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    Clinical Trial Results:
    A Phase 2a, Open-Label Study Assessing the Pharmacokinetics, Safety, Tolerability, and Immunogenicity of a Single Dose of Subcutaneous Anti-Spike SARS-CoV-2 Monoclonal Antibodies Casirivimab and Imdevimab in High-Risk Pediatric Subjects Under 12 Years of Age

    Summary
    EudraCT number
    		 2021-004590-30
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    01 Jun 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
    R10933-10987-COV-2121
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04992273
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Regeneron Pharmaceuticals, Inc.
    Sponsor organisation address
    777 Old Saw Mill River Road, Tarrytown, United States, NY
    Public contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 8447346643, clinicaltrials@regeneron.com
    Scientific contact
    Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 8447346643, clinicaltrials@regeneron.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002964-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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This was an open-label, phase 2a study to assess the pharmacokinetics, safety, tolerability, and immunogenicity of casirivimab+imdevimab in participants <12 years old who were not infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but are at high risk to develop severe coronavirus disease 2019 (COVID-19) if they became infected.
    Protection of trial subjects
    It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Sep 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
    United States: 7
    Worldwide total number of subjects
    7
    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)
    1
    Children (2-11 years)
    6
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 7 participants were screened & enrolled into Group A (≥10 kg to <40 kg). One discontinued at week 9 (lost to follow-up). Participants were subsequently divided into 2 groups: 2 participants in Group A1 (≥20 kg to <40 kg) & 5 in Group A2 (≥10 kg to <20 kg) & received different doses. All participants were enrolled & treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ≥20 kg to <40 kg
    Arm description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.
    Arm type
    		 Experimental

    Investigational medicinal product name
    casirivimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    600 milligram (mg) administered as 1 to 4 subcutaneous (SC) injections based on body weight

    Investigational medicinal product name
    imdevimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    600 milligram (mg) administered as 1 to 4 subcutaneous (SC) injections based on body weight

    Arm title
    		 ≥10 kg to <20 kg
    Arm description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.
    Arm type
    		 Experimental

    Investigational medicinal product name
    casirivimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    600 milligram (mg) administered as 1 to 4 subcutaneous (SC) injections based on body weight

    Investigational medicinal product name
    imdevimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    600 milligram (mg) administered as 1 to 4 subcutaneous (SC) injections based on body weight

    Number of subjects in period 1
    		≥20 kg to <40 kg ≥10 kg to <20 kg
    Started
    2
    5
    Completed
    2
    4
    Not completed
    0
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ≥20 kg to <40 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Reporting group title
    ≥10 kg to <20 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Reporting group values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg Total
    Number of subjects
    		 2 5 7
    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 1 1
        Children (2-11 years)
    		 2 4 6
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 9.5 ± 2.12 3.0 ± 1.58 -
    Sex: Female, Male
    Units: Participants
        Female
    		 1 4 5
        Male
    		 1 1 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 1 1
        White
    		 2 4 6
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 0 1
        Not Hispanic or Latino
    		 1 5 6
        Unknown or Not Reported
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    ≥10 kg to <40 kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Subject analysis sets values
    		 ≥10 kg to <40 kg
    Number of subjects
    7
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    1
        Children (2-11 years)
    6
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    ±
    Sex: Female, Male
    Units: Participants
        Female
        Male
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Native Hawaiian or Other Pacific Islander
        Black or African American
        White
        More than one race
        Unknown or Not Reported
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported

    End points

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    End points reporting groups
    Reporting group title
    ≥20 kg to <40 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Reporting group title
    ≥10 kg to <20 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose (600 mg of casirivimab and 600 mg of imdevimab) administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Subject analysis set title
    ≥10 kg to <40 kg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Primary: Concentrations of casirivimab+imdevimab in serum over time

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    End point title
    		 Concentrations of casirivimab+imdevimab in serum over time [1]
    End point description
    Concentrations reported in milligrams per Liter (mg/L)
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were performed on this outcome measure.
    End point values
    		 ≥10 kg to <40 kg
    Number of subjects analysed
    7
    Units: mg/L
    arithmetic mean (standard deviation)
        Day 0
    0 ± 0
        Day 14
    239.0 ± 36.3
    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
    End point type
    Secondary
    End point timeframe
    Through end of study, approximately 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    5
    Units: Participants
    2
    3
    No statistical analyses for this end point

