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    Clinical Trial Results:
    Intrathecal therapy with monoclonal antibodies in severe progressive multiple sclerosis

    Summary
    EudraCT number
    2008-002626-11
    Trial protocol
    SE  
    Global end of trial date
    01 Jun 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Mar 2019
    First version publication date
    12 Jul 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Publication added

    Trial information

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    Trial identification
    Sponsor protocol code
    ITT-PMS
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01719159
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Umeå University
    Sponsor organisation address
    Dept of Neurology, Umeå, Sweden, 90185
    Public contact
    Anders Svenningsson, MD, PhD, Dept of Neurology, Umeå University , anders.svenningsson@umu.se
    Scientific contact
    Anders Svenningsson,MD, PhD, Dept of Neurology, Umeå University , anders.svenningsson@umu.se
    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
    22 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate tolerability and efficacy of intrathecally administered Mabthera in severe progressive MS where there is no available effective treatment
    Protection of trial subjects
    1. Development of allergic and anaphylactic reactions Before each injection, antihistamine and corticosteroids were administered in order to prevent any allergic reaction precipitated by the study drug. There was continuous observation of the patient during the first 4 hours after each injection of study drug and emergency equipment were available for immediate use in case of signs of allergic reactions. Standard treatment with epinephrine, fluids, antihistamine and steroids were available, intensive care specialist were available to be consulted when necessary. 2. Symptoms related to cytokine release from the lysis of B lymphocytes This was anticipated to demonstrate as increase in neurological symptoms and possibly also diffuse cerebral symptoms. In case of signs of cytokine release symptom, further treatment with corticosteroids iv and/or was given as well as emergent MRI. Data from treatment of patients with CNS lymphoma indicate a relatively low risk of cytokine release syndrome since only one of the 24 studied cases de-veloped such symptoms which were rapidly reversible. 3. Development of opportunistic CNS infections. In the period immediately in relation with the it injections, the major risk was contaminating bacterial infections. Precautions were done to make the injections sterile. CSF samples were drawn for bacterial cultures at each time Rituximab is given in the Rickham reservoir. If any sign of infection clinically, infectious disease specialist was consultated. In the longer perspective, special attention will be paid regarding PML. Any type of neurological deterioration that that may raise the suspicion of PML will lead to emergent MRI and CSF examination regarding signs of PML/JC virus infection. Further potential dosing of Rituximab will be halted until PML is safely ruled out.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Sep 2009
    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
    Sweden: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    22
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 23 subjects were recruited for the study from two centra in Umeå and Uppsala. Three patients (included in total 23) were initially treated and evaluated regarding side-effects and safety and reported to the Swedish Medical Products Agency as well as the local ethical committee before the remaining patients were recruited.

    Pre-assignment
    Screening details
    Screening details: Subjects which fulfilled the inclusion criteria for the study. Adults, males or non lactating females with progressive MS since at least three years, EDSS 4,0 - 7.0 and where conventional therapy not indicated, contraindicated or failed.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Baseline
    Arm description
    The baseline values of the 23 patients fulfilling the inclusion criteria and enrolled in the study.
    Arm type
    Baseline

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Rituximab (10 mg/mL; Roche AB, Stockholm, Sweden) was administered as 3 doses of 25 mg at weekly intervals. The first injection was performed approximately 3 weeks after implantation of the Ommaya reservoir in order to allow surgery-related subcutaneous swelling to subside. Patients were premedicated with 1 mg IV clemastine and 4 mg oral betamethasone 1 hour before the IT rituximab injection. In order to assess tolerance, the rituximab dose was titrated for the first 3 patients, with daily doses of 1 mg, 2.5 mg, 5 mg, 10 mg, and finally 25 mg. Daily monitoring of routine blood parameters and lymphocyte subpopulations by flow cytometry was performed to assess the safety and pharmacodynamic profile of IT treatment.

    Number of subjects in period 1
    Baseline
    Started
    23
    Completed
    23
    Period 2
    Period 2 title
    Active treatment period
    Is this the baseline period?
    No
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dose titration treatment with Rituximab
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab dose titration
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    In order to assess tolerance, the rituximab dose was titrated for the first 3 patients, with daily doses of 1 mg, 2.5 mg, 5 mg, 10 mg, and finally 25 mg. Repeated by 25 mg once weekly two times. Daily monitoring of routine blood parameters and lymphocyte subpopulations by flow cytometry was performed to assess the safety and pharmacodynamic profile of IT treatment.

    Arm title
    Active treatment with Rituximab
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    Before the dose was given 1 ml liquor was drawn and sent for routin culture analysis. Another 4 ml liquor was draw and saved. Rituximab (10 mg/mL; Roche AB, Stockholm, Sweden) was administered as 3 doses of 25 mg at weekly intervals. The first injection was performed approximately 3 weeks after implantation of the Ommaya reservoir in order to allow surgery-related subcutaneous swelling to subside. Patients were premedicated with 1 mg IV clemastine and 4 mg oral betamethasone 1 hour before the IT rituximab injection. 20 patients fulfilled this treatment period.

