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    Clinical Trial Results:
    Optimal Repeated Dose Strategy for SARS-CoV-2 Vaccination in Kidney Transplant patients

    Summary
    EudraCT number
    		 2021-004558-44
    Trial protocol
    		 NL  
    Global end of trial date
    12 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2023
    First version publication date
    31 Dec 2023
    Other versions
    Summary report(s)
    		 RECOVAC Repeated Vaccination study

    Trial information

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    Trial identification
    Sponsor protocol code
    2021-00604
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05030974
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Medical Center Groningen
    Sponsor organisation address
    Hanzeplein 1, groningen, Netherlands, 9713 RZ
    Public contact
    JSF Sanders, UMCG, j.sanders@umcg.nl
    Scientific contact
    JSF Sanders, UMCG, j.sanders@umcg.nl
    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
    25 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the immunogenicity (expressed as percentage of responders) of various COVID-19 booster vaccination strategies in kidney transplant patients that failed to mount a sufficient antibody response after two primary doses of the mRNA-1273 vaccine.
    Protection of trial subjects
    The vaccines that are used in this study are approved by the EMA and administered to millions of people worldwide. In addition, there is experience with using these vaccines for third dose administrations. In one of the groups (B.2) the dose of 200 μg the vaccine is twice the standard dose (100 μg), but data from a published phase I trial with two administrations of 250 μg and additional information from the manufacturer do not raise safety concerns. Furthermore, the third or fourth vaccination, and in a subset (n=80) the interruption of one of the three immunosuppressive drugs, of all participants will probably be completed within 1-2 months. It will not be acceptable to postpone a third or fourth vaccination in this population since they are already eligible for third or fourth vaccination via clinical care. Therefore, interim safety analysis is deemed not feasible. Biweekly investigator meetings will be held until 4 weeks after the last patient has received the last vaccine administration and less frequently thereafter to discuss, among others, the different types of AEs.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Oct 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
    Netherlands: 333
    Worldwide total number of subjects
    333
    EEA total number of subjects
    333
    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)
    210
    From 65 to 84 years
    122
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Seronegative kidney transplant recipients were primarily recruited from previous RECOVAC studies (NCT04741386 and NCT04841785). Patients were also recruited from the participating centres when a negative seroresponse was detected with a validated in-hospital assay 14-56 days after a third mRNA vaccination.

    Pre-assignment
    Screening details
    		 A total of 1464 seronegative kidney transplant recipients were approached for inclusion in the study. Of these, 345 agreed to participate. Five withdrew before the screening visit and 7 patients were screeningfailures, leaving 233 patients for randomisation.

    Pre-assignment period milestones
    Number of subjects started
    		 1464 [1]
    Intermediate milestone: Number of subjects
    Agreed to participate: 345
    Intermediate milestone: Number of subjects
    Screened: 340
    Number of subjects completed
    		 333

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Was not interested: 1119
    Reason: Number of subjects
    		 Withdrew before screening: 5
    Reason: Number of subjects
    		 Screenfailure: 7
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: We included subjects that were approached and invited for a screening visit. After excluding patients that did not want to participate and screeningfailures, the numbers of enrollment are achieved
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Alternative vaccination group - 1x mRNA-1273
    Arm description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 vaccine
    Investigational medicinal product code
    Other name
    mRNA-1273, spikevax
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Spikevax is administered as a dose of 0.5 mL. One dose (0.5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles).

    Arm title
    		 Alternative vaccination group - 2x mRNA-1273
    Arm description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    COVID-19 vaccine
    Investigational medicinal product code
    Other name
    mRNA-1273, spikevax
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In this group, spikevax was administered as a dose of 2x 0.5 mL in both upper arms.

    Arm title
    		 Alternative vaccination group - Ad26.COV2-S
    Arm description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    COVID-19 vaccine
    Investigational medicinal product code
    Other name
    Ad26.COV2-S, Janssen COVID-19 vaccine
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The Janssen Ad26.COV2.S vaccine is administered as a single dose of 0.5 mL (5x1010 viral particles, corresponding to not less than 8.92 log10 infectious units).

    Arm title
    		 mycophenolate mofetil +
    Arm description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 vaccine
    Investigational medicinal product code
    Other name
    mRNA-1273, spikevax
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Spikevax is administered as a dose of 0.5 mL. One dose (0.5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles).

    Arm title
    		 mycophenolate mofetil -
    Arm description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 vaccine
    Investigational medicinal product code
    Other name
    mRNA-1273, spikevax
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Spikevax is administered as a dose of 0.5 mL. One dose (0.5 mL) contains 100 micrograms of messenger RNA (mRNA) (embedded in SM-102 lipid nanoparticles).

