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    Clinical Trial Results:
    Alemtuzumab and rheumatoid arthritis - an immunisation study

    Summary
    EudraCT number
    2010-021146-22
    Trial protocol
    GB  
    Global end of trial date
    20 Nov 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    28 Sep 2016
    First version publication date
    29 Jul 2016
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Chief Investigator has requested that the full data set be removed while the trial is awaiting publication for reasons of confidentiality.
    Summary report(s)
    Alemtuzumab EudraCT 2010-021146-22 Abstract of study and data

    Trial information

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    Trial identification
    Sponsor protocol code
    5339
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Newcastle upon Tyne Hospitals NHS Foundation Trust, Joint Research Office
    Sponsor organisation address
    Regent Point (Level 1), Gosforth, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Professor John Isaacs, Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, 0191 222 5337, j.d.isaacs@ncl.ac.uk
    Scientific contact
    Professor John Isaacs, Institute of Cellular Medicine, Musculoskeletal Research Group, Newcastle University, 0191 222 5337, j.d.isaacs@ncl.ac.uk
    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
    16 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the ability to mount immune responses (to measure the function of the immune system) in patients who received alemtuzumab for rheumatoid arthritis between 1991 and 1994 and a matched control group with long-standing rheumatoid arthritis. The control group will be matched for disease duration (within 5 years of matched case), age (within 10 years of matched case) and gender.
    Protection of trial subjects
    Potential participants will have the study explained to them and be given ample time to ask questions and consider participation prior to obtaining written informed consent. All study procedures performed by qualified and trained study staff All AEs/SAEs recorded by site staff during study participation. Trial Management Group to meet at regular intervals to discuss any study issues, especially information relevant to participant safety or welfare
    Background therapy
    -
    Evidence for comparator
    Patients receiving alemtuzumab for RA between 1991 and 1994 have remained lymphopenic during long-term follow-up but do not appear otherwise to be immunosuppressed. An observational study is performed approximately every 5 years on these patients, documenting mortality against a closely matched cohort of patients with RA who have never received alemtuzumab. This has confirmed no excess in mortality over 12 years follow-up to date. There were no specific control subjects in the original alemtuzumab studies but mortality has been compared with a closely matched control group of patients from the EULAR database. However, the latter database does not provide morbidity outcomes for comparison. A recent immunization study looked at serological responses to vaccines in alemtuzumab recipients but, due to restrictions within the study, it was not possible to compare responses with matched controls. The current study seeks to rectify that evidence gap.
    Actual start date of recruitment
    01 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    8
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients that were treated with alemtuzumab between 1991 and 1994 were identified by the Chief Investigator from the previous study database. Matched-control patients who had not received alemtuzumab, were identified locally in Addenbrookes Hospital, Cambridge, UK. All participants were recruited between October 2013 and October 2014.

    Pre-assignment
    Screening details
    Inclusion criteriafor for the study were as follows Alemtuzumab recipients -Received alemtuzumab in original Cambridge studies (1991-94) Matched controls - Rheumatoid arthritis according to 1987 ACR criteria, Disease duration within 5 years of matched case, Age within 10 years of matched case, Gender profile to match alemtuzumab recipients

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    n/a

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Alemtuzumab cohort
    Arm description
    Patients that were treated with alemtuzumab (CAMPATH-1H) for RA between 1991 and 1994
    Arm type
    Experimental

    Investigational medicinal product name
    Alemtuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in administration system
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Alemtuzumab administered previously to the Alemtuzumab cohort during 1991-1994 study, not administered in the current study

    Arm title
    Control
    Arm description
    Age and sex matched RA patients with a similar disease duration, who had not received alemtuzumab
    Arm type
    Experimental matched control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Alemtuzumab cohort Control
    Started
    9
    8
    Completed
    9
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Alemtuzumab cohort
    Reporting group description
    Patients that were treated with alemtuzumab (CAMPATH-1H) for RA between 1991 and 1994

    Reporting group title
    Control
    Reporting group description
    Age and sex matched RA patients with a similar disease duration, who had not received alemtuzumab

