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    Clinical Trial Results:
    Tracking the immune response to SARS-CoV-2 modRNA vaccines in an open-label multicenter study in participants with relapsing multiple sclerosis treated with ofatumumab s.c. (KYRIOS)

    Summary
    EudraCT number
    		 2021-000307-20
    Trial protocol
    		 DE  
    Global end of trial date
    13 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jun 2024
    First version publication date
    21 Jun 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COMB157GDE01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04869358
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To estimate the proportion of RMS patients having established SARSCoV-2-specific T-cells after receiving a modRNA vaccine (initial vaccination or booster) either before or after starting ofatumumab treatment.2
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All he local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 May 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    33
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Thirty-seven participants were screened and 34 participants met the criteria for entry into the trial.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1a
    Arm description
    		 Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SARS-CoV-2 modRNA vaccine (initial vaccination or booster)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    standard clinical routine

    Investigational medicinal product name
    ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    dose was 20 mg subcutaneous (s.c.) monthly

    Arm title
    		 Cohort 1b
    Arm description
    		 Patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SARS-CoV-2 modRNA vaccine (initial vaccination or booster)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    standard clinical routine

    Investigational medicinal product name
    ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    dose was 20 mg subcutaneous (s.c.) monthly

    Arm title
    		 Cohort 2a
    Arm description
    		 Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    dose was 20 mg subcutaneous (s.c.) monthly

    Investigational medicinal product name
    SARS-CoV-2 modRNA vaccine (initial vaccination or booster)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    standard clinical routine

    Arm title
    		 Cohort 2b
    Arm description
    		 Patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    SARS-CoV-2 modRNA vaccine (initial vaccination or booster)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    standard clinical routine

    Investigational medicinal product name
    ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    dose was 20 mg subcutaneous (s.c.) monthly

    Number of subjects in period 1
    		Cohort 1a Cohort 1b Cohort 2a Cohort 2b
    Started
    6
    8
    5
    15
    Completed
    5
    8
    5
    15
    Not completed
    1
    0
    0
    0
         Wish to have children.
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment.

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Reporting group title
    Cohort 2b
    Reporting group description
    		 Patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Reporting group values
    		 Cohort 1a Cohort 1b Cohort 2a Cohort 2b Total
    Number of subjects
    		 6 8 5 15 34
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 6 7 5 15 33
        From 65-84 years
    		 0 1 0 0 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 32.5 ( 8.1 ) 47.1 ( 14.1 ) 32.4 ( 7.7 ) 45.5 ( 12.4 ) -
    Sex: Female, Male
    Units:
        Female
    		 5 5 4 9 23
        Male
    		 1 3 1 6 11
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 6 8 5 13 32
        Missing
    		 0 0 0 2 2
    Subject analysis sets

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment or patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose) or patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Subject analysis sets values
    		 Total Total Total Cohort 1 Cohort 2
    Number of subjects
    32
    34
    28
    14
    20
    Age categorical
    Units: Subjects
        Adults (18-64 years)
        From 65-84 years
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    68.8 ( )
    ( )
    5.3 ( 13.2 )
    ( )
    ( )
    Sex: Female, Male
    Units:
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
        Missing

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment.

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Reporting group title
    Cohort 2b
    Reporting group description
    		 Patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All cohorts

    Subject analysis set title
    Cohort 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients received first SARS-CoV-2 vaccination within the study prior to starting ofatumumab treatment or patients had already completed initial vaccination cycle and received a booster vaccine within the study prior to starting ofatumumab treatment.

    Subject analysis set title
    Cohort 2
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients who received their first SARS-CoV-2 vaccination within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose) or patients who had already completed their initial vaccination cycle and received a booster vaccine within the study while already stable on ofatumumab treatment for at least 4 weeks (since the first dose).

