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    Clinical Trial Results:
    Evaluation of the Efficacy and Safety of PTC299 in Hospitalized Subjects with COVID-19 (FITE19)

    Summary
    EudraCT number
    		 2020-001872-13
    Trial protocol
    		 PT   FR   BE   GR  
    Global end of trial date
    20 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2023
    First version publication date
    15 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PTC299-VIR-015-COV19
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04439071
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    PTC Therapeutics, Inc.
    Sponsor organisation address
    100 Corporate Court, South Plainfield, United States, NJ 07080
    Public contact
    Medical Information, PTC Therapeutics International Limited, +353 19068700, medinfo@ptcbio.com
    Scientific contact
    Medical Information, PTC Therapeutics, Inc., +011 44 1-866-562-4620, medinfo@ptcbio.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Jul 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the clinical efficacy of PTC299 compared with placebo assessed by time to respiratory improvement in adult participants hospitalized with COVID 19.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in conformance with the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidance documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Brazil: 85
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    Portugal: 18
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    189
    EEA total number of subjects
    86
    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)
    0
    Adults (18-64 years)
    155
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled at study sites in 7 countries (Australia, Belgium, Brazil, Mexico, Portugal, Spain, and United States.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PTC299
    Arm description
    		 Participants received PTC299 at 200 milligrams (mg), administered orally, twice daily (BID) on Days 1 to 7, then at 50 mg administered orally, once daily (QD) on Days 8 to 14.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PTC299
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTC299 was administered per dose and schedule specified in the arm description.

    Arm title
    		 Placebo
    Arm description
    		 Participants received PTC299-matching placebo administered orally, BID on Days 1 to 7, then administered orally, QD on Days 8 to 14.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    PTC299-matching placebo was administered per schedule specified in the arm description.

    Number of subjects in period 1
    		PTC299 Placebo
    Started
    94
    95
    Received at least 1 dose of study drug
    92
    95
    Completed
    80
    77
    Not completed
    14
    18
         Adverse event, serious fatal
    6
    4
         Consent withdrawn by subject
    3
    8
         Randomized but not treated
    2
    -
         Other than specified
    3
    3
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PTC299
    Reporting group description
    		 Participants received PTC299 at 200 milligrams (mg), administered orally, twice daily (BID) on Days 1 to 7, then at 50 mg administered orally, once daily (QD) on Days 8 to 14.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received PTC299-matching placebo administered orally, BID on Days 1 to 7, then administered orally, QD on Days 8 to 14.

    Reporting group values
    		 PTC299 Placebo Total
    Number of subjects
    		 94 95 189
    Age categorical
    Units: Subjects
        <65 years
    		 78 77 155
        ≥65 years
    		 16 18 34
    Sex: Female, Male
    Units: participants
        Female
    		 26 27 53
        Male
    		 68 68 136
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 4 6 10
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 6 1 7
        White
    		 71 69 140
        More than one race
    		 12 19 31
        Unknown or Not Reported
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 55 64 119
        Not Hispanic or Latino
    		 34 26 60
        Unknown or Not Reported
    		 5 5 10

    End points

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    End points reporting groups
    Reporting group title
    PTC299
    Reporting group description
    		 Participants received PTC299 at 200 milligrams (mg), administered orally, twice daily (BID) on Days 1 to 7, then at 50 mg administered orally, once daily (QD) on Days 8 to 14.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received PTC299-matching placebo administered orally, BID on Days 1 to 7, then administered orally, QD on Days 8 to 14.

    Primary: Time from Randomization to Respiratory Improvement

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    End point title
    		 Time from Randomization to Respiratory Improvement
    End point description
    Respiratory improvement was defined as sustained peripheral oxygen saturation (SpO2) ≥94% on room air. Median time to respiratory improvement was estimated via the Kaplan-Meier product limit method. Intent-to-treat (ITT) population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    73
    76
    Units: days
        median (confidence interval 95%)
    10.0 (6.0 to 15.0)
    10.0 (8.0 to 13.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Time to respiratory improvement was compared between treatment groups using stratified log-rank test.
    Comparison groups
    PTC299 v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.949
    Method
    		 Logrank
    Confidence interval