    Reporting group values
    Alemtuzumab cohort Control Total
    Number of subjects
    9 8 17
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    4 4 8
        From 65-84 years
    5 4 9
    Gender categorical
    Units: Subjects
        Female
    7 7 14
        Male
    2 1 3
    Disease duration
    Units: Years
        median (full range (min-max))
    31 (23 to 40) 24.5 (20 to 41) -
    DAS-28
    Units: DAS score
        median (full range (min-max))
    3.44 (1.38 to 5.33) 3.9 (2.03 to 5.75) -
    CRP
    Units: mg/L
        median (full range (min-max))
    7 (2 to 134) 1.5 (1 to 2) -
    ESR
    Units: mm/hr
        median (full range (min-max))
    34 (4 to 104) 11.5 (2 to 38) -
    HAQ
    Units: HAQ score
        median (full range (min-max))
    2.25 (2 to 3) 1.69 (0.25 to 2.125) -
    VAS
    Units: VAS score
        median (full range (min-max))
    25 (2 to 56) 23 (4 to 75) -
    IgG
    Units: g/ml
        median (full range (min-max))
    9.5 (6.2 to 16.6) 9.95 (4.4 to 16.3) -
    IgA
    Units: g/ml
        median (full range (min-max))
    2.6 (1.1 to 4.2) 1.9 (0.4 to 3.9) -
    IgM
    Units: g/ml
        median (full range (min-max))
    0.85 (0.006 to 3.2) 0.85 (0.3 to 2.5) -
    RF
    Units: IU
        median (full range (min-max))
    0 (0 to 67) 39 (0 to 275) -
    CCP
    Units: U/ml
        median (full range (min-max))
    0.55 (0 to 340) 215 (1.2 to 340) -
    Total lymphocytes
    Units: x109/L
        median (full range (min-max))
    0.93 (0.41 to 3.1) 1.125 (0.34 to 2.38) -
    CD4+ T cells
    Units: x109/L
        median (full range (min-max))
    0.37 (0.13 to 0.94) 0.48 (0.13 to 0.65) -
    CD4+ naive T cells
    Units: x109/L
        median (full range (min-max))
    0.23 (0.01 to 0.61) 0.21 (0.07 to 0.29) -
    CD4+ total memory T cells
    Units: x109/L
        median (full range (min-max))
    0.13 (0.11 to 0.34) 0.26 (0.06 to 0.56) -
    CD4+ central memory T cells
    Units: x109/L
        median (full range (min-max))
    0.08 (0.05 to 0.16) 0.2 (0.03 to 0.42) -
    CD4+ effector memory T cells
    Units: x109/L
        median (full range (min-max))
    0.05 (0.02 to 0.17) 0.06 (0.02 to 0.14) -
    CD8+ T cells
    Units: x109/L
        median (full range (min-max))
    0.1 (0.04 to 0.72) 0.11 (0.05 to 0.42) -
    CD8+ naive T cells
    Units: x109/L
        median (full range (min-max))
    0.05 (0.01 to 0.14) 0.02 (0.01 to 0.08) -
    CD8+ total memory T cells
    Units: x109/L
        median (full range (min-max))
    0.07 (0.02 to 0.13) 0.06 (0.01 to 0.19) -
    CD8+ central memory T cells
    Units: x109/L
        median (full range (min-max))
    0.01 (0.003 to 0.01) 0.02 (0.005 to 0.11) -
    CD8+ effector memory T cells
    Units: x109/L
        median (full range (min-max))
    0.01 (0.007 to 0.07) 0.03 (0.007 to 0.1) -
    B cells
    Units: x109/L
        median (full range (min-max))
    0.01 (0.01 to 0.05) 0.09 (0.02 to 0.2) -
    Naive B cells
    Units: x109/L
        median (full range (min-max))
    0.01 (0.001 to 0.02) 0.08 (0.07 to 0.14) -
    Memory B cells
    Units: x109/L
        median (full range (min-max))
    0.006 (0.002 to 0.02) 0.01 (0.008 to 0.03) -
    CD5+ B cells
    Units: x109/L
        median (full range (min-max))
    0.001 (0.001 to 0.005) 0.03 (0.001 to 0.08) -
    CD19+ CD24hi CD38hi B cells
    Units: x109/L
        median (full range (min-max))
    0.001 (0.00005 to 0.002) 0.009 (0.0008 to 0.038) -
    NK cells
    Units: x109/L
        median (full range (min-max))
    0.1 (0.02 to 0.17) 0.07 (0.02 to 0.1) -
    NK T cells
    Units: x109/L
        median (full range (min-max))
    0.01 (0.0006 to 0.13) 0.009 (0.002 to 0.02) -

    End points

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    End points reporting groups
    Reporting group title
    Alemtuzumab cohort
    Reporting group description
    Patients that were treated with alemtuzumab (CAMPATH-1H) for RA between 1991 and 1994

    Reporting group title
    Control
    Reporting group description
    Age and sex matched RA patients with a similar disease duration, who had not received alemtuzumab

    Primary: Seroconversion rate

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    End point title
    Seroconversion rate [1]
    End point description
    End point type
    Primary
    End point timeframe
    Overall trial
    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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    6
    4
    Units: percentage
    number (not applicable)
        Diptheria toxoid
    33
    25
        Tetanus toxoid
    66.7
    50
        Poliovirus P1
    50
    100
        Poliovirus P2
    16.6
    100
        Poliovirus P3
    83.3
    100
    No statistical analyses for this end point

    Primary: Seroprotection rate

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    End point title
    Seroprotection rate [2]
    End point description
    End point type
    Primary
    End point timeframe
    Overall trial
    Notes
    [2] - 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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    6
    4
    Units: percentage
    number (not applicable)
        Diptheria toxoid
    66
    25
        Tetanus toxoid
    100
    100
        Poliovirus P1
    100
    100
        Poliovirus P2
    83.3
    100
        Poliovirus P3
    83.3
    100
    No statistical analyses for this end point

