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    Clinical Trial Results:
    A Phase 3 randomized, multi-center, open label study to assess the efficacy, safety, and tolerability of monoclonal antibody VIR-7831 (sotrovimab) given intramuscularly versus intravenously for the treatment of mild/moderate coronavirus disease 2019 (COVID-19) in high-risk non-hospitalized patients

    Summary
    EudraCT number
    		 2021-000623-13
    Trial protocol
    		 FR   AT   IT  
    Global end of trial date
    10 May 2022

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

    Trial information

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    Trial identification
    Sponsor protocol code
    VIR-7831-5008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04913675
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 GSK: 217114
    Sponsors
    Sponsor organisation name
    Vir Biotechnology, Inc.
    Sponsor organisation address
    499 Illinois St , San Francisco , United States, 94158
    Public contact
    n/a, Vir Biotechnology, Inc. , 1415 654-5281, clinicaltrials@vir.bio
    Scientific contact
    n/a, Vir Biotechnology, Inc. , 1415 654-5281, clinicaltrials@vir.bio
    Sponsor organisation name
    Vir Biotechnology, Inc.
    Sponsor organisation address
    499 Illinois St , San Francisco , United States, 94158
    Public contact
    n/a, GlaxoSmithKline (Ireland) Limited, 1415 6545281, na.na@na.com, 1415 654-5281, clinicaltrials@vir.bio
    Scientific contact
    n/a, GlaxoSmithKline (Ireland) Limited, 1415 6545281, na.na@na.com, 1415 654-5281, clinicaltrials@vir.bio
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002899-PIP01-20
    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
    07 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy of two dose levels of intramuscular (IM) VIR-7831 versus (vs) intravenous (IV) VIR-7831 in preventing the progression of mild/moderate COVID-19
    Protection of trial subjects
    N/A
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 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
    Ukraine: 2
    Country: Number of subjects enrolled
    United States: 981
    Worldwide total number of subjects
    983
    EEA total number of subjects
    0
    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)
    750
    From 65 to 84 years
    217
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, open label, non-inferiority study of intramuscular (IM) versus intravenous (IV) administration of sotrovimab (VIR-7831), a monoclonal antibody against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) for the treatment of mild/moderate coronavirus disease 2019 (COVID-19) in participants aged 12 years and older.

    Pre-assignment
    Screening details
    		 A total of 983 participants were enrolled in this study, of which 10 participants did not receive study intervention. Safety Population (973 participants) consisted of all randomized participants who were exposed to study intervention.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sotrovimab 500 mg IV
    Arm description
    		 Participants received a single dose of sotrovimab 500 milligram (mg), IV infusion over 15 minutes on Day 1.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sotrovimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Sotrovimab was administered IV infusion in a single dose

    Arm title
    		 Sotrovimab 500 mg IM
    Arm description
    		 Participants received a single dose of sotrovimab 500 mg, IM dose as 2*4 milliliter (mL) injections in each dorsogluteal muscle on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotrovimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Sotrovimab was administered IM injection in a single dose

    Arm title
    		 Sotrovimab 250 mg IM
    Arm description
    		 Participants received a single dose of sotrovimab 250 mg, IM dose either as a single 250 mg (4 mL) injection in the dorsogluteal muscle or as 2*2 mL injections in each deltoid muscle on Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotrovimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Sotrovimab was administered IM injection in a single dose

    Number of subjects in period 1 [1]
    		Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Started
    393
    385
    195
    Completed
    356
    341
    176
    Not completed
    37
    44
    19
         Consent withdrawn by subject
    25
    33
    12
         Physician decision
    -
    1
    1
         Death
    -
    2
    2
         Lost to follow-up
    12
    8
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 983 participants were enrolled in the study, of which 10 participants did not receive study treatment. Hence, 973 participants were considered in the Safety Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sotrovimab 500 mg IV
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 milligram (mg), IV infusion over 15 minutes on Day 1.

    Reporting group title
    Sotrovimab 500 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 mg, IM dose as 2*4 milliliter (mL) injections in each dorsogluteal muscle on Day 1.

    Reporting group title
    Sotrovimab 250 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 250 mg, IM dose either as a single 250 mg (4 mL) injection in the dorsogluteal muscle or as 2*2 mL injections in each deltoid muscle on Day 1.