    Number of subjects in period 2
    Dose titration treatment with Rituximab Active treatment with Rituximab
    Started
    3
    20
    Completed
    3
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    -

    Reporting group values
    Baseline Total
    Number of subjects
    23 23
    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)
    22 22
        From 65-84 years
    1 1
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    45 (29 to 65) -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    7 7

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    The baseline values of the 23 patients fulfilling the inclusion criteria and enrolled in the study.
    Reporting group title
    Dose titration treatment with Rituximab
    Reporting group description
    -

    Reporting group title
    Active treatment with Rituximab
    Reporting group description
    -

    Primary: Safety parameters during the study

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    End point title
    Safety parameters during the study
    End point description
    Baseline assessments will be done twice with 2-4 weeks apart to have a baseline of criti-cal variables. LP and MRI will be performed once during this period. The therapy will be performed inpatient and require approximately 3 weeks hospital stay. Follow-up exami-nations will be performed at month 1, 3, 6, 9 an 12 after the last IT infusion.
    End point type
    Primary
    End point timeframe
    During the active treatment.
    End point values
    Baseline Dose titration treatment with Rituximab Active treatment with Rituximab
    Number of subjects analysed
    23
    3
    20
    Units: Number of events
    23
    3
    20
    Attachments
    Endpoint AE disposition ITT-PMS
    Statistical analysis title
    Key Elements of analysis plan
    Statistical analysis description
    All statistical testing will be done as 2-sided on a 5 % level of significance, and in particu-lar all confidence intervals (CI) will be 95 % intervals. In general, no specific procedure will be done for treating missing data and testing for multiplicity will not be considered. Most data analysis and presentation will be on a descriptive level
    Comparison groups
    Dose titration treatment with Rituximab v Active treatment with Rituximab v Baseline
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.05 [1]
    Method
    Wilcoxon signed-rank test
    Confidence interval
    Notes
    [1] - All statistical testing will be done as 2-sided on a 5 % level of significance, and in particu-lar all confidence intervals (CI) will be 95 % intervals.

    Secondary: Clinical scoring

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    End point title
    Clinical scoring
    End point description
    End point type
    Secondary
    End point timeframe
    During active treatment
    End point values
    Baseline Dose titration treatment with Rituximab Active treatment with Rituximab
    Number of subjects analysed
    23
    3
    20
    Units: Units
        number (not applicable)
    23
    3
    20
    No statistical analyses for this end point

    Secondary: Questionaires regarding MS quality of life, symptom inventory and fatigue

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    End point title
    Questionaires regarding MS quality of life, symptom inventory and fatigue
    End point description
    9HPT SDMT FSMC SF12 25 FWT and 6 MWT if possible EDSS
    End point type
    Secondary
    End point timeframe
    During active treatment.
    End point values
    Baseline Dose titration treatment with Rituximab Active treatment with Rituximab
    Number of subjects analysed
    23
    3
    20
    Units: Units
        number (not applicable)
    23
    3
    20
    No statistical analyses for this end point

    Secondary: Neurofilament levels in the CSF

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    End point title
    Neurofilament levels in the CSF
    End point description
    End point type
    Secondary
    End point timeframe
    During active treatment.
    End point values
    Baseline Dose titration treatment with Rituximab Active treatment with Rituximab
    Number of subjects analysed
    23
    3
    20
    Units: Units
        number (not applicable)
    23
    3
    20
    No statistical analyses for this end point

    Secondary: Immunological markers in blood and CSF

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    End point title
    Immunological markers in blood and CSF
    End point description
    Immunologcal markers in blood and CSF such as absolute numbers of major lym-phocyte subset as well as regulatory cell subset.
    End point type
    Secondary
    End point timeframe
    During active treatment.
    End point values
    Baseline Dose titration treatment with Rituximab Active treatment with Rituximab
    Number of subjects analysed
    23
    3
    20
    Units: Units
        number (not applicable)
    23
    3
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are registered from the time point when the study participants sign the informed consent until their last visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTC AE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    -

    Serious adverse events
    All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 23 (17.39%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Viral infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 23 (78.26%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Injury, poisoning and procedural comlication -Other, tendon injury due to fall
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Injury, poisoning and procedural complication- Other: trauma to chest due to fall
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Nervous system disorders
    Paresthesia
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    5
    Nervous system disorders - Other, Vertigo
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    15
    Headache
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Nystagmus
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    5
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Eye disorder - Other, Double vision
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    3
    Eye disorder - Other, Impaired vision
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Fever
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Flu like symptoms
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders - Other, Eczema in the scalp
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Infections and infestations
    Lip infection, labial herpes simplex
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1
    Upper respiratory infection
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Urinary tract infection
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    5
    Vaginal infection, fungal
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences all number
    1

    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.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25745637
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