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    Clinical Trial Results:
    ITT-PMS Extension An extension study of intrathecal therapy with monoclonal antibodies in progressive multiple sclerosis

    Summary
    EudraCT number
    2012-000721-53
    Trial protocol
    SE  
    Global end of trial date
    07 Jun 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Oct 2018
    First version publication date
    07 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ITT-PMSExt
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    County council of Västerbotten
    Sponsor organisation address
    University Hospital of Umeå, Umeå, Sweden, 90185
    Public contact
    Anders Svenningsson, Dept of Neurology, University Hospital of Umeå, Umeå, Sweden, 46 702415852, anders.svenningsson@ki.se
    Scientific contact
    Anders Svenningsson, Dept of Neurology, University Hospital of Umeå, Umeå, Sweden, 46 702415852, anders.svenningsson@ki.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
    15 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess long-term stabilising effects of on neurological symptoms by regular IT administered monoclonal antibodies in MS.
    Protection of trial subjects
    1. Development of allergic and anaphylactic reactions. Before each injection antihistamine and corticosteroids were administered to prevent any allergic reaction precipitated by the study drug. Continuous observations was done of the patient during the first hour after each injection of study drug and emergency equipment was available for immediate use in case of signs of allergic reactions. Standard treatm. with epinephrine, fluids, antihistamine and steroids were used; intensive care specialist was 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 as diffuse cerebral symptoms. Our experience from the first study, this does not to appear as a problem in this population but rather belonged to treatment with Rituximab in CNS lymphoma patients. 3. Development of opportunistic CNS infections. In the period immediately in relation with the intrahtecal injections, the major risk is contaminating bacterial infections. Precautions were taken to make the injections sterile. CSF samples were drawn for bacterial cultures at each Rituximab injection in the Rickham reservoir. If any sign of infection occured, infectious disease specialist was consulted. In our first study (EudraCT number 2008-002626-11), one case of low virulent meningitis with propionebacteriae occurred which was treated successfully with standard antibiotics and removal of the Rickham reservoir. The patient recovered fully from the infection. In the longer perspective, special attention will be paid regarding PML. Any type of neurological deterioration that may raise the suspicion of PML will lead to emergent MRI and CSF examination regarding signs of PML/JC virus infectin. Further potential dosing of Retuximab will be halted until PML is ruled out
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jan 2013
    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: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    17
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 19 subjects were recruted for this study from two centra in Umeå and in Uppsala. The study population were subjects with secondary or primary progressive MS that had completed the first trial of intrathecal Rituximab with one year of follow-up (ITT-MS; EudraCT number 2008-002626-11) and signed consent to enrol in the extension study.

    Pre-assignment
    Screening details
    Subject were eligible for inclusion in this study if all of the following criteria applied: - Completed the ITT-MS trial (EudraCT number 2008-002626-11) - Other therapy not indicated, contraindicated or failed - Judged as compliant with the protocol - In fertile females, willing to comply with effective contraceptive methods.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Active treatment with Rituximab
    Arm description
    After signing the informed concent for the extension study patients were treated with Rituximab (Mabthera®) as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses.
    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
    Rituximab (Mabthera®) was given as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses.

    Number of subjects in period 1
    Active treatment with Rituximab
    Started
    19
    Completed
    16
    Not completed
    3
         Consent withdrawn by subject
    1
         Adverse event, non-fatal
    1
         Lack of efficacy
    1

    Baseline characteristics

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

    Reporting group values
    Overall trial Total
    Number of subjects
    19 19
    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)
    17 17
        From 65-84 years
    2 2
        85 years and over
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    47 (31 to 70) -
    Gender categorical
    Units: Subjects
        Female
    13 13
        Male
    6 6

    End points

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    End points reporting groups
    Reporting group title
    Active treatment with Rituximab
    Reporting group description
    After signing the informed concent for the extension study patients were treated with Rituximab (Mabthera®) as an intrathecal injection in a Rickham reservoir. A dose of 25 mg were given every 6 month for 2 years with a total of 5 doses.