    Primary: Percentage of participants having established SARS-CoV-2-specific T cells after receiving a modRNA vaccine

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    End point title
    		 Percentage of participants having established SARS-CoV-2-specific T cells after receiving a modRNA vaccine [1]
    End point description
    Participants who established SARS-CoV-2-specific T cells as defined by detection of SARS-CoV-2 reactive T-cells, measured by e.g. ELIspot assay from T-cells that were stimulated with SARS-CoV-2 peptide mix, either 1 month after second dose of vaccine or 1 month after booster vaccine in participants who received the respective vaccine before or after starting ofatumumab treatment.
    End point type
    Primary
    End point timeframe
    1 month after second dose of vaccine or booster vaccine
    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: No statistical analysis were planned for this endpoint.
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Cohort 2b Total
    Number of subjects analysed
    5
    8
    4
    15
    32
    Units: percentage of participants
        number (confidence interval 95%)
    80.0 (28.4 to 99.5)
    87.5 (47.3 to 99.7)
    100.0 (39.8 to 100.0)
    46.7 (21.3 to 73.4)
    68.8 (50 to 83.9)
    No statistical analyses for this end point

    Secondary: Percentage of participants who maintained T-cell response after receiving a modRNA vaccine

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    End point title
    		 Percentage of participants who maintained T-cell response after receiving a modRNA vaccine
    End point description
    Participants who maintained detectable SARS-CoV-2 reactive T-cells (measured by e.g. ELIspot assay from T-cells that were stimulated with SARS-CoV-2 peptide mix) after second dose of vaccine or 6 and 12 months after booster vaccine in participants who received the vaccine before or after starting ofatumumab treatment. First booster vaccination was optional for cohorts 1a and 2a. In cohorts 1b and 2b the time points "Month 1 after Vacc" and "1 Month after booster" are identical.
    End point type
    Secondary
    End point timeframe
    At Week 1, Months 6, 12 and 18 after second dose of vaccine or 1 Month after 1st booster, 1 Month after 2nd booster
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Cohort 2b Total
    Number of subjects analysed
    6
    8
    5
    15
    34
    Units: percentage of participants
    number (confidence interval 95%)
        Week 1 after vacc n=4,0,5,0,9
    100.0 (39.8 to 100.0)
    999.9 (999.9 to 999.9)
    100.0 (47.8 to 100.0)
    999.9 (999.9 to 999.9)
    100.0 (66.4 to 100.0)
        Month 6 after vacc n=4,8,5,14,31
    100 (39.8 to 100.0)
    62.5 (24.5 to 91.5)
    60.0 (14.7 to 94.7)
    57.1 (28.9 to 82.3)
    64.5 (45.4 to 80.8)
        Month 12 after vacc n=5,5,5,15,30
    100.0 (47.8 to 100.0)
    100.0 (47.8 to 100.0)
    80.0 (28.4 to 99.5)
    93.3 (68.1 to 99.8)
    93.3 (77.9 to 99.2)
        Month 18 after vacc n=4,0,4,0,8
    50.0 (6.76 to 93.2)
    999.9 (999.9 to 999.9)
    100.0 (39.8 to 100.0)
    999.9 (999.9 to 999.9)
    93.3 (77.9 to 99.2)
        Month 1 after 1st booster n=4,8,3,15,30
    75.0 (19.4 to 99.4)
    87.5 (47.3 to 99.7)
    66.7 (9.43 to 99.2)
    46.7 (21.3 to 73.4)
    63.3 (43.9 to 80.1)
        Month 1 after 2nd booster n=2,4,0,10,16
    100.0 (15.8 to 100.0)
    75.0 (19.4 to 99.4)
    999.9 (999.9 to 999.9)
    80.0 (44.4 to 97.5)
    81.3 (54.4 to 96.0)
    No statistical analyses for this end point

    Secondary: Increase in specific T-cells after receiving an modRNA booster vaccine

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    End point title
    		 Increase in specific T-cells after receiving an modRNA booster vaccine
    End point description
    Patients having established SARS-CoV-2-specific T cells as defined by detection of SARS-CoV-2 reactive T-cells, measured by e.g. ELIspot assay from T-cells that were stimulated with SARS-CoV-2 peptide mix 1 month after booster vaccine in participants who received the respective vaccine before or after starting ofatumumab treatment. The fold change of SI from last value before booster to Month 1 is the ratio of SI at Month 1 divided by SI at last value before booster.
    End point type
    Secondary
    End point timeframe
    Last value before 2nd booster vaccination to month 1 after 2nd booster vaccination
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Cohort 2b Total
    Number of subjects analysed
    4
    7
    3
    14
    28
    Units: stimulation index
        arithmetic mean (standard deviation)
    0.8 ( 0.9 )
    12.6 ( 25.5 )
    2.0 ( 2.1 )
    3.6 ( 4.4 )
    5.3 ( 13.2 )
    No statistical analyses for this end point

