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    Clinical Trial Results:
    An exploratory phase IIa study to evaluate the safety and immunological effects of intravenous interferonβ-1a (IFNβ-1a, Rebif®) therapy in the induction of tolerance to IFNβ in MS patients with neutralising antibodies (NAbs) to subcutaneous IFNβ-1a (Rebif® or Avonex®)

    Summary
    EudraCT number
    2008-000256-26
    Trial protocol
    GB  
    Global end of trial date
    12 Feb 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Apr 2019
    First version publication date
    25 Apr 2019
    Other versions
    Summary report(s)
    NAb Anergy End of STudy Report Feb 2015

    Trial information

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    Trial identification
    Sponsor protocol code
    006114QM
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Queen Mary University of London
    Sponsor organisation address
    5 Walden Street, London, United Kingdom, E1 2EF
    Public contact
    Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.ac.uk
    Scientific contact
    Prof Gavin Giovannoni, Queen Mary University of London, +44 02078822579, g.giovannoni@qmul.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
    11 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Feb 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Perform a “proof-of-concept” phase IIa clinical trial to induce tolerance to IFNβ in subjects with NAbs to IFNβ-1a.
    Protection of trial subjects
    AEs were monitored throughout the trial. Laboratory (haematology and biochemistry) tests, and physical examinations were performed at screening and thereafter at regular intervals throughout the trial.
    Background therapy
    Investigational Medicinal Product (IMP) Rebif® New Formulation EU/1/98/063/004, EU/1/98/063/005, EU/1/98/063/006 Mitoxantrone PL 04515/0127
    Evidence for comparator
    -
    Actual start date of recruitment
    22 May 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: 1
    Worldwide total number of subjects
    1
    EEA total number of subjects
    1
    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)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    One patient was consented and enrolled the study, out of the planned 15. It was difficult to recruit as new treatments were available once the trial started. This was an open label, UK study involving 1 site.

    Pre-assignment
    Screening details
    Male and female subjects with MS, aged 18 to 65 years (inclusive), who have been on IFNβ-1a for at least 12 months and have at least one significant relapse in the last 12 months and are considering switching therapy. Subjects with a positive NAb (neutralising antibody) titre of 20U will then be invited to continue in the study.

    Pre-assignment period milestones
    Number of subjects started
    1
    Number of subjects completed
    1

    Period 1
    Period 1 title
    Baseline - Visit 1 and Visit 2
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Rebif New Formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    (Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days. As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.

    Number of subjects in period 1
    Patient 1
    Started
    1
    Completed
    1
    Period 2
    Period 2 title
    Visit 3
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Mitoxantrone infusion

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Rebif New Formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    (Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days. As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.

    Number of subjects in period 2
    Patient 1
    Started
    1
    Completed
    1
    Period 3
    Period 3 title
    Visit 4
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    N/A

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Rebif New Formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    (Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days. As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.

    Number of subjects in period 3
    Patient 1
    Started
    1
    Completed
    1
    Period 4
    Period 4 title
    Visit 5 to Visit 9
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Rebif New Formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    (Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days. As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.

    Number of subjects in period 4
    Patient 1
    Started
    1
    Completed
    1
    Period 5
    Period 5 title
    Visit 10 and Visit 11
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mitoxantrone12mg/m2 /single dose

    Number of subjects in period 5
    Patient 1
    Started
    1
    Completed
    1
    Period 6
    Period 6 title
    Visit 12 to Visit 15
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Patient 1
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Interferon Rebif New Formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    (Rebif® New Formulation) 44mcg for injection. Rebif® New Formulation was administered via the IV route, under medical supervision, commencing with a dose of 44mcg. As this dose was tolerated, the subject received a further 88mcg IV on the same day followed by 132mcg IV daily for subsequent 4 days; the total intravenous dose administered will be 660mcg over 5 days. As the patient developed neutropenia WHO grave 4, the 5th day of treatment was suspended and the total dose was 528mcg over 4 days.

    Number of subjects in period 6
    Patient 1
    Started
    1
    Completed
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline - Visit 1 and Visit 2
    Reporting group description
    -

    Reporting group values
    Baseline - Visit 1 and Visit 2 Total
    Number of subjects
    1 1
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    1 1
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42 ± 0 -
    Gender categorical
    Units: Subjects
        Female
    1 1
        Male
    0 0
    Subject analysis sets

    Subject analysis set title
    patient 1
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.

    Subject analysis sets values
    patient 1
    Number of subjects
    1
    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)
    1
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42 ± 0
    Gender categorical
    Units: Subjects
        Female
    1
        Male
    0

    End points

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    End points reporting groups
    Reporting group title
    Patient 1
    Reporting group description
    -
    Reporting group title
    Patient 1
    Reporting group description
    -
    Reporting group title
    Patient 1
    Reporting group description
    -
    Reporting group title
    Patient 1
    Reporting group description
    -
    Reporting group title
    Patient 1
    Reporting group description
    -
    Reporting group title
    Patient 1
    Reporting group description
    -

    Subject analysis set title
    patient 1
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.