    Secondary: Number of Participants Requiring Invasive Ventilation

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    End point title
    		 Number of Participants Requiring Invasive Ventilation
    End point description
    Number of participants requiring invasive ventilation at any time during the study were reported. ITT population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    94
    95
    Units: participants
    16
    11
    No statistical analyses for this end point

    Secondary: Number of Participants Requiring Supplemental Oxygen or Non-Invasive Ventilation in Participants who did not Require Supplemental Oxygen at Baseline

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    End point title
    		 Number of Participants Requiring Supplemental Oxygen or Non-Invasive Ventilation in Participants who did not Require Supplemental Oxygen at Baseline
    End point description
    Number of participants requiring supplemental oxygen or non-invasive ventilation at any point during the study in participants who did not require supplemental oxygen at baseline were reported. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    24
    22
    Units: participants
    20
    19
    No statistical analyses for this end point

    Secondary: Time from Randomization to Defervescence in Participants Presenting With Fever at Enrollment (Temperature of ≥37.6℃ Axilla, ≥38.0℃ Oral, or ≥38.6°C Tympanic or Rectal)

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    End point title
    		 Time from Randomization to Defervescence in Participants Presenting With Fever at Enrollment (Temperature of ≥37.6℃ Axilla, ≥38.0℃ Oral, or ≥38.6°C Tympanic or Rectal)
    End point description
    Defervescence was defined as body temperature of <37.6° C axilla, <38.0° C oral, or <38.6° C tympanic or rectal without taking any antipyretic treatment and sustained until discharge or Day 28. Median time to defervescence was estimated via the Kaplan-Meier method. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. '99999' signifies "Due to smaller number of participants with an event, upper limit of 95% confidence interval (CI) could not be calculated".
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    31
    22
    Units: days
        median (confidence interval 95%)
    7.0 (5.0 to 28.0)
    18.0 (4.0 to 99999)
    No statistical analyses for this end point

    Secondary: Time from Randomization to Respiratory Rate ≤ 24 Breaths per Minute on Room Air

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    End point title
    		 Time from Randomization to Respiratory Rate ≤ 24 Breaths per Minute on Room Air
    End point description
    Median time to respiratory rate in participants who had abnormal respiratory rate at baseline was estimated via the Kaplan-Meier method. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    57
    62
    Units: days
        median (confidence interval 95%)
    7.0 (5.0 to 11.0)
    8.0 (6.0 to 11.0)
    No statistical analyses for this end point

    Secondary: Time from Randomization to Cough Reported as Mild or Absent

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    End point title
    		 Time from Randomization to Cough Reported as Mild or Absent
    End point description
    Cough was rated on a scale of severe, moderate, mild, absent, in those with cough at enrollment rated severe or moderate. Median time to cough reported as mild or absent was estimated via the Kaplan-Meier method. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    34
    34
    Units: days
        median (confidence interval 95%)
    3.0 (3.0 to 4.0)
    5.0 (3.0 to 7.0)
    No statistical analyses for this end point

    Secondary: Time from Randomization to Dyspnea Reported as Mild or Absent

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    End point title
    		 Time from Randomization to Dyspnea Reported as Mild or Absent
    End point description
    Dyspnea was rated on a scale of severe, moderate, mild, absent, in those with dyspnea at enrollment rated as severe or moderate. Median time to dyspnea reported as mild or absent was estimated via the Kaplan-Meier method. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    31
    35
    Units: days
        median (confidence interval 95%)
    6.0 (3.0 to 9.0)
    5.0 (4.0 to 7.0)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Cytokine Levels at Day 28

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    End point title
    		 Change From Baseline in Cytokine Levels at Day 28
    End point description
    Cytokines included Granulocyte Colony Stimulating factor; Interleukin 10, 17, 2, 6, 7; Macrophage Inflammatory Protein 1 Alpha; Monocyte Chemotactic Protein 1; and Tumor Necrosis Factor. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    66
    64
    Units: nanograms (ng)/liter (L)
    arithmetic mean (standard deviation)
        Granulocyte Colony Stimulating Factor
    -0.423 ( 0.4431 )
    -0.467 ( 0.4750 )
        Interleukin 10
    -0.367 ( 0.4655 )
    -0.491 ( 0.4003 )
        Interleukin 17
    0.018 ( 0.1447 )
    0.002 ( 0.1425 )
        Interleukin 2
    0.021 ( 0.0868 )
    0.022 ( 0.1448 )
        Interleukin 6
    -0.375 ( 0.5274 )
    -0.442 ( 0.5062 )
        Interleukin 7
    -0.025 ( 0.1233 )
    -0.035 ( 0.1556 )
        Macrophage Inflammatory Protein 1 Alpha
    0.072 ( 0.2459 )
    0.044 ( 0.1888 )
        Monocyte Chemotactic Protein 1
    -0.011 ( 0.4077 )
    0.018 ( 0.3804 )
        Tumor Necrosis Factor
    -0.015 ( 0.1509 )
    -0.027 ( 0.1666 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Level of Acute Phase Protein (C Reactive Protein) at Day 28