    Primary: The time to progression ≥ 1,0 step on the EDSS scale (Expanded Disability Status Scale)

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    End point title
    The time to progression ≥ 1,0 step on the EDSS scale (Expanded Disability Status Scale) [1]
    End point description
    Assessments were done every 6 months during the study in conjunction with administration of study drug.
    End point type
    Primary
    End point timeframe
    During the Active treatment
    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: Statistical testing will be done as 2-sided on a 5 % level of significance, all confidence intervals (CI) will be 95 % intervals. No specific procedure will be done for treating missing data and testing for multiplicity will not be considered. Data analysis and presentation will be on a descriptive level Each patient is it´s own control. There is no comparison between groups. Test of normality will be performed which will decide as to use parametric or non parametric statistics.
    End point values
    Active treatment with Rituximab
    Number of subjects analysed
    16
    Units: Number
    16
    No statistical analyses for this end point

    Secondary: Tests of walking ability and hand function (6MWAT or 25 FWT)

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    End point title
    Tests of walking ability and hand function (6MWAT or 25 FWT)
    End point description
    Assessments were done every 6 months during the study in conjunction with administration of study drug. 6 min walk test or 25 FWT and 9HPT (Ambulation, Arm function) were done at visit 0,6,12,18,24 month
    End point type
    Secondary
    End point timeframe
    During actve treatment
    End point values
    Number of subjects analysed
    Units: meter
    No statistical analyses for this end point

    Secondary: Questionaires regarding MS quality of life, symptom inventory and fatigue (SF12, FSMC)

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    End point title
    Questionaires regarding MS quality of life, symptom inventory and fatigue (SF12, FSMC)
    End point description
    Assessments were done every 6 months during the study in conjunction with administration of study drug. SF12, SDMT and FSMC (Quality of Life, Cogn function andv Fatigue) were done at visit 0,6,12,18,24 month.
    End point type
    Secondary
    End point timeframe
    During Active treatment
    End point values
    Number of subjects analysed
    Units: number
    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
    Assessments were done every 6 months during the study in conjunction with administration of study drug. LP (Biomarkers) were done at visit 0,12,24 month.
    End point type
    Secondary
    End point timeframe
    During Active treatment
    End point values
    Number of subjects analysed
    Units: number
    No statistical analyses for this end point

    Secondary: Immunological markers in blood and CSF such as absolute numbers of major lym-phocyte subset as well as regulatory cell subset

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    End point title
    Immunological markers in blood and CSF such as absolute numbers of major lym-phocyte subset as well as regulatory cell subset
    End point description
    Assessments were done every 6 months during the study in conjunction with administration of study drug. LP and Immunology (Biomarkers and Lymphocyte subsets) were done at visit 0,12,24 month.
    End point type
    Secondary
    End point timeframe
    During active treatment
    End point values
    Number of subjects analysed
    Units: number
    No statistical analyses for this end point

    Secondary: Safety assessment

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    End point title
    Safety assessment
    End point description
    Assessments were done every 6 months during the study in conjunction with administration of study drug. Blood chemistry, blood pressure and pulse were done at visit 0,6,12,18,24 month. MRI was done at visit 0,12,24 month
    End point type
    Secondary
    End point timeframe
    During Active treatment
    End point values
    Number of subjects analysed
    Units: Numbers
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time a patient consented to participate in the study until he/she completed the study all adverse events (AEs) and serious adverse events (SAEs) were collected, recorded and reported separately.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    All patients who consented to participate in the study.

    Serious adverse events
    All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 19 (5.26%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Infections and infestations
    Meningitis bacterial
    Additional description: Propionibacterium acne infection by the Rickham reservoir. Admitted to the hospital for an operation to take out the Rickham Reservoir. Treated with antibiotics intravenously for 10 days and additional 3-5 weeks with tablets. Fully recovered.
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    1 / 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
    15 / 19 (78.95%)
    Vascular disorders
    Deep venous thrombosis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Nervous system disorders
    Double vision
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Tremor
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    4
    Vertigo
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Paresthesia
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Basalioma
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Infections and infestations
    Small intestine infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    13
    Gastroenteritis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Fever
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Sore throat
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Upper respiratory infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Vaginal fungal infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Pharyngitis
    Additional description: viral throat infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Diabetes mellitus type 2
         subjects affected / exposed
    1 / 19 (5.26%)
         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
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