    Reporting group values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM Total
    Number of subjects
    		 393 385 195 973
    Age categorical
    Units: Subjects
        All Participants
    		 393 385 195 973
    Age continuous
    Baseline characteristics were reported for Safety Population which consisted of all randomized participants who were exposed to study intervention.
    Units: years
        arithmetic mean (standard deviation)
    		 50.8 ± 16.69 51.2 ± 16.77 48.3 ± 16.00 -
    Gender categorical
    Baseline characteristics were used for Safety Population which consisted of all randomized participants who were exposed to study intervention.
    Units: Subjects
        Female
    		 224 197 113 534
        Male
    		 169 188 82 439
    Race/ Ethnicity, Customized
    Baseline characteristics were used for Safety Population which consisted of all randomized participants who were exposed to study intervention.
    Units: Subjects
        Asian - Central/South Asian Heritage
    		 1 2 0 3
        Asian - South East Asian Heritage
    		 0 1 0 1
        Black or African American
    		 17 19 8 44
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        White - Arabic/North African Heritage
    		 10 21 8 39
        White - White/Caucasian/European
    		 362 336 176 874
        Mixed Race
    		 1 2 1 4
        Unknown
    		 0 3 1 4
        Missing
    		 1 1 1 3

    End points

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    End points reporting groups
    Reporting group title
    Sotrovimab 500 mg IV
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 milligram (mg), IV infusion over 15 minutes on Day 1.

    Reporting group title
    Sotrovimab 500 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 mg, IM dose as 2*4 milliliter (mL) injections in each dorsogluteal muscle on Day 1.

    Reporting group title
    Sotrovimab 250 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 250 mg, IM dose either as a single 250 mg (4 mL) injection in the dorsogluteal muscle or as 2*2 mL injections in each deltoid muscle on Day 1.

    Primary: Percentage of Participants who had Progression of COVID-19 through Day 29 by Hospitalization >24 hours or Death due to any cause (Weekly and Daily Imputation)

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    End point title
    		 Percentage of Participants who had Progression of COVID-19 through Day 29 by Hospitalization >24 hours or Death due to any cause (Weekly and Daily Imputation)
    End point description
    Progression of COVID-19 through Day 29 as defined by hospitalization >24 hours for acute management of illness due to any cause or death. Percentage values are rounded off. Primary Analysis Population consisted of all randomized participants excluding participants who were randomized under Protocol Amendment Version 1 and were immunocompetent and fully vaccinated at randomization and participants who did not meet key eligibility criteria. The statistical analysis was performed only for 500 mg IV versus 500 mg IM dose. It was not planned for 250 mg IM dose per statistical analysis plan.
    End point type
    Primary
    End point timeframe
    Up to Day 29
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    378
    376
    183
    Units: Percentage of participants
        number (not applicable)
    1.3
    2.7
    5.5
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis was performed using a binomial regression model with identity link function and with treatment (Sotrovimab 500mg IM, 500mg IV), age (<65, =>65 years old) and gender (male, female) as covariates.
    Comparison groups
    Sotrovimab 500 mg IV v Sotrovimab 500 mg IM
    Number of subjects included in analysis
    754
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 3.26
    Notes
    [1] - This outcome measure was analyzed using a hypothetical estimand and assessing non-inferiority of 500 mg IM dose versus 500 mg IV using a non-inferiority margin of 3.5 percent (%) on the risk difference scale. Weekly imputation algorithm imputes the missing outcome iteratively for each week, where missing outcomes at Day 8, 15, 22, 29 are imputed.
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Analysis was performed using a binomial regression model with identity link function and with treatment (Sotrovimab 500mg IM, 500mg IV), age (<65, =>65 years old) and gender (male, female) as covariates.
    Comparison groups
    Sotrovimab 500 mg IV v Sotrovimab 500 mg IM
    Number of subjects included in analysis
    754
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 3.56
    Notes
    [2] - This outcome measure was analyzed using a hypothetical estimand and assessing non-inferiority of 500 mg IM dose versus 500 mg IV using a non-inferiority margin of 3.5% on the risk difference scale. Daily imputation algorithm imputes the missing outcome iteratively for each study day starting with Day 2 and ending at Day 29.