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    End point title
    		 Change From Baseline in Level of Acute Phase Protein (C Reactive Protein) at Day 28
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    51
    46
    Units: mg/L
        arithmetic mean (standard deviation)
    -1.027 ( 0.5966 )
    -1.111 ( 0.5633 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Level of Acute Phase Protein (D-Dimer) at Day 28

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    End point title
    		 Change From Baseline in Level of Acute Phase Protein (D-Dimer) at Day 28
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    48
    45
    Units: micrograms (µg)/L D-dimer units (DDU)
        arithmetic mean (standard deviation)
    0.029 ( 0.9278 )
    -0.121 ( 0.9392 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Level of Acute Phase Protein (Ferritin) at Day 28

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    End point title
    		 Change From Baseline in Level of Acute Phase Protein (Ferritin) at Day 28
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    47
    44
    Units: picomoles (pmol)/L
        arithmetic mean (standard deviation)
    -0.410 ( 0.3096 )
    -0.497 ( 0.3162 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Level of Acute Phase Proteins (Troponin I and Troponin T) at Day 28

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    End point title
    		 Change From Baseline in Level of Acute Phase Proteins (Troponin I and Troponin T) at Day 28
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    32
    18
    Units: µg/L
    arithmetic mean (standard deviation)
        Troponin I (n = 32, 18)
    0.080 ( 1.5879 )
    -0.036 ( 0.2128 )
        Troponin T (n = 8, 11)
    0.001 ( 0.0015 )
    0.061 ( 0.1638 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Normalization of Complete Blood Count (CBC) who had CBC Out of Range at Baseline

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    End point title
    		 Number of Participants With Normalization of Complete Blood Count (CBC) who had CBC Out of Range at Baseline
    End point description
    Number of participants who returned to normal range CBC were reported. CBC included red blood cell (RBC), hemoglobin (HGB), white blood cell (WBC), and Platelets. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    27
    26
    Units: participants
        RBC (n = 13, 18)
    7
    13
        HGB (n = 13, 18)
    9
    13
        WBC (n = 27, 19)
    22
    17
        Platelets (n = 26, 26)
    21
    19
    No statistical analyses for this end point

    Secondary: Change From Baseline in Viral Load at Day 28: SARS-CoV-2 Immunoglobulin A (IgA) Antibody Ratio and SARS-CoV-2 Immunoglobulin G (IgG) Antibody Ratio

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    End point title
    		 Change From Baseline in Viral Load at Day 28: SARS-CoV-2 Immunoglobulin A (IgA) Antibody Ratio and SARS-CoV-2 Immunoglobulin G (IgG) Antibody Ratio
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable for specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    50
    49
    Units: ratio
    arithmetic mean (standard deviation)
        SARS-CoV-2 IgA Antibody Ratio (n=49,49)
    0.003 ( 0.6387 )
    0.165 ( 0.5122 )
        SARS-CoV-2 IgG Antibody Ratio (n=50,47)
    0.890 ( 0.6846 )
    0.874 ( 0.7604 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Viral Load at Day 28: SARS-CoV-2 IgM Antibody Absorbance

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    End point title
    		 Change From Baseline in Viral Load at Day 28: SARS-CoV-2 IgM Antibody Absorbance
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    45
    47
    Units: absorbance (Abs)
        arithmetic mean (standard deviation)
    0.000 ( 0.4691 )
    0.127 ( 0.4218 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Viral Load at Day 28: SARS-CoV2 v2, SARS-CoV2 v2 Nasopharyngeal Swab (NPsw), and Severe Acute Resp Syndrome Coronavirus 2