    Secondary: Percentage of RMS participants with quantifiable levels of SARS-CoV-2 serum functional antibodies by visits and subcohorts (EAS)

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    End point title
    		 Percentage of RMS participants with quantifiable levels of SARS-CoV-2 serum functional antibodies by visits and subcohorts (EAS)
    End point description
    Level of SARS-CoV-2 serum functional antibodies were measured by a central laboratory using a neutralizing antibody detection kit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1 after Vacc, Month 1, 6, 12 after Vacc, 1 month after 1st booster, 1 month after 2nd booster
    End point values
    		 Cohort 1a Cohort 1b Cohort 2a Cohort 2b
    Number of subjects analysed
    6
    8
    5
    15
    Units: percentage of participants
    number (confidence interval 95%)
        Baseline0 positive n=6,8, 5,14
    0 (0 to 45.9)
    100.0 (63.1 to 100.0)
    0 (0 to 52.2)
    71.4 (41.9 to 91.6)
        Week 1 after Vacc positive n=5,0,5,0
    100.0 (47.8 to 100.0)
    999.9 (999.9 to 999.9)
    40.0 (5.27 to 85.3)
    999.9 (999.9 to 999.9)
        Month 1 after Vacc positive n=5,8,4,15
    100.0 (47.8 to 100.0)
    100.0 (63.1 to 100.0)
    25.0 (0.63 to 80.6)
    93.3 (68.1 to 99.8)
        Month 6 after Vacc positive n=5,8,5,15
    100.0 (47.8 to 100.0)
    100.0 (63.1 to 100.0)
    40.0 (5.3 to 85.3)
    73.3 (44.9 to 92.2)
        Month 12 after Vacc positive n=5,7,5,14
    100.0 (47.8 to 100.0)
    100.0 (59.0 to 100.0)
    40.0 (5.3 to 85.3)
    92.9 (66.1 to 99.8)
        Month 1 after 1st booster postive n=5,8,5,15
    100.0 (47.8 to 100.0)
    100.0 (63.1 to 100.0)
    66.7 (9.4 to 99.2)
    93.3 (68.1 to 99.8)
        Month 1 after 2nd booster positive n=2,4,0,10
    100.0 (15.8 to 100.0)
    100.0 (39.8 to 100.0)
    0 (0 to 0)
    90.0 (55.5 to 99.7)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific CD4+ effector memory T-cells