    Secondary: Number of Participants With Common Non-Serious Adverse Events (non-SAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Participants With Common Non-Serious Adverse Events (non-SAEs) and Serious Adverse Events (SAEs)
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any serious adverse event that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, significant medical events that may jeopardize the participant or require medical or surgical intervention to prevent one of the other outcomes listed before. Adverse events which were not serious were considered as non-serious adverse events. Common (>=1%) non-SAEs and SAEs are presented. Safety Population consisted of all randomized participants who were exposed to study intervention.
    End point type
    Secondary
    End point timeframe
    Up to Week 36
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    393
    385
    195
    Units: Participants
        Common Non-SAEs
    8
    5
    12
        SAEs
    3
    7
    3
    No statistical analyses for this end point

    Secondary: Number of Participants With any Infusion- or Injection-related Reaction Including Hypersensitivity

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    End point title
    		 Number of Participants With any Infusion- or Injection-related Reaction Including Hypersensitivity
    End point description
    Data for number of participants with any infusion- or injection-related reaction including hypersensitivity has been presented. Safety Population.
    End point type
    Secondary
    End point timeframe
    Up to Week 36
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    393
    385
    195
    Units: Participants
    2
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With any Local Site Reaction by Maximum Severity After IM Administration

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    End point title
    		 Number of Participants With any Local Site Reaction by Maximum Severity After IM Administration [3]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. AESIs included any local site reactions. AESI were graded according to the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials 2007, Food and Drug Administration, where Grade 1=Mild toxicity; Grade 2=Moderate toxicity; Grade 3=Severe toxicity; and Grade 4= Potentially life-threatening toxicity. Higher Grade indicates higher severity. Data for any worst case post-Baseline has been presented. Safety Population.
    End point type
    Secondary
    End point timeframe
    Up to Week 36
    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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    385
    195
    Units: Participants
        Grade 1
    39
    22
        Grade 2
    7
    2
        Grade 3
    1
    0
        Grade 4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With any Disease Related Events

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    End point title
    		 Number of Participants With any Disease Related Events
    End point description
    AEs related to expected progression, signs, or symptoms of COVID-19, unless more severe than expected for the participant’s current clinical status and medical history, were reported as a disease related events. Safety Population.
    End point type
    Secondary
    End point timeframe
    Up to Week 36
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    393
    385
    195
    Units: Participants
    18
    16
    20
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-emergent Positive Anti-drug Antibody

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    End point title
    		 Number of Participants With Treatment-emergent Positive Anti-drug Antibody
    End point description
    Serum samples were collected for the determination of treatment-emergent anti-drug antibodies (ADA) using a validated electrochemiluminescent (ECL) immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for the specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'positive'. Confirmed treatment-emergent positive ADA samples were further characterized in the titration assay to quasi-quantitate the amount of ADA in the sample. Safety Population.
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    393
    385
    195
    Units: Participants
    25
    51
    26
    No statistical analyses for this end point

    Secondary: Titers of Anti-drug Antibodies Against Sotrovimab

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    End point title
    		 Titers of Anti-drug Antibodies Against Sotrovimab
    End point description
    Serum samples were collected for the determination of treatment-emergent ADA using a validated ECL immunoassay. The assay involved screening, confirmation and titration steps. If serum samples contained treatment-emergent ADA, they were further analyzed for the specificity of antibodies by a confirmation assay. Confirmed treatment-emergent positive samples were titrated to obtain the titers of antibodies. Titers were categorized as treatment-induced, treatment-boosted, and treatment-unaffected. Treatment-induced=those who are ADA negative or missing data and who have at least one post-dose ADA positive sample; Treatment boosted=those who are ADA positive and have a >4*Baseline titer; Treatment unaffected=those who are positive and (post-Baseline titer <=4*Baseline titer or all post-Baseline positive). Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).99999 indicates, data not available
    End point type
    Secondary
    End point timeframe
    Up to Week 24
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    393
    385
    195
    Units: Titers
    median (full range (min-max))
        Treatment-induced, n=41,104,57
    80.0 (40 to 5120)
    80.0 (40 to 5120)
    80.0 (40 to 20480)
        Treatment-boosted, n=1,4,0
    1280.0 (1280 to 1280)
    400.0 (40 to 640)
    99999 (99999 to 99999)
        Treatment-unaffected, n=20,4,15
    40.0 (40 to 320)
    40.0 (40 to 80)
    40.0 (40 to 160)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who had Progression of COVID-19 through Day 29 by Emergency Room visit or Hospitalization or Death (Weekly Imputation)