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    End point title
    		 Change From Baseline in Viral Load at Day 28: SARS-CoV2 v2, SARS-CoV2 v2 Nasopharyngeal Swab (NPsw), and Severe Acute Resp Syndrome Coronavirus 2
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable for specified category. '99999' signifies "data not available since no participant was analyzed". '9999' signifies "due to single participant, standard deviation (SD) could not be calculated".
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    4
    2
    Units: copies/mL
    arithmetic mean (standard deviation)
        SARS-CoV2 v2 (n = 0, 2)
    99999 ( 99999 )
    -0.345 ( 0.2235 )
        SARS-CoV2 v2 NPsw (n = 4, 1)
    -1.201 ( 0.7503 )
    1.532 ( 9999 )
        SARS Coronavirus 2 (n = 1, 0)
    -0.432 ( 9999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Duration of Hospitalization

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    End point title
    		 Duration of Hospitalization
    End point description
    ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    77
    83
    Units: days
        arithmetic mean (standard deviation)
    8.1 ( 4.87 )
    9.3 ( 5.49 )
    No statistical analyses for this end point

    Secondary: Number of Mortalities at Day 28

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    End point title
    		 Number of Mortalities at Day 28
    End point description
    Mortality was defined as a death event occurring at anytime before the specific date, after the first dose has been received. Safety population included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    92
    95
    Units: participants
    6
    4
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An AE was as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. SAE: an AE that met at least 1 of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, congenital anomaly/birth defect, important medical event. TEAEs were defined as any AEs that occurred on or after the first study treatment through 30 days after the last dose, or any AEs occurring before the first study treatment but worsening during the treatment through 30 days after the last dose. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the ‘Reported Adverse Events’ Section. Safety population included all randomized participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to Day 60
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    92
    95
    Units: participants
    52
    67
    No statistical analyses for this end point

    Other pre-specified: Time from Randomization to Respiratory Improvement Where Symptom Onset Occurred ≤5 Days

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    End point title
    		 Time from Randomization to Respiratory Improvement Where Symptom Onset Occurred ≤5 Days
    End point description
    Respiratory improvement was defined as SpO2 ≥94% on room air. Median time to respiratory improvement was estimated via the Kaplan-Meier product limit method. ITT population included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint. '99999' signifies "Due to smaller number of participants with an event, upper limit of 95% CI could not be calculated."
    End point type
    Other pre-specified
    End point timeframe
    up to Day 28
    End point values
    		 PTC299 Placebo
    Number of subjects analysed
    13
    10
    Units: days
        median (confidence interval 95%)
    10.0 (4.0 to 28.0)
    28.0 (7.0 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Time to respiratory improvement was compared between treatment groups using stratified log-rank test.
    Comparison groups
    PTC299 v Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.033
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to Day 60
    Adverse event reporting additional description
    Safety population included all randomized participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received PTC299-matching placebo administered orally, BID on Days 1 to 7, then administered orally, QD on Days 8 to 14.

    Reporting group title
    PTC299
    Reporting group description
    		 Participants received PTC299 at 200 mg, administered orally, BID on Days 1 to 7, then at 50 mg administered orally, QD on Days 8 to 14.

