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    Clinical Trial Results:
    A Phase 3b Open-label Study to Assess the Effect of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Cystic Fibrosis Subjects with Abnormal Glucose Metabolism

    Summary
    EudraCT number
    2020-003170-44
    Trial protocol
    BE   CZ   FR   NL   IT  
    Global end of trial date
    14 Jul 2022

    Results information
    Results version number
    v2(current)
    This version publication date
    20 Aug 2023
    First version publication date
    29 Jan 2023
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Addition of Secondary data

    Trial information

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    Trial identification
    Sponsor protocol code
    VX19-445-117
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04599465
    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
    19 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) on glucose tolerance in Cystic Fibrosis (CF) subjects with impaired glucose tolerance (IGT) or CF-related diabetes (CFRD)
    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
    15 Jan 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Australia: 11
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Netherlands: 9
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    Belgium: 7
    Worldwide total number of subjects
    69
    EEA total number of subjects
    58
    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)
    19
    Adults (18-64 years)
    50
    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 subjects with CF aged 12 years and older who are heterozygous for the F508del mutation and a minimal function mutation (F/MF genotypes), with abnormal glucose metabolism.

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

    Arms
    Arm title
    ELX/TEZ/IVA
    Arm description
    Subjects received elexacaftor (ELX) 200 milligram (mg)/ tezacaftor (TEZ) 100 mg/ ivacaftor (IVA)150 mg in the morning and IVA 150 mg in the evening.
    Arm type
    Experimental

    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 FDC 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 dose once daily in the evening.

    Number of subjects in period 1
    ELX/TEZ/IVA
    Started
    69
    Completed
    66
    Not completed
    3
         Physician decision
    1
         Withdrawal of consent (not due to AE)
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    Subjects received ELX/TEZ/IVA fixed dose combination (FDC) in the morning and ivacaftor (IVA) in the evening.

    Reporting group values
    Overall Period Total
    Number of subjects
    69 69
    Age categorical
    Units: Subjects
        Less than (<)18 years
    19 19
        More than or equal to (≥)18 years
    50 50
    Gender categorical
    Units: Subjects
        Female
    31 31
        Male
    38 38
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    8 8
        Not Hispanic or Latino
    41 41
        Not collected per local regulations
    20 20
    Race
    Units: Subjects
        White
    48 48
        Black or African American
    0 0
        Asian
    0 0
        American Indian or Alaska Native
    0 0
        Native Hawaiian or Other Pacific Islander
    0 0
        Other
    1 1
        Not collected per local regulations
    20 20
    2-hour Post-OGTT Blood Glucose Levels
    Baseline 2-hour post-Oral Glucose Tolerance Test (OGTT) blood glucose level was defined as the average of valid pre-dose measurements at screening and Day 1. OGTT results were considered valid only when the subjects was fasting for at least 8 hours.
    Units: milligrams per deciliter (mg/dl)
        arithmetic mean (standard deviation)
    217.6 ± 73.1 -

    End points

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    End points reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    Subjects received elexacaftor (ELX) 200 milligram (mg)/ tezacaftor (TEZ) 100 mg/ ivacaftor (IVA)150 mg in the morning and IVA 150 mg in the evening.

    Primary: Change From Baseline in 2-hour Blood Glucose Levels Following an OGTT to the Average of Week 36 and Week 48

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    End point title
    Change From Baseline in 2-hour Blood Glucose Levels Following an OGTT to the Average of Week 36 and Week 48 [1]
    End point description
    Baseline 2-hour post-OGTT blood glucose level was defined as the average of valid pre-dose measurements at screening and Day 1. OGTT results were considered valid only when the subject was fasting for at least 8 hours. The Full Analysis Set (FAS) will include all enrolled subjects who carry the intended CFTR allele mutation and have received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Week 36 and 48
    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: This is a single arm study, and thus no between-group comparisons were planned. However, subjects’ post-baseline values were compared to their pre-treatment baseline values with a mixed model for repeated measures (MMRM) with change from baseline in 2-hour post-OGTT blood glucose levels at each post-baseline visit as the dependent variable. The primary result obtained from the model was the estimated mean change from baseline to the average of Week 36 and Week 48.
    End point values
    ELX/TEZ/IVA
    Number of subjects analysed
    66
    Units: milligrams per deciliter (mg/dl)
        least squares mean (confidence interval 95%)
    -35.0 (-49.2 to -20.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Improvement in Dysglycemia Categorization at Week 48

