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    Clinical Trial Results:
    Natalizumabbehandling af progressiv multipel sklerose

    Summary
    EudraCT number
    		 2009-016703-35
    Trial protocol
    		 DK  
    Global end of trial date
    26 Jan 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jun 2022
    First version publication date
    26 Jun 2022
    Other versions
    Summary report(s)
    		 NAPMS summary

    Trial information

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    Trial identification
    Sponsor protocol code
    NAPMSv3.4
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01077466
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Danish Multiple Sclerosis Center, Rigshospitalet
    Sponsor organisation address
    Valdemar Hansens Vej 13, Glostrup, Denmark, 2600
    Public contact
    Per Soelberg Sørensen Valdemar Hansens Vej 13 2600 Glostrup, Denmark, Danish Multiple Sclerosis Center, Rigshospitalet Valdemar Hansens Vej 13 2600 Glostrup, Denmark, 0045 38633379, jeppe.romme.christensen@regionh.dk
    Scientific contact
    Per Soelberg Sørensen Valdemar Hansens Vej 13 2600 Glostrup, Denmark, Danish Multiple Sclerosis Center, Rigshospitalet Valdemar Hansens Vej 13 2600 Glostrup, Denmark, 0045 38633406, pss@rh.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
    10 Dec 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study safety and efficacy of natalizumab treatment of primary and secondary progressive multiple sclerosis. This will be done by measuring the effect of treatment on inflammation in the CNS by means of osteopontin levels in the cerebrospinal fluid (CSF). Safety measures further includes physical and neurological exmination, blood samples and MRI measures of disease activity.
    Protection of trial subjects
    Natalizumab is approved for the treatment of RRMS and is generally well tolerated. There is a known risk of 1:1000 for developing progressive multifocal leukoencephalopathy (PML). All patients will be observed for the known side effects throughout the course of the trial and all side effects are recorded. It has been previously shown that natalizumab may reduce some of the inflammation seen in progressive MS. It is not possible to say whether this effect is synonymous with a positive effect on the course of the disease. There is no placebo group in the study, so all patients will have the opportunity to achieve a beneficial effect. Since there are few or no effective treatments for progressive MS, a positive result of this study will have great significance for the development of new treatments for progressive MS. No patient will be deprived of active treatment. There is no approved treatment for PPMS. All patients participating in the study will be informed about the risk of known side effects, including the risk of PML, as well as the risk of unforeseen side effects in connection with drug trials. Participants in the trial will at can withdraw from the study any time. The study will be performed in accordance with the Helsinki Declaration of Biomedical research involving human individuals and ICH GCP. The potential beneficial effects of natalizumab in the treatment of progressive MS are estimated to outweigh the possible side effects. The rationale for the study is emphasized by the fact that only a few or no effective treatments for progressive MS and the outcome will be of great importance for patients, regardless of the outcome. Based on the above considerations, it is assessed that ethically, there is not arguments against performing the experiment.
    Background therapy
    		 Mitoxantrone and interferon-beta are approved for the treatment of SPMS. Before the patient beginning the study, these treatment options will be discussed with the patient.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2010
    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: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study Start Date : March 2010 Actual Primary Completion Date: January 2012 Actual Study Completion Date: January 2012

    Pre-assignment
    Screening details
    		 Inclusion Criteria: Age between 19 and 55 years Progressive disease course of multiple sclerosis (primary or secondary) Duration of progressive phase of at least 1 year Progression of > 1 EDSS point during the last 2 years (>½ EDSS point if EDSS > 5,5) EDSS </= 6.5 Written and informed consent

    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
    		 Open label uncontrolled
    Arm description
    		 300 mg Natalizumab IV for every 4 week for 56 weeks (15 doses for every patient).
    Arm type
    		 Experimental

    Investigational medicinal product name
    natalizumab
    Investigational medicinal product code
    AN100226
    Other name
    Tysabri
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    300 mg every 4 week

    Number of subjects in period 1
    		Open label uncontrolled
    Started
    24
    Completed
    17
    Not completed
    7
         Physician decision
    4
         Consent withdrawn by subject
    3

    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
    		 24 24
    Age categorical
    Median (range) age was 44 (36-53) for SPMS and 48 (27-55) for PPMS.
    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)
    		 24 24
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Female/male ratio was 7/5 for SPMS and 6/6 for PPMS.
    Units: Subjects
        Female
    		 13 13
        Male
    		 11 11
    Subject analysis sets

    Subject analysis set title
    NAPMS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The included patients in the NAPMS trial were 12 secondary progressive MS patients (SPMS) and 12 primary progressive MS (PPMS) patients. Female/male ratio was 7/5 for SPMS and 6/6 for PPMS. Median (range) age was 44 (36-53) for SPMS and 48 (27-55) for PPMS. Disease duration 14 years for SPMS and 4 years for PPMS. Median EDSS was 5.25 for SPMS and 5.0 for PPMS.