    Serious adverse events
    		 Placebo PTC299
    Total subjects affected by serious adverse events
         subjects affected / exposed
    24 / 95 (25.26%)
    21 / 92 (22.83%)
         number of deaths (all causes)
    4
    9
         number of deaths resulting from adverse events
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 95 (2.11%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral ischaemia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    2 / 95 (2.11%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    2 / 95 (2.11%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    8 / 95 (8.42%)
    10 / 92 (10.87%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Organising pneumonia
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 95 (3.16%)
    3 / 92 (3.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 95 (3.16%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 95 (2.11%)
    4 / 92 (4.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (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
    Septic shock
         subjects affected / exposed
    1 / 95 (1.05%)
    4 / 92 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pneumonia acinetobacter
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 95 (0.00%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 95 (1.05%)
    1 / 92 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacteraemia
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (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
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 95 (1.05%)
    2 / 92 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 95 (1.05%)
    0 / 92 (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
    		 Placebo PTC299
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 95 (66.32%)
    50 / 92 (54.35%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    16 / 95 (16.84%)
    14 / 92 (15.22%)
         occurrences all number
    25
    18
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 95 (12.63%)
    12 / 92 (13.04%)
         occurrences all number
    14
    15
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 92 (4.35%)
         occurrences all number
    9
    8
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 95 (2.11%)
    7 / 92 (7.61%)
         occurrences all number
    3
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 95 (5.26%)
    2 / 92 (2.17%)
         occurrences all number
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 95 (3.16%)
    8 / 92 (8.70%)
         occurrences all number
    11
    10
    Lymphopenia
         subjects affected / exposed
    6 / 95 (6.32%)
    4 / 92 (4.35%)
         occurrences all number
    9
    5
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    9 / 95 (9.47%)
    3 / 92 (3.26%)
         occurrences all number
    11
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 95 (12.63%)
    10 / 92 (10.87%)
         occurrences all number
    13
    10
    Diarrhoea
         subjects affected / exposed
    5 / 95 (5.26%)
    3 / 92 (3.26%)
         occurrences all number
    5
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 95 (5.26%)
    2 / 92 (2.17%)
         occurrences all number
    5
    2
    Insomnia
         subjects affected / exposed
    6 / 95 (6.32%)
    2 / 92 (2.17%)
         occurrences all number
    6
    2
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    2 / 95 (2.11%)
    6 / 92 (6.52%)
         occurrences all number
    2
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2020
    It included following changes: - The protocol was updated throughout to replace the standard of care (SOC) comparison arm with placebo control. - The primary objective was updated to be the time to respiratory improvement. - The primary endpoint was updated, consistent with the new primary objective. - For those secondary endpoints recording time to improvement, it was clarified that the time starts at randomization. Clarification was added on the cough severity scale. D-dimer and cardiac troponin were specified in the list of potential acute phase proteins to be assessed. - The study design was updated to reflect the change to a placebo-controlled, double blind study and to include stratification by remdesivir, prohibition of sensitive CYP2D6 substrates and investigational therapies, an increased sample size, and the addition of the Day 60 safety telephone call. - The study population size was increased. - Exclusion criterion was changed to exclude participants with ≥3 × upper limit of normal (ULN) alanine transaminase (ALT) or aspartate aminotransferase (AST) or ≥2 × ULN Tbili. - Exclusion criterion was added to exclude participants with low lymphocyte count or hemoglobin levels. - A recommendation to take PTC299 with food was added. - A safety telephone call at Day 60 was added and clarification was added around Screening and Day 1 occurring on the same day or 1 day apart. - Clarification was added that vital signs are part of safety assessments.
    05 Jun 2020
    It included following changes: - The primary endpoint was amended to the time from randomization to respiratory improvement, defined as peripheral oxygen saturation (SpO2) ≥94% on room air sustained until discharge from the hospital or the end of the study (Day 28). - The study design was amended to reflect changes made elsewhere, namely exclusion of CYP2C inducers, inclusion of the Hepatic Advisory Safety Committee (HAC), and addition of the interim analysis for futility.
    23 Jul 2020
    It included following changes: - The number of sites was increased to approximately 40. - An error in the number of study participants was corrected. - Stratification factors were amended to remove hydroxychloroquine and add dexamethasone. - Exclusion criterion was amended to clarify that participation in interventional studies is not permitted. - Exclusion criterion was amended to permit use of dexamethasone.
    08 Oct 2020
    It included following changes: - Clarification was added that the secondary endpoint of time from randomization to defervescence applies only to subjects with fever at enrollment. - Inclusion criterion, requiring participants to present with fever, was removed. - Exclusion Criterion was modified to exclude participants with lymphocyte count <500 lymphocytes/microliter (μL) and any participant with hemoglobin <11.0 grams (g)/deciliter (dL).
    18 Dec 2020
    It included following changes: - In Inclusion criterion, the window for symptom onset prior to Screening was changed from 7 to 10 days. - Clarification was added that transfer to intensive care unit (ICU), mechanical ventilation, or another medically important event (at the discretion of the investigator) as a result of disease progression would be classified as an SAE. - Text was amended to clarify that the first interim analysis would be after the first 40 participants reached Day 28 or died, withdrew consent, or were lost to follow-up and to clarify those participants who would be censored.
    02 Jun 2021
    It included following changes: - The new nonproprietary name was added. - The number of sites was increased to approximately 50. - Inclusion criterion was changed to allow symptom onset ≤14 days. - Hepatic abnormalities of Grade ≥4 will be considered unexpected adverse events.

    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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