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    End point title
    		 Percentage of Participants who had Progression of COVID-19 through Day 29 by Emergency Room visit or Hospitalization or Death (Weekly Imputation)
    End point description
    Progression of COVID-19 through Day 29 as defined by visit to a hospital emergency room for management of illness or hospitalization for acute management of illness for any duration and for any cause or death. Percentage values are rounded off. Primary Analysis Population. The statistical analysis was performed only for 500 mg IV versus 500 mg IM dose. It was not planned for 250 mg IM dose per statistical analysis plan.
    End point type
    Secondary
    End point timeframe
    Up to Day 29
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    378
    376
    183
    Units: Percentage of participants
        number (not applicable)
    2.4
    3.2
    6.0
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Analysis was performed using a binomial regression model with identity link function and with treatment (Sotrovimab 500mg IM, 500mg IV), age (<65, =>65 years old) and gender (male, female) as covariates.
    Comparison groups
    Sotrovimab 500 mg IV v Sotrovimab 500 mg IM
    Number of subjects included in analysis
    754
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.56
         upper limit
    		 3.28
    Notes
    [4] - This outcome measure was analyzed using a hypothetical estimand and assessing non-inferiority of IM dose versus IV using a non-inferiority margin of 3.5% on the risk difference scale. Weekly imputation algorithm imputes the missing outcome iteratively for each week, where missing outcomes at Day 8, 15, 22, 29 are imputed.

    Secondary: Percentage of Participants Who Progress to Develop Severe and/or Critical Respiratory COVID-19 by Visit

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    End point title
    		 Percentage of Participants Who Progress to Develop Severe and/or Critical Respiratory COVID-19 by Visit
    End point description
    Participants were defined as progressing to develop severe respiratory COVID-19 if they required supplemental oxygen either by nasal cannula, face mask, high-flow oxygen devices, or non-invasive ventilation. Participants were defined as progressing to develop critical respiratory COVID-19 if they required invasive mechanical ventilation or extracorporeal membrane oxygenation. Percentage values are rounded off. Intent-to-Treat (ITT) Population consisted of all randomized participants excluding participants who were randomized under Protocol Amendment Version 1 and were immunocompetent and fully vaccinated at randomization.
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, and Day 29
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    385
    383
    185
    Units: Percentage of participants
    number (not applicable)
        Day 8
    0.3
    1.0
    3.8
        Day 15
    0.3
    1.3
    4.3
        Day 22
    0.3
    1.6
    4.3
        Day 29
    0.3
    1.6
    4.3
    No statistical analyses for this end point

    Secondary: Mean Area Under the Curve (AUC) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Viral Load From Day 1 to Day 8

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    End point title
    		 Mean Area Under the Curve (AUC) of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Viral Load From Day 1 to Day 8
    End point description
    AUC of SARS-CoV-2 viral load was measured by Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) from Day 1 to Day 8 in nasopharyngeal swab samples. Virology Population consisted of all participants in the ITT Population with a central laboratory confirmed quantifiable Baseline nasopharyngeal swab at Day 1. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    287
    278
    136
    Units: Day*log10 copies/mL
        geometric mean (geometric coefficient of variation)
    25.42 ± 34.144
    25.56 ± 36.936
    25.46 ± 37.899
    No statistical analyses for this end point

    Secondary: Mean AUC of SARS-CoV-2 Viral Load From Day 1 to Day 8 After Administration of Sotrovimab 500 mg IV and IM

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    End point title
    		 Mean AUC of SARS-CoV-2 Viral Load From Day 1 to Day 8 After Administration of Sotrovimab 500 mg IV and IM [5]
    End point description
    AUC of SARS-CoV-2 viral load was measured by qRT-PCR from Day 1 to Day 8 in nasopharyngeal swab samples. Least squares geometric mean and 90 percent (%) confidence interval has been presented. Virology Population. Only those participants with data available at the specified time points were analyzed. The statistical analysis was performed only for 500 mg IV versus 500 mg IM dose. It was not planned for 250 mg IM dose per statistical analysis plan.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 8
    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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM
    Number of subjects analysed
    287
    278
    Units: Day*log10 copies/mL
        least squares mean (confidence interval 90%)
    25.03 (24.45 to 25.63)
    25.96 (25.35 to 26.59)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    LS geometric mean was calculated for 500mg IV versus IM by using an Analysis of Covariance (ANCOVA) Model with treatment group (sotrovimab 500mg IM, 500mg IV), age (<65, =>65 years old), gender (male, female) and Baseline viral load as covariates.
    Comparison groups
    Sotrovimab 500 mg IV v Sotrovimab 500 mg IM
    Number of subjects included in analysis
    565
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Ratio of least square(LS) geometric mean
    Point estimate
    1.04
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.07
    Notes
    [6] - IM dose was assessed for equivalence to IV based on the two-sided 90% confidence interval for the treatment ratio falling within equivalence bounds of 0.5 to 2.0.