    Subject analysis set title
    NAPMS completed
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    17 patients completed the study

    Subject analysis sets values
    		 NAPMS NAPMS completed
    Number of subjects
    24
    17
    Age categorical
    Median (range) age was 44 (36-53) for SPMS and 48 (27-55) for PPMS.
    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)
    24
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Female/male ratio was 7/5 for SPMS and 6/6 for PPMS.
    Units: Subjects
        Female
    13
        Male
    11

    End points

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    End points reporting groups
    Reporting group title
    Open label uncontrolled
    Reporting group description
    		 300 mg Natalizumab IV for every 4 week for 56 weeks (15 doses for every patient).

    Subject analysis set title
    NAPMS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The included patients in the NAPMS trial were 12 secondary progressive MS patients (SPMS) and 12 primary progressive MS (PPMS) patients. Female/male ratio was 7/5 for SPMS and 6/6 for PPMS. Median (range) age was 44 (36-53) for SPMS and 48 (27-55) for PPMS. Disease duration 14 years for SPMS and 4 years for PPMS. Median EDSS was 5.25 for SPMS and 5.0 for PPMS.

    Subject analysis set title
    NAPMS completed
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    17 patients completed the study

    Primary: Cerebrospinal fluid osteopontin

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    End point title
    		 Cerebrospinal fluid osteopontin
    End point description
    Mean change in CSF osteopontin from baseline to week 60
    End point type
    Primary
    End point timeframe
    Baseline (week 0) to week 60
    End point values
    		 Open label uncontrolled NAPMS completed
    Number of subjects analysed
    17 [1]
    17
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    65 (34 to 96)
    65 (34 to 96)
    Attachments
    		 CSF endpoints
    Notes
    [1] - Analysis made on the 17 patients completing the trial
    Statistical analysis title
    		 CSF osteopontin change
    Comparison groups
    Open label uncontrolled v NAPMS completed
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0004
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 34
         upper limit
    		 96
    Variability estimate
    Standard deviation
    Dispersion value
    60
    Notes
    [2] - Single-arm longitudinal. Paired T-test.

    Secondary: Cerebrospinal fluid CXCL13

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    End point title
    		 Cerebrospinal fluid CXCL13
    End point description
    Mean change from baseline to week 60.
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17 [3]
    Units: pg/mL
        arithmetic mean (confidence interval 95%)
    28.6 (9.1 to 51.8)
    Notes
    [3] - Analysis made on the 17 patients who completed the study
    No statistical analyses for this end point

    Secondary: Cerebrospinal fluid MMP9

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    End point title
    		 Cerebrospinal fluid MMP9
    End point description
    Mean change from baseline to week 60
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    0.28 (0.18 to 0.4)
    No statistical analyses for this end point

    Secondary: Cerebrospinal fluid neurofilament light chain

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    End point title
    		 Cerebrospinal fluid neurofilament light chain
    End point description
    Mean change from baseline to week 60
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    243 (23 to 462)
    No statistical analyses for this end point

    Secondary: Cerebrospinal fluid myelin basic protein

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    End point title
    		 Cerebrospinal fluid myelin basic protein
    End point description
    MEan change from baseline to week 60
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: ng/mL
        arithmetic mean (confidence interval 95%)
    0.21 (0.003 to 0.43)
    No statistical analyses for this end point

    Secondary: Percentage brain volume change

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    End point title
    		 Percentage brain volume change
    End point description
    Change in percentage normalised brain volume from week 12 to week 60
    End point type
    Secondary
    End point timeframe
    Week 12 to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: percentage
        arithmetic mean (confidence interval 95%)
    -0.55 (-0.83 to -0.26)
    No statistical analyses for this end point

