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    Clinical Trial Results:
    A Multicenter, Phase III Randomized, Double-Blind, Placebo-Controlled, Outpatient Study to Evaluate the Efficacy, Safety, Antiviral Activity of RO7496998 (AT-527) in Patients With Mild or Moderate COVID-19

    Summary
    EudraCT number
    2020-005759-18
    Trial protocol
    DE   BE   DK   FR   PT   IT   RO  
    Global end of trial date
    02 Dec 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jun 2022
    First version publication date
    15 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV43043
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04889040
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002963-PIP01-21
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of RO7496998 (AT-527) compared with placebo
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Apr 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Brazil: 17
    Country: Number of subjects enrolled
    Japan: 39
    Country: Number of subjects enrolled
    Mexico: 32
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Turkey: 35
    Country: Number of subjects enrolled
    Ukraine: 42
    Worldwide total number of subjects
    216
    EEA total number of subjects
    39
    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)
    3
    Adults (18-64 years)
    201
    From 65 to 84 years
    11
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were non-hospitalized, with mild to moderate COVID-19, with or without risk factors for severe disease.

    Pre-assignment
    Screening details
    216 subjects were enrolled in the study and 212 subjects received either AT-527 or matching placebo.

    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
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    The dose and regimen of the placebo will match that of AT-527.
    Arm type
    Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose and regimen of the placebo will match that of AT-527.

    Arm title
    RO7496998 (AT-527)
    Arm description
    Orally administered, 550 mg twice daily (BID) for 5 days
    Arm type
    Experimental

    Investigational medicinal product name
    AT-527
    Investigational medicinal product code
    Other name
    RO7496998
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    550 mg twice daily (BID) for 5 days

    Number of subjects in period 1
    Placebo RO7496998 (AT-527)
    Started
    73
    143
    Received Treatment
    71
    141
    Completed
    68
    138
    Not completed
    5
    5
         Adverse event, non-fatal
    2
    1
         Consent withdrawn by subject
    3
    3
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    The dose and regimen of the placebo will match that of AT-527.

    Reporting group title
    RO7496998 (AT-527)
    Reporting group description
    Orally administered, 550 mg twice daily (BID) for 5 days

    Reporting group values
    Placebo RO7496998 (AT-527) Total
    Number of subjects
    73 143 216
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    2 1 3
        Adults (18-64 years)
    66 135 201
        From 65-84 years
    4 7 11
        85 years and over
    1 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.7 ± 14.9 41.1 ± 13.2 -
    Sex: Female, Male
    Units:
        Female
    32 62 94
        Male
    41 81 122
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    6 9 15
        Asian
    14 26 40
        Native Hawaiian or Other Pacific Islander
    1 0 1
        Black or African American
    1 3 4
        White
    50 105 155
        More than one race
    0 0 0
        Unknown or Not Reported
    1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    The dose and regimen of the placebo will match that of AT-527.

    Reporting group title
    RO7496998 (AT-527)
    Reporting group description
    Orally administered, 550 mg twice daily (BID) for 5 days

    Primary: Time to Alleviation or Improvement of COVID-19 Symptoms (21.5 hours)

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    End point title
    Time to Alleviation or Improvement of COVID-19 Symptoms (21.5 hours) [1]
    End point description
    COVID-19 symptoms will be evaluated using the COVID-19 Symptom Diary (questions 1-12). The severity of each COVID-19 symptom will be recorded on a Likert scale (i.e none/mild/moderate/severe). The time to alleviation or improvement of COVID-19 symptoms is defined as follows: for new symptoms, it is defined as the length of time taken from randomization to the point at which a Score of 0 or 1 has been maintained for a duration of at least 21.5 hours. For preexisting symptoms, it is defined as the time from randomization to when a patient's symptoms have been maintained or improved (requires at least a single category improvement from baseline on the COVID-19 Symptom Diary Likert scale) for a duration of 21.5 hours.
    End point type
    Primary
    End point timeframe
    Up to 29 days
    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: Due to early trial termination, the targeted enrolment numbers were not reached and no meaningful statistical analyses could be performed.
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: hours
        median (confidence interval 97.5%)
    73.7 (47.1 to 105.8)
    94.5 (68.1 to 131.7)
    No statistical analyses for this end point

