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    Clinical Trial Results:
    Pneumococcal vaccination of rheumatoid arthritis patients in immunomodulatory therapy

    Summary
    EudraCT number
    		 2014-001299-79
    Trial protocol
    		 DK  
    Global end of trial date
    19 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2021
    First version publication date
    12 Aug 2021
    Other versions
    Summary report(s)
    		 IMVX2014 summary

    Trial information

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    Trial identification
    Sponsor protocol code
    IMVX2014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of infectious Diseases, Odense University Hospital
    Sponsor organisation address
    Sdr. Boulevard 29, Entrance 18, 2nd floor Penthouse, Odense C, Denmark, 5000
    Public contact
    A. Mai Nguyen, Department of Infectious Diseases, 45 40259507, mai.nguyen@rsyd.dk
    Scientific contact
    A. Mai Nguyen, Department of Infectious Diseases, 45 40259507, mai.nguyen@rsyd.dk
    Sponsor organisation name
    Department of Infectious Diseases, Odense University Hospital
    Sponsor organisation address
    Sdr. Boulevard 29, Entrance 18, 2nd floor Penthouse, Odense C, Denmark, 5000
    Public contact
    Mai Nguyen, Department of Infectious Disease, Odense University Hospital, +45 40259507, mai.nguyen@rsyd.dk
    Scientific contact
    Mai Nguyen, Department of Infectious Disease, Odense University Hospital, mai.nguyen@rsyd.dk
    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
    15 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the serological responses to prime-boost pneumococcal vaccination with PCV13 followed by PPV23 among patients with RA treated with bDMARD according to dosing and intervals between immunizations, according to individual biological drug groups, and compared to responses in patients with RA treated with csDMARD.
    Protection of trial subjects
    Adverse effect/reactions were reported after vaccination with the 13-valent protein conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) 4 or 6 months later. Both vaccines are natonally and internatonally approved to prevent pneumococcal disease in our study poulation. All participants were offered follow up after vaccination as a part of the trial. In case of the adverse effects/reactions were not resolved after 4 weeks the participants was referred to a specialist who could examine the partcipant regarding the symptoms. All serious adverse effects were reported during the trial.
    Background therapy
    		 Only PCV13 and PPV23 were used across all groups.
    Evidence for comparator
    		 National Danish and international guidelines recommend pneumococcal vaccination with PCV13 followed by PPV23 at least 8 weeks later to prevent penumococcal disease among risk Groups. Our risk group was immunosuppressed rheumatoid arthritis patients (RA) treated with either conventional synthetic disease modifying anti-rheumatic drugs (csDMARD) or biological disease modifying anti-rheumatic drugs (bDMARD). Previous studies have show that vaccination with either the 7-valent conjugated pneumococcal vaccine (PCV7) or PPV23 gave a rise i pneumococcal antibodies among RA patients.
    Actual start date of recruitment
    01 May 2014
    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
    Denmark: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    58
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from 2 centers starting 01 October 2014. All participants were recruited from af survey carried out in the two centers. All aprticipants signed a informed consent.

    Pre-assignment
    Screening details
    		 192 participants were screened from a previous survey carried out in the two centers. Screening criteria: a diagnosis of RA, age > 18 years, and ongoing immunosuppressive therapy with cDMARDs and/or bDMARDs.

    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
    		 Control
    Arm description
    		 csDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)
    Arm type
    		 Control arm

    Investigational medicinal product name
    13-valent conjugate pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Prevenar 13
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Investigational medicinal product name
    23-valent polysaccharide pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Pneumovax
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Arm title
    		 Arm IA
    Arm description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    13-valent conjugate pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Prevenar 13
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Investigational medicinal product name
    13-valent conjugate pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Prevenar 13
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Arm title
    		 Arm IB
    Arm description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (24 weeks)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    13-valent conjugate pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Prevenar 13
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Investigational medicinal product name
    23-valent polysaccharide pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Pneumovax
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Arm title
    		 Arm II
    Arm description
    		 bDMARD treated participants. Vaccination: Double PCV13 (0 weeks) + PPV23 (16 weeks)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    13-valent conjugate pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Prevenar 13
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Investigational medicinal product name
    23-valent polysaccharide pneumooccal vaccine
    Investigational medicinal product code
    Other name
    Pneumovax
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    0.5mL contains polysaccharides of serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F and 33F. The vaccine administered as an intramuscular injection in the deltoid or the gluteus maximus muscle.

    Number of subjects in period 1
    		Control Arm IA Arm IB Arm II
    Started
    35
    21
    23
    21
    Completed
    33
    20
    22
    21
    Not completed
    2
    1
    1
    0
         Adverse event, non-fatal
    2
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Control
    Reporting group description
    		 csDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)

    Reporting group title
    Arm IA
    Reporting group description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)

    Reporting group title
    Arm IB
    Reporting group description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (24 weeks)

    Reporting group title
    Arm II
    Reporting group description
    		 bDMARD treated participants. Vaccination: Double PCV13 (0 weeks) + PPV23 (16 weeks)