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    End point title
    		 SARS-CoV-2 specific CD4+ effector memory T-cells
    End point description
    Phenotypic description of the cellular immune response was performed at the central laboratory. T-cells were stimulated with SARS-CoV-2 peptide mix and analyzed for IFNg- and IL4 secretion using FACS analysis. Results are inconclusive due to low participant numbers.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1 ,6, 12 and 18 after vaccinationse of vaccine or 1,6 and 12 months after booster vaccine
    End point values
    		 Cohort 1 Cohort 2
    Number of subjects analysed
    14
    20
    Units: % of CD4+/CD8+ cells
    arithmetic mean (standard deviation)
        BL before initial Vacc IL4 basal n=4,5
    2.458 ( 4.915 )
    0.262 ( 05.86 )
        BL before initial Vacc IL4 stim.n=4,5
    2.583 ( 5.165 )
    0.264 ( 0.59 )
        BL before initial Vacc INFg basal n=4,5
    0.555 ( 0.549 )
    0.03 ( 0.067 )
        BL before initial Vacc INGg stim n=4,5
    0.235 ( 0.191 )
    0.146 ( 0.326 )
        Month 1 after Vacc Il4 basal n=12,19
    0.396 ( 2.318 )
    1.209 ( 6.919 )
        Month 1 after Vacc IL4 stim. n=12,19
    0.719 ( 0.62 )
    2.449 ( 0.283 )
        Month 1 after Vacc INFg basal n=12,19
    0.258 ( 2.165 )
    0.171 ( 0.917 )
        Month 1 after Vacc INFg stim. n=12,19
    0.947 ( 2.165 )
    0.381 ( 0.917 )
        Month 6 after Vacc Il4 basal n=12,20
    0.662 ( 1.44 )
    0.061 ( 0.273 )
        0Month 6 after Vacc IL4 stim.n=12,20
    0.93 ( 2.043 )
    0.44 ( 0.197 )
        Month 6 after Vacc INFg basal n=12,20
    0.236 ( 0.344 )
    0.123 ( 0.205 )
        Month 6 after Vacc INFg stim.n=12,20
    0.305 ( 0.352 )
    0.342 ( 0.644 )
        Month 12 after Vacc Il4 basal n=10,17
    0.361 ( 1.142 )
    1.078 ( 2.468 )
        Month 12 after Vacc IL4 stim.n=10,17
    0.174 ( 0.55 )
    1.031 ( 2.491 )
        Month 12 after Vacc INFg basal n=10,17
    0.132 ( 0.192 )
    0.226 ( 0.478 )
        Month12 after Vacc INFg stim. n=10,17
    0.122 ( 0.26 )
    0757 ( 2.332 )
        Month 18 after Vacc IL4 basal n=4,5
    2.368 ( 4.735 )
    0.118 ( 0.264 )
        Month 18 after Vacc IL4 stim.l n=4,5
    1.833 ( 3.665 )
    0.176 ( 0.394 )
        Month 18 after Vacc INFg basal l n=4,5
    0.148 ( 0.295 )
    0.11 ( 0.246 )
        Month 18 after Vacc INFg stim.l n=4,5
    0.138 ( 0.159 )
    0.12 ( 0.268 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from first dose of study treatment until the end of the treatment period plus an additional 30 day safety follow up period for a maximum time of 22 months.
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Cohort 1a
    Reporting group description
    		 Cohort 1a

    Reporting group title
    Cohort 2a
    Reporting group description
    		 Cohort 2a

    Reporting group title
    Cohort 2b
    Reporting group description
    		 Cohort 2b

    Reporting group title
    Cohort 1b
    Reporting group description
    		 Cohort 1b

    Serious adverse events
    		 Cohort 1a Cohort 2a Cohort 2b Cohort 1b
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neurilemmoma benign
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Cohort 1a Cohort 2a Cohort 2b Cohort 1b
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    5 / 5 (100.00%)
    15 / 15 (100.00%)
    6 / 8 (75.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Flushing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    4
    1
    Chills
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    1
    Asthenia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Vaccination site reaction
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injection site swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injection site pain
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Immune system disorders
    Immune-mediated adverse reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Breast mass
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Erectile dysfunction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dry throat
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pleurisy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Throat irritation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Adjustment disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Epicondylitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    3
    Radius fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    2 / 15 (13.33%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Headache
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 5 (80.00%)
    3 / 15 (20.00%)
    2 / 8 (25.00%)
         occurrences all number
    4
    6
    3
    3
    Meralgia paraesthetica
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Multiple sclerosis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Multiple sclerosis relapse
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    0
    1
    Peripheral nerve lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sciatica
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Onychoclasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Alopecia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin exfoliation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Renal colic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    2
    Muscle twitching
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    1 / 15 (6.67%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    1
    1
    Spinal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 5 (40.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    3 / 15 (20.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Oral herpes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    0
    1
    Fungal skin infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    COVID-19
         subjects affected / exposed
    2 / 6 (33.33%)
    5 / 5 (100.00%)
    9 / 15 (60.00%)
    2 / 8 (25.00%)
         occurrences all number
    2
    5
    9
    2
    Bacterial infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abscess limb
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 5 (20.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 5 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2021
    Main changes included: an additional interim analysis as well as prolongation of the study period in order to investigate sustainability of SARS-CoV-2 vaccination induced immune reaction and reaction towards possible additional booster vaccinations. Furthermore,vadditional exploratory endpoints were added to investigate the immune response towards these additional vaccinations.
    20 Sep 2021
    Main changes in the amendment included: splitting of each cohort into two subcohorts (1a, 1b and 2a, 2b), corresponding changes in the treatment schedule, adaption of the primary endpoint and the exclusion criteria, and the addition of an interim analysis.
    15 Mar 2022
    Main changes included: termination of recruitment, addition of a study visit and omitting of study exclusion after use of prohibited medication.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results.
    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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