    Secondary: Time to Alleviation or Improvement of COVID-19 Symptoms (43 hours)

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    End point title
    Time to Alleviation or Improvement of COVID-19 Symptoms (43 hours)
    End point description
    COVID-19 symptoms will be evaluated using the COVID-19 Symptom Diary (questions 1-12). The severity of each COVID-19 symptom will be recorded on a Likert scale (i.e none/mild/moderate/severe). The time to alleviation or improvement of COVID-19 symptoms is defined as follows: for new symptoms, it is defined as the length of time taken from randomization to the point at which a Score of 0 or 1 has been maintained for a duration of at least 43 hours. For preexisting symptoms, it is defined as the time from randomization to when a patient's symptoms have been maintained or improved (requires at least a single category improvement from baseline on the COVID-19 Symptom Diary Likert scale) for a duration of 43 hours.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: hours
        median (confidence interval 97.5%)
    79.6 (55.7 to 108.2)
    109.5 (83.8 to 147.5)
    No statistical analyses for this end point

    Secondary: Time to Alleviation of COVID-19 Symptoms (21.5 hours)

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    End point title
    Time to Alleviation of COVID-19 Symptoms (21.5 hours)
    End point description
    Time from randomization to the point at which the following criterion is met and maintained for at least 21.5 hours. - Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: hours
        median (confidence interval 97.5%)
    73.7 (47.1 to 105.8)
    94.5 (68.1 to 131.7)
    No statistical analyses for this end point

    Secondary: Time to Alleviation of COVID-19 Symptoms (43 hours)

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    End point title
    Time to Alleviation of COVID-19 Symptoms (43 hours)
    End point description
    Time from randomization to the point at which the following criterion is met and maintained for at least 43 hours. - Score of 0 or 1 on Items 1-12 of the COVID-19 Symptom Diary.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: hours
        median (confidence interval 97.5%)
    79.6 (55.7 to 108.2)
    109.5 (83.8 to 147.5)
    No statistical analyses for this end point

    Secondary: Time to One-Category Improvement of Baseline Presenting COVID-19 Symptoms

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    End point title
    Time to One-Category Improvement of Baseline Presenting COVID-19 Symptoms
    End point description
    Time from randomization to the point at which symptoms (Items 1-12 of the COVID-19 Symptom Diary) have improved by at least one category from baseline on the COVID-19 Symptom Diary Likert scale, maintained for at least 21.5 hours.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    68
    130
    Units: hours
        median (confidence interval 97.5%)
    70.9 (41.8 to 91.8)
    81.5 (60.5 to 119.9)
    No statistical analyses for this end point

    Secondary: Time to Alleviation of Individual Symptoms

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    End point title
    Time to Alleviation of Individual Symptoms
    End point description
    Time from randomization to the point at which the following criterion is met and maintained (for each individual symptom) for at least 21.5 hours. - Score of 0 or 1 for Items 1-14 of the COVID-19 Symptom Diary Here 99999 or 0.99999 represents values that were not evaluable due to an insufficient number of events.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: hours
    median (confidence interval 97.5%)
        Nasal Congestion or Runny Nose
    36.4 (23.4 to 60.6)
    37.3 (23.4 to 57.6)
        Sore Throat
    45.6 (23.4 to 75.1)
    33.2 (20.9 to 54.3)
        Cough
    37.6 (26.8 to 118.7)
    49.5 (28.4 to 106.4)
        Shortness of Breath
    24.0 (11.8 to 106.8)
    47.5 (32.4 to 96.8)
        Muscle or Body Aches
    35.3 (14.3 to 59.4)
    44.9 (33.1 to 53.0)
        Fatigue
    66.6 (36.5 to 118.9)
    61.3 (47.1 to 108.1)
        Headache
    23.2 (14.5 to 41.8)
    41.4 (24.4 to 59.5)
        Chills/Sweats
    36.0 (22.5 to 57.6)
    39.0 (28.4 to 50.5)
        Feeling Hot or Feverish
    24.6 (16.4 to 66.7)
    36.2 (19.7 to 61.4)
        Nausea
    31.4 (11.1 to 99999)
    43.5 (22.6 to 73.4)
        Vomiting
    20.1 (16.4 to 99999)
    33.0 (0.99999 to 99999)
        Diarrhea
    17.6 (14.9 to 73.6)
    66.7 (19.8 to 107.2)
        Sense of Smell
    132.6 (84.3 to 229.0)
    104.9 (72.6 to 206.0)
        Sense of Taste
    128.9 (84.3 to 202.2)
    155.7 (52.5 to 371.7)
    No statistical analyses for this end point