    Reporting group values
    		 Control Arm IA Arm IB Arm II Total
    Number of subjects
    		 35 21 23 21 100
    Age categorical
    The median age among the 96 participants was 62 years (range 23-82 years). The demographics were similar in the four arms
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 21 14 12 11 58
        From 65-84 years
    		 14 7 11 10 42
        85 years and over
    		 0 0 0 0 0
    Age continuous
    The overall median age was 62 years (range 23-82 years).
    Units: years
        median (full range (min-max))
    		 59 (23 to 82) 62 (32 to 73) 59 (38 to 75) 64 (46 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 21 14 13 14 62
        Male
    		 14 7 10 7 38
    RA disease duration
    Duration of RA disease. The median duration was 12 years (range 0.5-33 years)
    Units: years
        median (full range (min-max))
    		 7 (0 to 54) 11 (3 to 33) 14 (5 to 32) 15 (0.5 to 30) -

    End points

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    End points reporting groups
    Reporting group title
    Control
    Reporting group description
    		 csDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)

    Reporting group title
    Arm IA
    Reporting group description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (16 weeks)

    Reporting group title
    Arm IB
    Reporting group description
    		 bDMARD treated participants. Vaccination: Single PCV13 (0 weeks) + PPV23 (24 weeks)

    Reporting group title
    Arm II
    Reporting group description
    		 bDMARD treated participants. Vaccination: Double PCV13 (0 weeks) + PPV23 (16 weeks)

    Primary: primary endpoint

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    End point title
    		 primary endpoint
    End point description
    The participants had a blood test drawn before and 4 weeks after each vaccination. Specific antipneumoccal antibodies for 12 specific serotypes were measured (mg/L). The prmary endpoint was defined as theproportion of participants in each treatment group responsive to ≥ 6 of 12 antipneumococcal antibody serotypes at week 4 after completion of the prime-boost vaccination series. A positive serological response was defined as a 4-fold increase from baseline or achieving a level of > 0.35 mg/L.
    End point type
    Primary
    End point timeframe
    The participants were vaccinated with PCV13 followed by PPV23. The primary endpoint was the seological response after completion after completion of the vaccination series.
    End point values
    		 Control Arm IA Arm IB Arm II
    Number of subjects analysed
    33
    20
    22
    21
    Units: subjects
    33
    20
    22
    21
    Statistical analysis title
    		 Statistical analysis for serological response
    Statistical analysis description
    Descriptive statistics are presented along with 95% CI for vaccine response. For variables that were not normally distributed, the median (range) was reported. For binary variables, the number (%) of participants was listed relatively to the total number of participants. Serological responses for pneumococcal antibodies were log-trans-formed and tested with Shapiro-Wilk test for normality.
    Comparison groups
    Control v Arm IA v Arm IB v Arm II
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [1] - The geometric mean concentration (GMC) and geometric mean fold rise for each serotype were calculated before and 4 weeks after both vaccinations. Differences in serological outcome between the 3 randomization arms, the 2 treatment Groups (bDMARD and csDMARD), and in subgroup analysis for the bDMARD were tested using 2-sample t-test or Fisher’s exact test as appropriate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events collected 28 November 2014 - 18 February 2016. For each participant adverse events were collected up to six months after completion of the prime-boost vaccination.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Control group
    Reporting group description
    		 Participants in control group suffering from adverse and serious adverse events after completion of PCV13 and PPV23 prime-boost vaccination.

    Reporting group title
    Arm IA
    Reporting group description
    		 Participants in Arm IA suffering from adverse and serious adverse events after completion of PCV13 and PPV23 prime-boost vaccination.

    Reporting group title
    Arm IB
    Reporting group description
    		 Participants in Arm IB suffering from adverse and serious adverse events after completion of PCV13 and PPV23 prime-boost vaccination.

    Reporting group title
    Arm II
    Reporting group description
    		 Participants in Arm II suffering from adverse and serious adverse events after completion of PCV13 and PPV23 prime-boost vaccination.

    Serious adverse events
    		 Control group Arm IA Arm IB Arm II
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 20 (5.00%)
    5 / 22 (22.73%)
    3 / 21 (14.29%)
         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)
    Cancer pain
    Additional description: One participant was admitted because of cancer pain after chemotherapy treatment
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    cancer
    Additional description: One participant was diagnosed with cancer mamma
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Vascular disorders
    Transient ischaemic attack
    Additional description: One participant experienced a transient ischemic attack.
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Cardiac disorders
    Chest pain
    Additional description: One participant experienced chest pain. Acute myocardial infarction was refuted.
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
    Additional description: One participant experienced pulmonary embolism
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 21 (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
    Infections and infestations
    Pneumonia
    Additional description: A total of 5 participants suffered from pneumonia. One participant suffered from pneumonia 3 times. They all resulted in admission to the hospital.
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    3 / 21 (14.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
    Additional description: Two participants suffered from urosepsis. One of them was admitted 2 times during the trial.
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    post operative infection
    Additional description: One participant experienced post operative infection. The operation was elective and not related to the vaccination
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Skin infection
    Additional description: One participant experienced a toe infection caused by Staphylococcus aureus
         subjects affected / exposed
    0 / 33 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 21 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Control group Arm IA Arm IB Arm II
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 33 (87.88%)
    18 / 20 (90.00%)
    17 / 22 (77.27%)
    18 / 21 (85.71%)
    Skin and subcutaneous tissue disorders
    Pain of skin, Swelling, Erythema, Itching
    Additional description: Local reaction after vaccination
         subjects affected / exposed
    29 / 33 (87.88%)
    18 / 20 (90.00%)
    17 / 22 (77.27%)
    18 / 21 (85.71%)
         occurrences all number
    62
    33
    49
    42

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jul 2015
    Number of participants reduced from 300 to 100. Thus resukting in a new power calculation.

    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/28966211
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