    Number of subjects in period 1
    		Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Started
    75
    77
    78
    51
    52
    Completed
    74
    75
    75
    47
    48
    Not completed
    1
    2
    3
    4
    4
         Consent withdrawn by subject
    -
    -
    -
    -
    1
         COVID-19
    1
    2
    3
    3
    2
         Lost to follow-up
    -
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alternative vaccination group - 1x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - 2x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - Ad26.COV2-S
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    mycophenolate mofetil +
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Reporting group title
    mycophenolate mofetil -
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Reporting group values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil - Total
    Number of subjects
    		 75 77 78 51 52 333
    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)
    		 0
        Children (2-11 years)
    		 0
        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)
    		 57.4 ( 13.4 ) 57.7 ( 12.1 ) 60.6 ( 12.3 ) 59.1 ( 11.9 ) 60.5 ( 12.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 27 30 27 26 18 128
        Male
    		 48 47 51 25 34 205

    End points

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    End points reporting groups
    Reporting group title
    Alternative vaccination group - 1x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - 2x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - Ad26.COV2-S
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    mycophenolate mofetil +
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Reporting group title
    mycophenolate mofetil -
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Primary: SARS-CoV-2 specific seroconversion rate

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    End point title
    		 SARS-CoV-2 specific seroconversion rate [1]
    End point description
    The primary endpoint is the percentage of subjects with a serum anti-S1 IgG concentration ≥10 BAU/mL measured with a validated fluorescent bead-based multiplex-immunoassay at 28 days after the third or fourth vaccine administration.
    End point type
    Primary
    End point timeframe
    28 days after repeated COVID-19 vaccination
    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: The statistical analysis are described in the article that is attached as a summary
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    73
    72
    73
    46
    46
    Units: number of patients
        Non-Responder
    23
    23
    27
    15
    9
        Responder
    50
    49
    46
    31
    37
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific antibody concentrations

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    End point title
    		 SARS-CoV-2 specific antibody concentrations
    End point description
    End point type
    Secondary
    End point timeframe
    28 dat after repeated COVID-19 vaccination
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    73
    72
    73
    46
    46
    Units: BAU/mL
        median (inter-quartile range (Q1-Q3))
    156 (2.47 to 797)
    92.2 (1.77 to 648)
    74.7 (1.60 to 250)
    143 (4.58 to 966)
    119 (23.0 to 1279)
    No statistical analyses for this end point

    Secondary: Neultralisation titer against ancestral SARS-CoV-2

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    End point title
    		 Neultralisation titer against ancestral SARS-CoV-2
    End point description
    Plaque reduction neutralisation tests against the ancestral, delta, and omicron SARS-CoV-2 variants were done. For feasibility, it was a priori decided to measure neutralising antibodies only in a random sample of 25 KTRs in each study group.
    End point type
    Secondary
    End point timeframe
    28 days after repeated vaccination
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    25
    24
    25
    25
    25
    Units: PRNT50
        median (inter-quartile range (Q1-Q3))
    33 (10 to 464)
    65 (10 to 1393)
    143 (10 to 549)
    58 (10 to 616)
    100 (10 to 781)
    No statistical analyses for this end point

    Secondary: Neutralisation titer against Delta SARS-CoV-2

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    End point title
    		 Neutralisation titer against Delta SARS-CoV-2
    End point description
    End point type
    Secondary
    End point timeframe
    28 days after repeated vaccination
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    25
    24
    25
    25
    25
    Units: PRNT50
        median (inter-quartile range (Q1-Q3))
    10 (10 to 250)
    10 (10 to 361)
    52 (10 to 522)
    10 (10 to 537)
    90 (10 to 934)
    No statistical analyses for this end point

    Secondary: Neutralisation titer against Omicron SARS-CoV-2

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    End point title
    		 Neutralisation titer against Omicron SARS-CoV-2
    End point description
    End point type
    Secondary
    End point timeframe
    28 days after repeated vaccination
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    25
    24
    25
    25
    25
    Units: PRNT50
        median (inter-quartile range (Q1-Q3))
    10 (10 to 10)
    10 (10 to 39)
    10 (10 to 10)
    10 (10 to 10)
    10 (10 to 84)
    No statistical analyses for this end point

    Secondary: SARS-CoV-2 specific T cell response

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    End point title
    		 SARS-CoV-2 specific T cell response
    End point description
    Measuring ex vivo production of T cell related cytokines by peripheral blood mononuclear cells (PBMC) in ELISpot assays
    End point type
    Secondary
    End point timeframe
    28 days after repeated vaccination
    End point values
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Number of subjects analysed
    21
    22
    21
    25
    25
    Units: SFCs/10^6 PBMCs
        median (inter-quartile range (Q1-Q3))
    55.0 (13.9 to 128)
    50.0 (1.53 to 158)
    26.7 (14.2 to 123)
    86.6 (28.3 to 228)
    51.6 (20.0 to 214)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs - during 7 days after vaccination SAEs - within 28 days after vaccination
    Adverse event reporting additional description
    In this study, solicited AEs are reported by all participants on a daily basis for 7 days after vaccine administration and all SAEs are reported that occur within 28 days after vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24
    Reporting groups
    Reporting group title
    Alternative vaccination group - 1x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - 2x mRNA-1273
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    Alternative vaccination group - Ad26.COV2-S
    Reporting group description
    		 The study was done in two different cohorts. In cohort one, KTRs receiving any combination of immunosuppressive drugs were included. These patients were randomly assigned in a 1:1:1 manner to receive either a single dose of the mRNA-1273 vaccine (100 μg, intramuscularly), two doses of mRNA-1273 simultaneously in both upper arms (2 × 100 μg, intramuscularly), or the Ad26.COV2-S vaccine (Janssen Biologics, Leiden, The Netherlands; 5 × 10¹⁰ viral particles, intramuscularly). This cohort is referred to as the alternative vaccination study group.