    Secondary: Proportion of Participants Requiring Hospitalization for COVID-19

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    End point title
    Proportion of Participants Requiring Hospitalization for COVID-19
    End point description
    Hospitalizations for COVID-19 are defined as SAEs for which the investigator has cited that the suspected cause was the disease under study and where there is a non-missing hospital admission date.
    End point type
    Secondary
    End point timeframe
    Up to Day 33 visit
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: percentage of participants
        number (confidence interval 97.5%)
    10.0 (1.25 to 18.75)
    2.9 (0.00 to 6.51)
    No statistical analyses for this end point

    Secondary: Proportion of Participants with Greater than or Equal to 1 COVID-19 Related Medically Attended Visit

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    End point title
    Proportion of Participants with Greater than or Equal to 1 COVID-19 Related Medically Attended Visit
    End point description
    Medically attended visit is defined as hospitalization, emergency room (ER) visit, urgent care visit, physician’s office visit, or telemedicine visit, with the primary reason for the visit being COVID-19.
    End point type
    Secondary
    End point timeframe
    Up to Day 33 visit
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: percentage of participants
        number (confidence interval 97.5%)
    14.3 (4.20 to 24.37)
    10.2 (4.05 to 16.38)
    No statistical analyses for this end point

    Secondary: Duration of Fever

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    End point title
    Duration of Fever
    End point description
    Time to return to an afebrile state (temperature ≤ 37.5°C) maintained for at least 21.5 hours in patients with a fever at baseline.
    End point type
    Secondary
    End point timeframe
    Up to 29 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    12
    20
    Units: hours
        median (confidence interval 97.5%)
    47.3 (12.6 to 82.2)
    55.7 (25.9 to 96.4)
    No statistical analyses for this end point

    Secondary: Frequency of COVID-19 Related Complications

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    End point title
    Frequency of COVID-19 Related Complications
    End point description
    COVID-related complications are defined as death, hospitalization, pneumonia, sepsis, coagulopathy, pericarditis/myocarditis and cardiac failure. Pneumonia, acute respiratory failure, sepsis, coagulopathy, pericarditis/myocarditis, and cardiac failure were adjudicated per blinded manual medical review of events by an internal adjudication team before study readout.
    End point type
    Secondary
    End point timeframe
    Up to Day 33 visit
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: percentage of participants
        number (confidence interval 97.5%)
    10.0 (1.25 to 18.75)
    4.4 (0.10 to 8.66)
    No statistical analyses for this end point

    Secondary: Proportion of Participants with any Post-Treatment Infection

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    End point title
    Proportion of Participants with any Post-Treatment Infection
    End point description
    Post-treatment infections were defined as any treatment-emergent adverse event with a primary system organ class of infections and infestations.
    End point type
    Secondary
    End point timeframe
    Up to Day 33 visit
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: percentage of participants
        number (confidence interval 97.5%)
    14.3 (4.20 to 24.37)
    9.5 (3.51 to 15.47)
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Amount of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus RNA

