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    Clinical Trial Results:
    A Randomized, Parallel Group, Single-Blind, Phase 2 Study to Evaluate the immune response of two classes of SARS-Cov-2 Vaccines employed as Third Vaccination in Patients under current Rituximab Therapy and no humoral response after standard mRNA vaccination

    Summary
    EudraCT number
    		 2021-002348-57
    Trial protocol
    		 AT  
    Global end of trial date
    08 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Aug 2023
    First version publication date
    23 Aug 2023
    Other versions
    Summary report(s)
    		 Study summary

    Trial information

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    Trial identification
    Sponsor protocol code
    2021-002348-57
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Währinger Gürtel 18-20, Vienna, Austria,
    Public contact
    Selma Tobudic, Medical University of Vienna, 0043 1404004440, selma.tobudic@meduniwien.ac.at
    Scientific contact
    Selma Tobudic, Medical University of Vienna, 0043 1404004440, selma.tobudic@meduniwien.ac.at
    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
    21 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study aims to investigate the humoral and cellular immune responses after a second boost vaccination with either an mRNA or an vector vaccine against SARS-CoV-2 in adult patients treated with rituximab who did not develop antibodies to the first two vaccinations with an mRNA vaccine. Primary Objective: To assess the immunogenicity to a third vaccination mRNA-SARS-CoV-2 vaccine (Biontech/Pfizer or Moderna) compared to a vector SARS-CoV-2 (AstraZeneca) vaccination as a second boost in patients with rituximab by measuring quantitative antibody levels by enzyme-linked immunosorbent assay test (ELISA) and neutralization test (NT) or pseudo viral neutralization assay. Null hypothesis: There is no statistical difference in the seroconversion rate between patients receiving a third mRNA vaccination and the patients receiving a second boost with AstraZeneca.
    Protection of trial subjects
    The trial was approved by the local IRB. An insurance was acquired for all participants. All included participants signed an informed consent and were given adequate time to consider their decision. All types of vaccines used were approved in the use against SARS-CoV-2. Participants received emergency contact information 24/7 in case of unexpected adverse events.
    Background therapy
    		 All patients recvied rituximab i.v. infusions in regular intervals as part of their routine care (inclusion criteria), as well as, when deemed necessesary, additional immunosuppressive medication. All Background therapy was left unaltered during the clinical trial.
    Evidence for comparator
    		 Both groups recivied a vaccine compound which was approved for SARS-CoV-2, thus the safety and efficacy was proven (Falsey et al NEJM 2021, Polack et al NEJM 2021, Baden et al NEJM 2021).
    Actual start date of recruitment
    25 May 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 60
    Worldwide total number of subjects
    60
    EEA total number of subjects
    60
    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)
    32
    From 65 to 84 years
    27
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adults (≥18 years) with chronic inflammatory rheumatic or neurologic diseases under current rituximab therapy and without detectable SARS-CoV-2 spike (S) were recruited at the rheumatology and neurology outpatient department of the Vienna General Hospital.

    Pre-assignment
    Screening details
    		 68 patients were screened for this trial. 8 patients did not fullfill the inclusion criteria and were thus not included.

    Pre-assignment period milestones
    Number of subjects started
    		 60
    Intermediate milestone: Number of subjects
    Randomization: 60
    Number of subjects completed
    		 55

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Adverse event, non-fatal: 1
    Reason: Number of subjects
    		 Consent withdrawn by subject: 4
    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Binding of vaccines was ensured by using pre-arranged dose aliquots in syringes without reference to the type used by the Central Pharmacy of the Vienna General Hospital.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vector vaccine
    Arm description
    		 Patient being randomized to the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca) arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vaxzevria
    Investigational medicinal product code
    ChAdOx1-S
    Other name
    Covid-19 Vaccine AstraZeneca
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0,5 mL dispersion for intramuscular use.

    Arm title
    		 mRNA vaccine
    Arm description
    		 Patient being randomized to the mRNA vaccine (BNT162b2 or mRNA-1273, respective of their initial vaccination compound) arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    COVID-19 Vaccine Moderna
    Investigational medicinal product code
    mRNA-1273
    Other name
    Spikevax
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    100 µg for intramuscular use

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    BNT162B2
    Other name
    Biontech/Pfizer COVID Vaccine
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    30 µg dispersion for intramuscular use

    Number of subjects in period 1 [1]
    		Vector vaccine mRNA vaccine
    Started
    27
    28
    Vaccination
    27
    28
    Week 1 - cellular immunity
    27
    28
    Week 4 - humoral immunity
    27
    28
    Completed
    27
    28
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Patients were revoked their consent in the pre-assignment period.
    Period 2
    Period 2 title
    Extension period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded, open label

    Arms
    Arm title
    		 mRNA vaccine
    Arm description
    		 4th dose open label mRNA vaccination
    Arm type
    		 Experimental

    Investigational medicinal product name
    COVID-19 Vaccine Moderna
    Investigational medicinal product code
    mRNA-1273
    Other name
    Spikevax
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    100 µg for intramuscular use

    Investigational medicinal product name
    Comirnaty
    Investigational medicinal product code
    BNT162B2
    Other name
    Biontech/Pfizer COVID Vaccine
    Pharmaceutical forms
    Concentrate for dispersion for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    30 µg dispersion for intramuscular use

    Number of subjects in period 2 [2]
    		mRNA vaccine
    Started
    37
    4th vaccination
    37
    Week 1 - Cellular immunity
    37
    Week 4 - Humoral immunity
    36
    Completed
    36
    Not completed
    1
         Adverse event, non-fatal
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patients withdrew their consent to the extension period before starting in the period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vector vaccine
    Reporting group description
    		 Patient being randomized to the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca) arm.