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    End point title
    Percentage of Subjects With Improvement in Dysglycemia Categorization at Week 48
    End point description
    Baseline dysglycemia category was defined as the most recent non-missing measurement before the first dose of study drug in the Treatment Period. Improvement in dysglycemia is to change from cystic fibrosis-related diabetes (CFRD) at baseline to impaired glucose tolerance (IGT)/normal glucose tolerance (NGT) at Week 48 OR change from IGT at baseline to NGT at Week 48. CFRD: 2-hour post-OGTT blood glucose level ≥200 mg/dL or fasting blood glucose level ≥126 mg/dL; IGT: 2-hour post-OGTT blood glucose level ≥140 to <200 mg/dL and fasting blood glucose level <126 mg/dL; NGT: 2 hour post-OGTT blood glucose level <140 mg/dL and fasting blood glucose level <126 mg/dL. FAS subjects with abnormal glucose tolerance at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    ELX/TEZ/IVA
    Number of subjects analysed
    53
    Units: percentage of subjects
        number (confidence interval 95%)
    37.7 (24.8 to 52.1)
    No statistical analyses for this end point

    Secondary: 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
    Safety and Tolerability as Assessed by Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    Safety set included all subjects who received at least 1 dose of study drug in the treatment period.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Week 52
    End point values
    ELX/TEZ/IVA
    Number of subjects analysed
    69
    Units: Subjects
        Subjects with TEAEs
    67
        Subjects with SAEs
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Week 52
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    ELX/TEZ/IVA
    Reporting group description
    Subjects received ELX 200 mg/ TEZ 100 mg/ IVA 150 mg in the morning and IVA 150 mg in the evening.

    Serious adverse events
    ELX/TEZ/IVA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 69 (8.70%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 69 (1.45%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ELX/TEZ/IVA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 69 (89.86%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    6
    Blood creatine phosphokinase increased
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    6
    Blood bilirubin increased
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 69 (23.19%)
         occurrences all number
    22
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    16 / 69 (23.19%)
         occurrences all number
    22
    Fatigue
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    5
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    9 / 69 (13.04%)
         occurrences all number
    13
    Nausea
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    6
    Diarrhoea
         subjects affected / exposed
    13 / 69 (18.84%)
         occurrences all number
    16
    Abdominal pain upper
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    9
    Vomiting
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 69 (15.94%)
         occurrences all number
    12
    Productive cough
         subjects affected / exposed
    5 / 69 (7.25%)
         occurrences all number
    7
    Oropharyngeal pain
         subjects affected / exposed
    8 / 69 (11.59%)
         occurrences all number
    9
    Dyspnoea
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Sputum increased
         subjects affected / exposed
    12 / 69 (17.39%)
         occurrences all number
    13
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    10
    Acne
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    22 / 69 (31.88%)
         occurrences all number
    22
    Influenza
         subjects affected / exposed
    6 / 69 (8.70%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    15 / 69 (21.74%)
         occurrences all number
    17
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    10 / 69 (14.49%)
         occurrences all number
    14
    Tonsillitis
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    4
    Rhinitis
         subjects affected / exposed
    7 / 69 (10.14%)
         occurrences all number
    11
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    4 / 69 (5.80%)
         occurrences all number
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2020
    Removed option for use of remote measures at certain study visits such that those visits are to be performed in the clinic; clarified different glomerular filtration rates for subjects ≥18 years of age and subjects <18 years of age; clarified that during in-clinic visits, spirometry assessments may be performed on more than 1 spirometer, as applicable; removed sweat chloride assessment at Week 4.
    26 Apr 2021
    Updated the definition of IGT to 2 hour post-OGTT blood glucose level ≥140 to <200 mg/dL (≥7.77 to <11.10 mmol/L) to eliminate a gap in glucose values in previous protocol versions, and to clarify both the glucose values (in mmol/L) and the dysglycemia categories; Updated the definition of CFRD to either fasting hyperglycemia (blood glucose level ≥126 mg/dL [≥7.00 mmol/L] after an 8 hour fast) or 2 hour post OGTT blood glucose level ≥200 mg/dL (≥11.10 mmol/L) to eliminate a gap in glucose values in previous protocol versions, and to clarify both the glucose values (in mmol/L) and the dysglycemia categories; Added a waiver of the Safety Follow-up Visit for subjects who complete the Week 48 Visit and transition to a commercially available CFTR modulator regimen within 28 days after the last dose of study drug, given the possibility of commercial availability of ELX/TEZ/IVA in certain countries.

    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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