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    End point title
    Change from Baseline in the Amount of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Virus RNA
    End point description
    SARS-CoV-2 virus RNA will be measured by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR)
    End point type
    Secondary
    End point timeframe
    Baseline and on Days 3, 5, 7 and 14
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: log10 copies/mL
    arithmetic mean (standard deviation)
        Baseline
    6.49 ± 1.61
    6.59 ± 1.54
        Day 3
    -1.05 ± 1.06
    -1.07 ± 1.16
        Day 5
    -2.24 ± 1.40
    -2.01 ± 1.50
        Day 7
    -3.10 ± 1.38
    -2.98 ± 1.66
        Day 14
    -4.21 ± 1.64
    -4.25 ± 1.64
    No statistical analyses for this end point

    Secondary: Time to Cessation of SARS-CoV-2 Viral Shedding

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    End point title
    Time to Cessation of SARS-CoV-2 Viral Shedding
    End point description
    Defined as time from randomization to the first time when a negative qualitative virus RNA by RT-PCR test result is obtained. Here 99999 represents data that were not evaluable.
    End point type
    Secondary
    End point timeframe
    Up to 14 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: days
        median (confidence interval 97.5%)
    13.0 (12.8 to 99999)
    13.0 (13.0 to 13.1)
    No statistical analyses for this end point

    Secondary: Proportion of Participants Positive for SARS-CoV-2 Virus RNA at Specified Timepoints

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    End point title
    Proportion of Participants Positive for SARS-CoV-2 Virus RNA at Specified Timepoints
    End point description
    Defined as proportion of patients with a positive qualitative virus RNA by RT-PCR.
    End point type
    Secondary
    End point timeframe
    Baseline and on Days 3, 5, 7 and 14
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    70
    137
    Units: percentage of participants
    number (not applicable)
        Baseline
    97.1
    100
        Day 3
    98.5
    96.4
        Day 5
    89.7
    91.9
        Day 7
    74.6
    76.3
        Day 14
    43.9
    34.4
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) in the Amount of SARS-CoV-2 Virus RNA

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    End point title
    Area Under the Curve (AUC) in the Amount of SARS-CoV-2 Virus RNA
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 14 days
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    69
    137
    Units: log10 copies/mL*hour
        arithmetic mean (standard deviation)
    1122.39 ± 339.70
    1174.30 ± 377.49
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs)

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    End point title
    Percentage of Participants with Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 33 visit
    End point values
    Placebo RO7496998 (AT-527)
    Number of subjects analysed
    71
    141
    Units: percentage of participants
        number (not applicable)
    36.6
    39.0
    No statistical analyses for this end point

    Secondary: Plasma Concentration of AT-511 at Specified Timepoints

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    End point title
    Plasma Concentration of AT-511 at Specified Timepoints [2]
    End point description
    AT-511 is the free base form of RO7496998 (AT-527).
    End point type
    Secondary
    End point timeframe
    Up to 7 days
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint.
    End point values
    RO7496998 (AT-527)
    Number of subjects analysed
    137
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, 0 hour
    17.4 ± 158.6
        Day 1, 1 hour
    1456.8 ± 1757.7
        Day 1, 2 hours
    1029.3 ± 1085.5
        Day 1, 4 hours
    206.3 ± 289.5
        Day 5, 0 hour
    52.8 ± 271.0
        Day 5, 1 hour
    1659.0 ± 2213.9
        Day 5, 2 hours
    1934.5 ± 2210.6
        Day 5, 4 hours
    202.3 ± 310.7
        Day 5, 8 hours
    8.8 ± 9.5
        Day 5, 48 hours
    4.6 ± 40.9
    No statistical analyses for this end point

    Secondary: Plasma Concentration of AT-551 at Specified Timepoints

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    End point title
    Plasma Concentration of AT-551 at Specified Timepoints [3]
    End point description
    AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
    End point type
    Secondary
    End point timeframe
    Up to 7 days
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint.
    End point values
    RO7496998 (AT-527)
    Number of subjects analysed
    137
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, 0 hour
    1.9 ± 12.2
        Day 1, 1 hour
    166.9 ± 209.8
        Day 1, 2 hours
    335.7 ± 257.6
        Day 1, 4 hours
    195.0 ± 146.4
        Day 5, 0 hour
    49.1 ± 65.0
        Day 5, 1 hour
    150.2 ± 144.5
        Day 5, 2 hours
    213.6 ± 201.7
        Day 5, 4 hours
    138.8 ± 136.2
        Day 5, 8 hours
    27.5 ± 17.5
        Day 5, 48 hours
    2.6 ± 5.2
    No statistical analyses for this end point

