 / 457 (9.19%)
    1 / 66 (1.52%)
         occurrences all number
    75
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    30 / 457 (6.56%)
    2 / 66 (3.03%)
         occurrences all number
    41
    3
    Diarrhoea
         subjects affected / exposed
    33 / 457 (7.22%)
    1 / 66 (1.52%)
         occurrences all number
    41
    1
    Nausea
         subjects affected / exposed
    40 / 457 (8.75%)
    2 / 66 (3.03%)
         occurrences all number
    54
    2
    Vomiting
         subjects affected / exposed
    25 / 457 (5.47%)
    6 / 66 (9.09%)
         occurrences all number
    28
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    26 / 457 (5.69%)
    1 / 66 (1.52%)
         occurrences all number
    33
    1
    Cough
         subjects affected / exposed
    114 / 457 (24.95%)
    6 / 66 (9.09%)
         occurrences all number
    170
    7
    Oropharyngeal pain
         subjects affected / exposed
    61 / 457 (13.35%)
    1 / 66 (1.52%)
         occurrences all number
    89
    1
    Haemoptysis
         subjects affected / exposed
    41 / 457 (8.97%)
    5 / 66 (7.58%)
         occurrences all number
    69
    13
    Nasal congestion
         subjects affected / exposed
    52 / 457 (11.38%)
    0 / 66 (0.00%)
         occurrences all number
    72
    0
    Sputum increased
         subjects affected / exposed
    67 / 457 (14.66%)
    0 / 66 (0.00%)
         occurrences all number
    94
    0
    Sinus congestion
         subjects affected / exposed
    26 / 457 (5.69%)
    0 / 66 (0.00%)
         occurrences all number
    37
    0
    Rhinorrhoea
         subjects affected / exposed
    36 / 457 (7.88%)
    2 / 66 (3.03%)
         occurrences all number
    46
    3
    Respiration abnormal
         subjects affected / exposed
    24 / 457 (5.25%)
    0 / 66 (0.00%)
         occurrences all number
    28
    0
    Productive cough
         subjects affected / exposed
    27 / 457 (5.91%)
    0 / 66 (0.00%)
         occurrences all number
    32
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    26 / 457 (5.69%)
    1 / 66 (1.52%)
         occurrences all number
    32
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    27 / 457 (5.91%)
    2 / 66 (3.03%)
         occurrences all number
    28
    2
    Back pain
         subjects affected / exposed
    31 / 457 (6.78%)
    1 / 66 (1.52%)
         occurrences all number
    36
    1
    Myalgia
         subjects affected / exposed
    23 / 457 (5.03%)
    0 / 66 (0.00%)
         occurrences all number
    27
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    71 / 457 (15.54%)
    10 / 66 (15.15%)
         occurrences all number
    107
    10
    Sinusitis
         subjects affected / exposed
    31 / 457 (6.78%)
    3 / 66 (4.55%)
         occurrences all number
    44
    3
    Nasopharyngitis
         subjects affected / exposed
    61 / 457 (13.35%)
    1 / 66 (1.52%)
         occurrences all number
    90
    1
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    107 / 457 (23.41%)
    12 / 66 (18.18%)
         occurrences all number
    222
    15
    COVID-19
         subjects affected / exposed
    30 / 457 (6.56%)
    18 / 66 (27.27%)
         occurrences all number
    32
    18
    Viral upper respiratory tract infection
         subjects affected / exposed
    46 / 457 (10.07%)
    0 / 66 (0.00%)
         occurrences all number
    56
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2021
    Amended to include an optional at-home sweat chloride sample collection; Amended the treatment period by an additional 48 weeks (Part B) to evaluate the safety of ELX/TEZ/IVA beyond 96 weeks of treatment; Amended the study design to provide the opportunity for subjects who depart this study to enroll in another qualified Vertex study of investigational CFTR modulators, but do not receive the first study drug dose in the Treatment Period of the other study, to return to this study (applies to both Part A and Part B); Amended the statistical analysis section to reflect the updated study design.

    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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