    Secondary: Severity of TEAEs

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    End point title
    		 Severity of TEAEs
    End point description
    End point type
    Secondary
    End point timeframe
    Through end of study, approximately 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    5
    Units: Participants
        Infections and Infestations - Grade 1
    1
    1
        Infections and Infestations - Grade 2
    1
    1
        Infections and Infestations - Grade 3
    0
    0
        Infections and Infestations - Grade 4
    0
    0
        Infections and Infestations - Grade 5
    0
    0
        Respiratory disorders - Grade 1
    0
    1
        Respiratory disorders - Grade 2
    1
    1
        Respiratory disorders - Grade 3
    0
    0
        Respiratory disorders - Grade 4
    0
    0
        Respiratory disorders - Grade 5
    0
    0
        Nervous system disorders - Grade 1
    0
    1
        Nervous system disorders - Grade 2
    0
    0
        Nervous system disorders - Grade 3
    0
    0
        Nervous system disorders - Grade 4
    0
    0
        Nervous system disorders - Grade 5
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Grade ≥3 Injection Site Reactions

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    End point title
    		 Number of Participants with Grade ≥3 Injection Site Reactions
    End point description
    End point type
    Secondary
    End point timeframe
    Through Day 4
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    5
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with grade ≥3 hypersensitivity reactions

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    End point title
    		 Number of participants with grade ≥3 hypersensitivity reactions
    End point description
    End point type
    Secondary
    End point timeframe
    Through Day 4
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    5
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Immunogenicity as measured by ADA to imdevimab over time

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    End point title
    		 Immunogenicity as measured by ADA to imdevimab over time
    End point description
    Negative response
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    4
    Units: Participants
    2
    3
    No statistical analyses for this end point

    Secondary: Immunogenicity as measured by anti-drug antibodies (ADA) to casirivimab over time

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    End point title
    		 Immunogenicity as measured by anti-drug antibodies (ADA) to casirivimab over time
    End point description
    Negative response
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    2
    4
    Units: Participants
    2
    3
    No statistical analyses for this end point

    Secondary: Immunogenicity as measured by neutralizing antibodies (NAb) to casirivimab over time

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    End point title
    		 Immunogenicity as measured by neutralizing antibodies (NAb) to casirivimab over time
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Antibodies
        number (not applicable)
    Notes
    [2] - Neutralizing antibody (NAb) analysis data was not collected.
    [3] - Neutralizing antibody (NAb) analysis data was not collected.
    No statistical analyses for this end point

    Secondary: Immunogenicity as measured by NAb to imdevimab over time

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    End point title
    		 Immunogenicity as measured by NAb to imdevimab over time
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 ≥20 kg to <40 kg ≥10 kg to <20 kg
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Antibodies
        number (not applicable)
    Notes
    [4] - Neutralizing antibody (NAb) analysis data was not collected.
    [5] - Neutralizing antibody (NAb) analysis data was not collected.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to week 24
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Group A2 ≥10 kg to <20 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Reporting group title
    Group A1 ≥20 kg to <40 kg
    Reporting group description
    		 Single dose of casirivimab+imdevimab, that was the body weight dose equivalent to the 1200 mg adult dose administered as 1 to 4 subcutaneous (SC) injections based on body weight.

    Serious adverse events
    		 Group A2 ≥10 kg to <20 kg Group A1 ≥20 kg to <40 kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group A2 ≥10 kg to <20 kg Group A1 ≥20 kg to <40 kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 5 (60.00%)
    2 / 2 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    1
    Cough variant asthma
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    1
    Pneumonia viral
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2021
    Updated route of administration in participants with lower body weight (subcutaneous rather than intramuscular), included additional sample collections for drug concentration assessment at later time points, and addition of an adverse event of special interest (AESI).
    08 Mar 2022
    Updates included shortening length of gollow-up period from 225 days to 169 days (32 weeks to 24 weeks), and to add that the end of study visit (EOS) visit is required to be performed in person.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Dec 2021
    The study was paused for new enrollment on 23 Dec 2021 due to the increasing prevalence of the Omicron-lineage variants and the lack of sufficient neutralization by casirivimab+imdevimab of Omicron-lineage variants in vitro. Study was not restarted and was terminated on 28 Jun 2022. The participants who had been enrolled prior to the pause date continued to participate in study visits and study activities according to the protocol.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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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