    Primary: % Satisfactory response

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    End point title
    % Satisfactory response [3]
    End point description
    End point type
    Primary
    End point timeframe
    Overall trial
    Notes
    [3] - 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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    7
    4
    Units: percentage
    number (not applicable)
        Pneumococcus antigen
    66
    0
    No statistical analyses for this end point

    Primary: Seroprotection rate

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    End point title
    Seroprotection rate [4]
    End point description
    Including patients who had influenza vaccine out with this study period.
    End point type
    Primary
    End point timeframe
    Overall trial
    Notes
    [4] - 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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    9
    8
    Units: percentage
    number (not applicable)
        Influenza vaccine A/Cal/7/09
    22
    87.5
        Influenza vaccine A/Texas/50/12
    56
    87.5
        Influenza vaccine B/Mass/02/12
    11
    37.5
    No statistical analyses for this end point

    Primary: Seroconversion rate

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    End point title
    Seroconversion rate [5]
    End point description
    Patients vaccinated at interview
    End point type
    Primary
    End point timeframe
    Overall trial
    Notes
    [5] - 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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    4
    3
    Units: percentage
    number (not applicable)
        Influenza vaccine A/Cal/7/09
    25
    0
        Influenza vaccine A/Texas/50/12
    0
    0
        Influenza vaccine B/Mass/02/12
    0
    0
    No statistical analyses for this end point

    Primary: Seroprotection rate

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    End point title
    Seroprotection rate [6]
    End point description
    Patients vaccinated at interview
    End point type
    Primary
    End point timeframe
    Overall trial
    Notes
    [6] - 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: Vaccine data not result of statistical tests
    End point values
    Alemtuzumab cohort Control
    Number of subjects analysed
    4
    3
    Units: percentage
    number (not applicable)
        Influenza vaccine A/Cal/7/09
    50
    66.7
        Influenza vaccine A/Texas/50/12
    50
    100
        Influenza vaccine B/Mass/02/12
    25
    33.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study participation
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    As reported
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Alemtuzumab cohort
    Reporting group description
    Patients that were treated with alemtuzumab (CAMPATH-1H) for RA between 1991 and 1994

    Reporting group title
    Control
    Reporting group description
    Age and sex matched RA patients with a similar disease duration, who had not received alemtuzumab

    Serious adverse events
    Alemtuzumab cohort Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Alemtuzumab cohort Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 9 (33.33%)
    5 / 8 (62.50%)
    Immune system disorders
    common cold
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 8 (37.50%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    injection site reaction
         subjects affected / exposed
    2 / 9 (22.22%)
    3 / 8 (37.50%)
         occurrences all number
    3
    4
    Feeling unwell
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Loss of appetite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Sep 2012
    • Re-classification of IMP by MHRA. MHRA now define the alemtuzumab (administered to the alemtuzumab recipients at Cambridge between 1991 and 1994) as the IMP for this study. The seasonal flu, pneumonia and diptheria, polio and tetanus booster vaccines to be administered within the context of this study are now NIMPs (physiological probes). • The Pharmacovigilance section of the protocol is substantially altered to reflect the IMP & NIMP definitions. The time elapsed since last administration of IMP is also referenced (stipulating that adverse reactions to the IMP, or SUSARs linked to an interaction between the IMP and NIMP are NOT anticipated) . Pregnancy information for female partners of male participants will also now be collected only for the alemtuzumab group (who were originally administered the IMP). • Streamline participant follow-up and the time points I assessments as per the primary and secondary outcome measures; also amended are the time points stipulated in the definition of end of study and the time points for collecting AEs/SAEs. • Reduction in the total volume of blood required at the screening and follow­ up visit. • SmPC documentation is updated to incorporate the re-classification of the IMP, change of flu vaccine brand routinely available at Addenbrooke's Hospital in 2012- 2013 and an update to Pneumovax II SmPC. • Logistics to now allow the screening and baseline visit to be combined into one single clinic visit (with the exception of female participants of child bearing potential, where results from the study-specific serum pregnancy test are required prior to vaccination) . • Protocol section 11 is substantially reworded, primarily to reflect that the ONS data (for alemtuzumab recipients) as received by the Chief Investigator does not contain patient contact details (as was previously perceived). • Amendments to study documentation in line with the changes outlined in protocol
    18 Jul 2013
    SmPC documentation updated The process outlined for identification, screening and recruitment of alemtuzumab participants (protocol section 11.1) has been amended/further clarification provided. Exclusion criteria amended for control patients to exclude patients who received rituximab within the past 6 months (extended from 3 months, as per previous study protocol) Exclusion criteria amended for control patients to exclude females who are known to be pregnant or breast feeding Reduction in total volume of blood required for analysis, following latest confirmation from labs. Following Sponsor confirmation, statistical input to the Trial Oversight Committee is not deemed necessary. The Independent Chair and Independent Assessor for safety/adverse events are now appointed. The format/layout of the DAS28 (incorporated as protocol Appendix E) has been amended. Minor changes to study documentation, including change to contact details/name of central labs, blood volume inconsistency within protocol, etc.

    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.
    We acknowledge that due to the small numbers in both groups robust statistical comparison was not possible. Additionally, the timing of vaccination outwith this study was unknown potentially making meaningful comparison difficult
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