    Secondary: Change from Baseline in Viral Load as Measured by qRT-PCR at Day 8

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    End point title
    		 Change from Baseline in Viral Load as Measured by qRT-PCR at Day 8
    End point description
    Viral load was based on nasopharyngeal swab samples and was measured by qRT-PCR. Baseline was defined as the latest non-missing value prior to dosing (or latest value on or prior to nominal Day 1 for participants that were not dosed). Change from Baseline was calculated by subtracting the Baseline value from the post-dose visit value. Virology Population. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) and at Day 8
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    279
    271
    132
    Units: Log10 copies/mL
        arithmetic mean (standard deviation)
    -2.979 ± 1.6965
    -2.752 ± 1.7594
    -2.488 ± 1.6628
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Persistently High SARS-CoV-2 Viral Load at Day 8

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    End point title
    		 Percentage of Participants with Persistently High SARS-CoV-2 Viral Load at Day 8
    End point description
    Percentage of participants with a persistently high viral load were categorized as >=4.1 log10 copies/mL and <4.1 log10 copies/mL. Percentage of participants with a persistently high SARS-CoV-2 viral load at Day 8 was assessed via qRT-PCR in nasopharyngeal swab samples. Percentage values are rounded off. Virology Population. Only those participants with data available at the specified time points were analyzed.
    End point type
    Secondary
    End point timeframe
    At Day 8
    End point values
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    279
    271
    132
    Units: Percentage of participants
    number (not applicable)
        >=4.1 log 10 copies/mL
    13
    12
    17
        <4.1 log 10 copies/mL
    87
    88
    83
    No statistical analyses for this end point

    Secondary: Serum Concentration of Sotrovimab After Intravenous Administration

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    End point title
    		 Serum Concentration of Sotrovimab After Intravenous Administration [7]
    End point description
    Blood samples were collected at indicated time points for pharmacokinetic (PK) analysis of Sotrovimab. Pharmacokinetic Population consisted of all participants in the Safety Population who had at least 1 non-missing PK assessment (non-quantifiable values were considered as non-missing values). Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates that, data was not available as all concentration values were below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Day 1: Pre-dose, Day 8, Day 15, Day 29, Week 12, Week 20 and Week 24
    Notes
    [7] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Sotrovimab 500 mg IV
    Number of subjects analysed
    393
    Units: Microgram per mL
    geometric mean (geometric coefficient of variation)
        Day 1: Pre-dose, n=363
    99999 ± 99999
        Day 8: n=337
    53.67 ± 54.21
        Day 15: n=338
    44.62 ± 51.54
        Day 29: n=356
    33.89 ± 72.61
        Week 12: n=353
    19.10 ± 55.20
        Week 20: n=325
    9.96 ± 53.24
        Week 24: n=344
    7.66 ± 56.73
    No statistical analyses for this end point

    Secondary: Serum Concentration of Sotrovimab After Intramuscular Administration

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    End point title
    		 Serum Concentration of Sotrovimab After Intramuscular Administration [8]
    End point description
    Blood samples were collected at indicated time points for PK analysis of Sotrovimab. Pharmacokinetic Population. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). 99999 indicates that, data was not available as all concentration values were below the lower limit of quantification.
    End point type
    Secondary
    End point timeframe
    Day 1: Pre-dose, Day 8, Day 15, Day 29, Week 12, Week 20 and Week 24
    Notes
    [8] - 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: This endpoint is only reporting on a subset of the arms that are contained in the Baseline period.
    End point values
    		 Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Number of subjects analysed
    385
    195
    Units: Microgram per mL
    geometric mean (geometric coefficient of variation)
        Day 1: Pre-dose, n=365,187
    99999 ± 99999
    99999 ± 99999
        Day 8: n=339,166
    20.50 ± 88.70
    10.93 ± 92.47
        Day 15: n=344,166
    20.60 ± 84.01
    10.90 ± 77.68
        Day 29: n=355,174
    18.92 ± 77.00
    10.20 ± 61.80
        Week 12: n=333,171
    11.15 ± 64.01
    6.15 ± 54.22
        Week 20: n=315,167
    5.83 ± 65.44
    3.19 ± 57.05
        Week 24: n=315,168
    4.48 ± 71.57
    2.34 ± 62.49
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality, SAEs were collected up to Week 36; non-serious AEs were collected through Week 12
    Adverse event reporting additional description
    Safety Population consisted of all randomized participants who were exposed to study intervention.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Sotrovimab 500 mg IV
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 milligram (mg), IV infusion over 15 minutes on Day 1.