    Secondary: Plasma Concentration of AT-229 at Specified Timepoints

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    End point title
    Plasma Concentration of AT-229 at Specified Timepoints [4]
    End point description
    AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
    End point type
    Secondary
    End point timeframe
    Up to 7 days
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint.
    End point values
    RO7496998 (AT-527)
    Number of subjects analysed
    137
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, 0 hour
    2.2 ± 18.4
        Day 1, 1 hour
    123.6 ± 172.5
        Day 1, 2 hours
    507.8 ± 497.5
        Day 1, 4 hours
    354.4 ± 259.2
        Day 5, 0 hour
    367.8 ± 259.1
        Day 5, 1 hour
    418.0 ± 257.6
        Day 5, 2 hours
    454.3 ± 331.7
        Day 5, 4 hours
    490.1 ± 296.4
        Day 5, 8 hours
    279.6 ± 176.0
        Day 5, 48 hours
    118.7 ± 127.2
    No statistical analyses for this end point

    Secondary: Plasma Concentration of AT-273 at Specified Timepoints

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    End point title
    Plasma Concentration of AT-273 at Specified Timepoints [5]
    End point description
    AT-511 is the free base form of RO7496998 (AT-527). Major metabolites are AT-551, AT-229, and AT-273 (a surrogate for the intracellular concentration of the active triphosphate metabolite AT-9010)
    End point type
    Secondary
    End point timeframe
    Up to 7 days
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Plasma concentrations were measured in subjects that received AT-527. Therefore the placebo arm was excluded from this endpoint.
    End point values
    RO7496998 (AT-527)
    Number of subjects analysed
    137
    Units: nanograms per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Day 1, 0 hour
    0.7 ± 2.5
        Day 1, 1 hour
    15.5 ± 26.9
        Day 1, 2 hours
    135.1 ± 136.2
        Day 1, 4 hours
    173.5 ± 120.6
        Day 5, 0 hour
    149.8 ± 78.1
        Day 5, 1 hour
    141.7 ± 72.7
        Day 5, 2 hours
    108.8 ± 61.0
        Day 5, 4 hours
    172.7 ± 129.2
        Day 5, 8 hours
    118.6 ± 80.2
        Day 5, 48 hours
    48.4 ± 32.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to the Day 33 visit
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.1.
    Reporting groups
    Reporting group title
    AT-527
    Reporting group description
    Orally administered, 550 mg twice daily (BID) for 5 days

    Reporting group title
    Placebo
    Reporting group description
    The dose and regimen of the placebo will match that of AT-527.

    Serious adverse events
    AT-527 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 141 (3.55%)
    7 / 71 (9.86%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 71 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 71 (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
    COVID-19
         subjects affected / exposed
    2 / 141 (1.42%)
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 141 (0.71%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 141 (0.71%)
    4 / 71 (5.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    AT-527 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 141 (7.80%)
    5 / 71 (7.04%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 141 (2.84%)
    5 / 71 (7.04%)
         occurrences all number
    4
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 141 (5.67%)
    0 / 71 (0.00%)
         occurrences all number
    8
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2021
    The purpose of this update was to address the feedback and questions received as part of a multinational clinical trial authorization application process.
    02 Jun 2021
    Major updates included Study Rationale and Benefit-Risk Assessment, addition of 2 additional efficacy endpoints, updated number of study sites and eligibility criteria.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Dec 2021
    The study was terminated with 16% of the planned sample size with enrollment initially paused on 29 October 2021. Subsequently, study CV43043 was terminated early on 07 December 2021 due to program level decisions. The LPLV was 02 December 2021.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated with only 16% of the planned sample size.
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