    Reporting group title
    mycophenolate mofetil +
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Reporting group title
    mycophenolate mofetil -
    Reporting group description
    		 In cohort two, only patients receiving triple immunosuppressive therapy consisting of a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid, and steroids were included. These patients were randomly assigned to either continuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil+) or discontinuation of mycophenolate mofetil or mycophenolic acid (mycophenolate mofetil−) from 1 week before until 1 week after vaccination with a single 100 μg intramuscular dose of the mRNA-1273 vaccine. This cohort is referred to as the mycophenolate mofetil– mycophenolic acid discontinuation study group.

    Serious adverse events
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Dehydration
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
    0 / 51 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
    0 / 51 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
    0 / 51 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 77 (0.00%)
    1 / 78 (1.28%)
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 77 (0.00%)
    0 / 78 (0.00%)
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Alternative vaccination group - 1x mRNA-1273 Alternative vaccination group - 2x mRNA-1273 Alternative vaccination group - Ad26.COV2-S mycophenolate mofetil + mycophenolate mofetil -
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 75 (90.67%)
    72 / 77 (93.51%)
    60 / 78 (76.92%)
    49 / 51 (96.08%)
    47 / 51 (92.16%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 75 (33.33%)
    31 / 77 (40.26%)
    40 / 78 (51.28%)
    22 / 51 (43.14%)
    20 / 51 (39.22%)
         occurrences all number
    25
    31
    40
    22
    20
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    13 / 75 (17.33%)
    16 / 77 (20.78%)
    12 / 78 (15.38%)
    10 / 51 (19.61%)
    9 / 51 (17.65%)
         occurrences all number
    13
    16
    12
    10
    9
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    5 / 75 (6.67%)
    10 / 77 (12.99%)
    3 / 78 (3.85%)
    12 / 51 (23.53%)
    10 / 51 (19.61%)
         occurrences all number
    5
    10
    3
    12
    10
    Induration
         subjects affected / exposed
    8 / 75 (10.67%)
    17 / 77 (22.08%)
    5 / 78 (6.41%)
    15 / 51 (29.41%)
    15 / 51 (29.41%)
         occurrences all number
    8
    17
    5
    15
    15
    Pain
    Additional description: Pain at injection side
         subjects affected / exposed
    64 / 75 (85.33%)
    67 / 77 (87.01%)
    38 / 78 (48.72%)
    47 / 51 (92.16%)
    45 / 51 (88.24%)
         occurrences all number
    64
    67
    38
    47
    45
    Endocrine disorders
    Fatigue
         subjects affected / exposed
    36 / 75 (48.00%)
    44 / 77 (57.14%)
    37 / 78 (47.44%)
    28 / 51 (54.90%)
    23 / 51 (45.10%)
         occurrences all number
    36
    44
    37
    28
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 75 (28.00%)
    19 / 77 (24.68%)
    24 / 78 (30.77%)
    15 / 51 (29.41%)
    15 / 51 (29.41%)
         occurrences all number
    21
    19
    24
    15
    15
    Myalgia
         subjects affected / exposed
    32 / 75 (42.67%)
    43 / 77 (55.84%)
    31 / 78 (39.74%)
    19 / 51 (37.25%)
    22 / 51 (43.14%)
         occurrences all number
    32
    43
    31
    19
    22
    Infections and infestations
    Fever
         subjects affected / exposed
    2 / 75 (2.67%)
    5 / 77 (6.49%)
    1 / 78 (1.28%)
    3 / 51 (5.88%)
    3 / 51 (5.88%)
         occurrences all number
    2
    5
    1
    3
    3
    Chills
         subjects affected / exposed
    15 / 75 (20.00%)
    27 / 77 (35.06%)
    13 / 78 (16.67%)
    18 / 51 (35.29%)
    12 / 51 (23.53%)
         occurrences all number
    15
    27
    13
    18
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Dec 2021
    1. Addition of extra exclusion criterion of vaccination with COVID-19 Janssen vaccine ; exclusion of subjects with ITP or aHus or patients with recurrent or recent (<2 years) trombotic events. 2. Adjustment of exclusion criterion that subject could not be vaccinated within a month before inclusion: adjusted to a week before start of study. 3. Inclusion of subjects who were seronegative after 3 previous mRNA vaccinations
    01 Mar 2022
    The plan was to follow subjects for 1 year after repeated vaccination. However, due to increasing SARS-CoV-2 infections, the government decided to offer a repeated vaccination sooner than anticipated after our study. Moreover, many subjects expierenced COVID-19 after the study. Therefore adequate analysis of the effect of the different vaccination strategies on the long term would be very difficult, maybe impossible. We therefore decided to end the study after the primary endpoint of 28 days after vaccination. The time point 6 months and 12 months after vaccination were removed from the original protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36354032
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