    Reporting group title
    Sotrovimab 500 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 500 mg, IM dose as 2*4 milliliter (mL) injections in each dorsogluteal muscle on Day 1.

    Reporting group title
    Sotrovimab 250 mg IM
    Reporting group description
    		 Participants received a single dose of sotrovimab 250 mg, IM dose either as a single 250 mg (4 mL) injection in the dorsogluteal muscle or as 2*2 mL injections in each deltoid muscle on Day 1.

    Serious adverse events
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 393 (0.76%)
    7 / 385 (1.82%)
    3 / 195 (1.54%)
         number of deaths (all causes)
    0
    2
    2
         number of deaths resulting from adverse events
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 385 (0.00%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial mass
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 385 (0.00%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    1 / 195 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 385 (0.00%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 385 (0.26%)
    0 / 195 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Sotrovimab 500 mg IV Sotrovimab 500 mg IM Sotrovimab 250 mg IM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 393 (2.04%)
    5 / 385 (1.30%)
    12 / 195 (6.15%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    5 / 393 (1.27%)
    2 / 385 (0.52%)
    3 / 195 (1.54%)
         occurrences all number
    5
    2
    3
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 385 (0.78%)
    2 / 195 (1.03%)
         occurrences all number
    2
    3
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    2 / 195 (1.03%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 385 (0.00%)
    4 / 195 (2.05%)
         occurrences all number
    1
    0
    4
    Gastroenteritis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 385 (0.00%)
    2 / 195 (1.03%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2021
    Amendment 1: The major changes and rationale for the changes from the original protocol to protocol amendment 1 are as follows: Study Design: Change from placebo to active comparator of VIR-7831 IV, removal of Lead-in, addition of 250 milligram (mg) IM arm; Change from placebo to active comparator of VIR-7831 IV, removal of Lead-in, addition of 250 mg IM arm; Study population: Study population was expanded to include ages 12-17 years of age with risk factors for severe disease; Allow participants who previously received COVID-19 vaccines; Changed high-risk adult definition to include those with body mass index less than or equal to (<=)30, immunocompromised participants, those receiving immunosuppressive medicines, and chronic liver disease; Post treatment observation of vital signs and local tolerability assessments timepoints on Day 1 may be reduced if recommended by the Joint Safety Review Team after the first 300 participants; Biostatistics: Number of statistical hypotheses changed from 1 to 2 for primary endpoint analysis, sample size, analysis sets, primary endpoint analysis method, interim analysis and Independent Data Monitoring Committee removed, estimand method as new approach for primary endpoint analysis, multiplicity strategy for primary endpoint analysis changed.
    29 Jun 2021
    Amendment 2: The major changes and rationale for the changes from the protocol amendment 1 to protocol amendment 2 are as follows: Added an Independent Data Monitoring Committee and provisions for one interim analysis to assess for safety, futility, and efficacy; Removed the option to decrease post-treatment monitoring time to 15 minutes. All participants will be monitored for 30 minutes after treatment; Added exclusion criteria to exclude fully vaccinated immunocompetent participants; Added a new exploratory objective to assess the incidence and severity of Long COVID symptoms at Week 12 and Week 24.
    04 Oct 2021
    Amendment 3: The major changes and rationale for the changes from protocol amendment 2 to protocol amendment 3 are as follows: Updated clinical pharmacology background information with new data about sotrovimab half-life and extended the study duration from 24 weeks to 36 weeks of follow up; Enrollment into the 250 mg IM arm was discontinued which resulted in changes to the overall study design, the planned interim analysis and primary endpoint analyses.

    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.
    The pre-specified daily imputation resulted in overly high inflation in the estimated progression rates for missing data. To reduce this bias and to account for progression history, weekly imputation was used for final conclusions.
    For support, Contact us.
    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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