    Reporting group title
    mRNA vaccine
    Reporting group description
    		 Patient being randomized to the mRNA vaccine (BNT162b2 or mRNA-1273, respective of their initial vaccination compound) arm.

    Reporting group values
    		 Vector vaccine mRNA vaccine Total
    Number of subjects
    		 27 28 55
    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)
    		 60.9 ± 15.0 58.9 ± 18.4 -
    Gender categorical
    Units: Subjects
        Female
    		 18 23 41
        Male
    		 9 5 14
    Detectable peripheral B cells
    Units: Subjects
        B cell detectable
    		 8 10 18
        B cells not detectable
    		 19 18 37

    End points

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    End points reporting groups
    Reporting group title
    Vector vaccine
    Reporting group description
    		 Patient being randomized to the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca) arm.

    Reporting group title
    mRNA vaccine
    Reporting group description
    		 Patient being randomized to the mRNA vaccine (BNT162b2 or mRNA-1273, respective of their initial vaccination compound) arm.
    Reporting group title
    mRNA vaccine
    Reporting group description
    		 4th dose open label mRNA vaccination

    Primary: Rate of seroconversion

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    End point title
    		 Rate of seroconversion
    End point description
    End point type
    Primary
    End point timeframe
    4 weeks after baseline (=vaccination)
    End point values
    		 Vector vaccine mRNA vaccine
    Number of subjects analysed
    27
    28
    Units: Rate of seroconversion
        Seroconversion
    6
    9
        No Seroconversion
    21
    19
    Statistical analysis title
    		 Chi-Squared
    Comparison groups
    Vector vaccine v mRNA vaccine
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Detectable cellular immunity

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    End point title
    		 Detectable cellular immunity
    End point description
    End point type
    Secondary
    End point timeframe
    Cellular immunit at week 1 after baseline (=vaccination)
    End point values
    		 Vector vaccine mRNA vaccine
    Number of subjects analysed
    20 [1]
    16 [2]
    Units: Rate of detectable cellular immunity
        Cellular immunity
    20
    13
        No cellular immunity
    0
    3
    Notes
    [1] - Matched samples before and after the third vaccination were available from 36 patients.
    [2] - Matched samples before and after the third vaccination were available from 36 patients.
    No statistical analyses for this end point

    Post-hoc: Factors associated with seroconversion

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    End point title
    		 Factors associated with seroconversion
    End point description
    End point type
    Post-hoc
    End point timeframe
    At week 4 after vaccination
    End point values
    		 Vector vaccine mRNA vaccine
    Number of subjects analysed
    27
    28
    Units: Rate of seroconversion
        Seroconversion
    6
    9
        No seroconversion
    21
    19
    Statistical analysis title
    		 Multivariable logistic regression
    Comparison groups
    mRNA vaccine v Vector vaccine
    Number of subjects included in analysis
    55
    Analysis specification
    Post-hoc
    Analysis type
    		 other [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Regression, Logistic
    Confidence interval
    Notes
    [3] - Exploratory post-hoc univariate logistic regression models revealed that detectable peripheral B cells strongly favoured the likelihood of seroconversion (OR: 22.67, 95% CI 5.46 to 125.10), while co-medication with any conventional synthetic disease-modifying antirheumatic drug (csDMARD) favoured non-seroconversion. Compared with mRNA booster vaccination, the vector vaccine showed a lower likelihood of inducing humoral response though not statistically significant.
    [4] - Detectable peripheral B cells.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 weeks.
    Adverse event reporting additional description
    Paper based diary for vaccine related AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Vector vaccine
    Reporting group description
    		 Patient being randomized to the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca) arm.

    Reporting group title
    mRNA vaccine
    Reporting group description
    		 Patient being randomized to the mRNA vaccine (BNT162b2 or mRNA-1273, respective of their initial vaccination compound) arm.

    Serious adverse events
    		 Vector vaccine mRNA vaccine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
    Additional description: Reoccurance of known Afbil before vaccination.
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Vector vaccine mRNA vaccine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 27 (88.89%)
    22 / 28 (78.57%)
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    7 / 27 (25.93%)
    6 / 28 (21.43%)
         occurrences all number
    7
    6
    Local reaction
         subjects affected / exposed
    11 / 27 (40.74%)
    12 / 28 (42.86%)
         occurrences all number
    11
    12
    Fatigue
         subjects affected / exposed
    21 / 27 (77.78%)
    13 / 28 (46.43%)
         occurrences all number
    21
    13
    Headache
         subjects affected / exposed
    14 / 27 (51.85%)
    14 / 28 (50.00%)
         occurrences all number
    14
    14
    Arthralgia
         subjects affected / exposed
    13 / 27 (48.15%)
    8 / 28 (28.57%)
         occurrences all number
    13
    8
    Myalgia
         subjects affected / exposed
    15 / 27 (55.56%)
    9 / 28 (32.14%)
         occurrences all number
    15
    9
    Nausea
         subjects affected / exposed
    10 / 27 (37.04%)
    7 / 28 (25.00%)
         occurrences all number
    10
    7
    Pruritus
         subjects affected / exposed
    5 / 27 (18.52%)
    3 / 28 (10.71%)
         occurrences all number
    5
    3
    Local pain
         subjects affected / exposed
    10 / 27 (37.04%)
    16 / 28 (57.14%)
         occurrences all number
    10
    16
    Worsening of underlying disease
    Additional description: Subjective by participant.
         subjects affected / exposed
    5 / 27 (18.52%)
    2 / 28 (7.14%)
         occurrences all number
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    One limitation of the trial is the absence of a placebo control, which was considered unethical in this high-risk population.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/35977809
    http://www.ncbi.nlm.nih.gov/pubmed/35027397
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