    Primary: Safety

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    End point title
    Safety [1]
    End point description
    There was a SAE as for Grade 4 laboratory results that caused the last dose of interferon not to be injected, as per protocol. There were no other relevant safety issues with the trial’s only participant.
    End point type
    Primary
    End point timeframe
    From Visit 5, when treatment starts, to Visit 15, last visit.
    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: Descriptive statistics only
    End point values
    patient 1
    Number of subjects analysed
    1
    Units: Grade
        number (not applicable)
    1
    No statistical analyses for this end point

    Primary: NAb titre at 3, 6, 9 and 12 months post intravenous IFN -1a relative to baseline

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    End point title
    NAb titre at 3, 6, 9 and 12 months post intravenous IFN -1a relative to baseline [2]
    End point description
    NAb titre for Interferon-beta is a biological assay and reports in TRU/mL units Visit 4. 171 Visit 12. 180 Visit 13. <20 Visit 14. <20 Visit 15. <20
    End point type
    Primary
    End point timeframe
    NAb titre at 3 (Visit 12), 6 (Visit 13), 9 (Visit 14) and 12 (Visit 15) months post intravenous IFN -1a relative to baseline (Visit 4)
    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: Descriptive statistics only
    End point values
    Patient 1 Patient 1 Patient 1 Patient 1 Patient 1 Patient 1 patient 1
    Number of subjects analysed
    1
    1
    1
    1
    1
    1
    1
    Units: TRU/mL
        number (not applicable)
    1
    1
    1
    1
    1
    1
    1
    No statistical analyses for this end point

    Other pre-specified: Immunological tests

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    End point title
    Immunological tests
    End point description
    T-cell proliferative response to rhuIFN -1a compared to baseline, change in T-and B-cell cytokine production in response to rhu-IFN -1a, as assessed using Elispot assays, intracellular cytokine staining, protein and mRNA levels, every 3 months post intravenous IFN-1a relative to baseline and the antigen-specific response will be compared to the changes in control antigen (tetanus toxoid) were not tested as only one patient was enrolled and completed and no significant value would be added with these analyses for one patient only.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Visit 12, Visit 13, Visit 14 and Visit 15.
    End point values
    patient 1
    Number of subjects analysed
    Units: Number
        number (not applicable)
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline Visit 4 to Visit 15
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    SNOMED CT
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Patient 1
    Reporting group description
    AEs: neutropenia grade IV (1), lymphopenia grade III (1), hypotension moderate (1), mild alopecia (1), cold sores (1), back pain (1), numbness of fingers (1) and rigors (1)

    Serious adverse events
    Patient 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: SAE with WHO grade IV neutropenia was detected pre Visit 9, so the 5th day of intravenous Rebif was not given. This was considered to be IMP related. This was reported to the sponsor, and discussed in the DSMB meeting.
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Patient 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    Blood and lymphatic system disorders
    lymphopenia
    Additional description: grade 3 lymphopenia
         subjects affected / exposed
    1 / 1 (100.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Apr 2011
    (a)AMENDMENT - (b)DATE APPROVED BY ETHICS - (c)DATE APPROVED BY MHRA - (d)DATE APPROVED BY R&D - (e)Study Documents Included - (f)Comments (a1)Initial Submission - (b1)Rejected - (c1)Rejected - (d1)N/A - (e1)Protocol Version 1.0; PIS Version 1.0/Version 2.0; ICF Version 1.0; GP Letter Version 1.0; Investigators Brochure IFN-Beta- 1a; SmPC Mitoxantrone; SmPC Rebif-44mcg - (f1)Resubmission to MHRA made on 9 September as initial submission not valid. (a2)Resubmission - (b2)16 Feb 2009 - (c2)24 Nov 2008 - (d2)20 Feb 2009 - (e2)Protocol Version 2.0; GP Letter Version 2.0; PIS Version 3.0; ICF Version 1.0; Tissues for Future Use ICF 1.0; Investigators Brochure IFN-Beta- 1a; SmPC Mitoxantrone; SmPC Rebif-44mcg; IMP Labels - (f2)Updates based on rejection by both MHRA and REC (a3)Substantial Amendment 1 - (b3)Rejected 12 Mar 2010; Modified Amendment Sent Approved 26 Aug 2010 - (c3)Acknowledged 11 Mar 2010 - (d3)8 Apr 2011 - (e3)Protocol Version 3.0 and PIS Version 4.0 - (f3)Clarification of IMP name Rebif: New Formulation (RNF); Use of algorithm to calculate dose of IFNbeta; Introduction of ECG Monitoring at dosing; More study visits; PIS Updated with new Rebif algorithm for administration. (a4)Minor Amendment 1 - (b4)29 Jun 2013 - (c4)N/A Minor - (d4)12 Sep 2012 - (e4)ICF Version 2.0; Tissues for Future Use ICF 2.0 and PIS Version 5.0 - (f4)Update to Barts Health (a5)Minor Amendment 2 - (b5)11 Sep 2012 - (c5)N/A Minor - (d5)17 Sep 2012 - (e5)Protocol Version 4.0 - (f5)Update of mitoxantrone administration guidelines; Extension of trial to August 2014; Update to details of where patients are seen (a6)Amendment 3 - (b6)13 Nov 2013 - (e6)Protocol Version 5.0 - (f6)Update to DSMB charter as the previous charter had not been followed correctly and was not proportionate to the study risks

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Feb 2014
    End of trial because of difficulty in recruitment
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Only 1 out of 15 planned patients were recruited, which limits the analysis and conclusions
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