    Secondary: Normal apperaing white matter volume

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    End point title
    		 Normal apperaing white matter volume
    End point description
    Change in normal appearing white matter volume from week 12 to week 60
    End point type
    Secondary
    End point timeframe
    Week 12 to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: mL
        arithmetic mean (confidence interval 95%)
    -24.1 (-29.6 to -18.6)
    No statistical analyses for this end point

    Secondary: Grey matter volume

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    End point title
    		 Grey matter volume
    End point description
    Change in grey matter volume (GMV) from week 12 to week 60
    End point type
    Secondary
    End point timeframe
    Week 12 to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: mL
        arithmetic mean (confidence interval 95%)
    2.3 (-2.8 to 7.4)
    No statistical analyses for this end point

    Secondary: Number of new lesions on T2-weighted MRI images

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    End point title
    		 Number of new lesions on T2-weighted MRI images
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: New T2 lesions
    0
    No statistical analyses for this end point

    Secondary: Number of enlarging lesions on T2-weighted MRI images

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    End point title
    		 Number of enlarging lesions on T2-weighted MRI images
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: enlarging lesions
    2
    No statistical analyses for this end point

    Secondary: Volume of lesions on T2-weighted MRI images

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    End point title
    		 Volume of lesions on T2-weighted MRI images
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: mL
        arithmetic mean (confidence interval 95%)
    -0.4 (-1.2 to 0.5)
    No statistical analyses for this end point

    Secondary: Magnetization transfer ratio (MTR) in NAWM

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    End point title
    		 Magnetization transfer ratio (MTR) in NAWM
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    10
    Units: ratio
        arithmetic mean (confidence interval 95%)
    0.55 (0.11 to 0.99)
    No statistical analyses for this end point

    Secondary: Magnetization transfer ratio (MTR) in grey matter

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    End point title
    		 Magnetization transfer ratio (MTR) in grey matter
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    10
    Units: ratio
        arithmetic mean (confidence interval 95%)
    0.63 (0.13 to 1.14)
    No statistical analyses for this end point

    Secondary: Magnetization transfer ratio (MTR) lesions

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    End point title
    		 Magnetization transfer ratio (MTR) lesions
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    10
    Units: ratio
        arithmetic mean (confidence interval 95%)
    0.39 (-0.13 to 0.91)
    No statistical analyses for this end point

    Secondary: EDSS change

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    End point title
    		 EDSS change
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: points
        arithmetic mean (confidence interval 95%)
    -0.31 (-0.54 to -0.07)
    No statistical analyses for this end point

    Secondary: Timed 25 foot walk

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    End point title
    		 Timed 25 foot walk
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: seconds
        arithmetic mean (confidence interval 95%)
    0.22 (-1.09 to 1.53)
    No statistical analyses for this end point

    Secondary: 9 hole peg test

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    End point title
    		 9 hole peg test
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 60
    End point values
    		 Open label uncontrolled
    Number of subjects analysed
    17
    Units: seconds
        arithmetic mean (confidence interval 95%)
    -1.3 (-3.3 to 0.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to week 60
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD10
    Dictionary version
    2010
    Reporting groups
    Reporting group title
    Open label uncontrolled
    Reporting group description
    		 300 mg Natalizumab IV for every 4 week for 56 weeks (15 doses for every patient).

    Serious adverse events
    		 Open label uncontrolled
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 24 (12.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pneumonia
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    ureteral stone
         subjects affected / exposed
    3 / 24 (12.50%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    		 Open label uncontrolled
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 24 (75.00%)
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Pain in ear and jaw
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Gastrointestinal disorders
    nausea
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Postmenopausal bleeding
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 24 (20.83%)
         occurrences all number
    5
    Bronchitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Hand dermatitis
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Urticaria
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Tension
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Arthritis reactive
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Product issues
    Infusion related reaction
         subjects affected / exposed
    1 / 24 (4.17%)
         occurrences all number
    1
    Infections and infestations
    viral infection
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    herpes labialis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 24 (8.33%)
         occurrences all number
    3
    Pneumonia
         subjects affected / exposed
    18 / 24 (75.00%)
         occurrences all number
    29
    Urinary tract infection
         subjects affected / exposed
    1 / 24 (4.17%)
         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/24682973
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