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    Clinical Trial Results:
    Natural history study in adult patients with SMA types 2-3-4 and Role of neurodegenerative and neuro-inflammatory biomarkers in SMA adults treated with nusinersen.

    Summary
    EudraCT number
    		 2019-005007-40
    Trial protocol
    		 BE  
    Global end of trial date
    30 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jun 2023
    First version publication date
    03 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    S62874
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospitals Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Department of Neurology, University Hospitals Leuven, 32 16344280, secretariaat.neuro@uzleuven.be
    Scientific contact
    Department of Neurology, University Hospitals Leuven, 32 16344280, secretariaat.neuro@uzleuven.be
    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
    30 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To perform a detailed clinical and functional characterization and natural history analysis in adult patients with SMA types 2-3-4 with and without nusinersen (Spinraza®) treatment.
    Protection of trial subjects
    - Safety assessment of nusinersen treatment during trial (reporting of AE and SAE) - Data handling: All data collected in this study will be coded (pseudonymized) and only the principal investigator of the study will have access to the key linking the code to the patient identification. The study nurses/investigators/ evaluators that carry out the study will be blinded to the test result. - Ethics/Regulatory approvals: The trial will be conducted in compliance with the principles of the Declaration of Helsinki (2008), the principles of GCP and in accordance with all applicable regulatory requirements. This protocol and related documents will be submitted for review to the Ethical Committee. The principal investigator of this study, Prof. dr. K. Claeys, obtained the GCP certificate. The Study can and will be conducted only on the basis of prior informed consent by the Patients to participate in the Study (informed consent only in those patients that are treated and are included in the prospective part of the study; not in the patients in the retrospective part of the study only). The Participating Site shall obtain a signed informed consent form (ICF) for the subjects prior to their enrollment and participation in the Study in compliance with all applicable laws, regulations and the approval of the (local) Ethics Committee, if required. The Participating Site shall retain such ICFs in accordance with the requirements of all applicable regulatory agencies and laws. The Investigator and the Participating Site shall treat all information and data relating to the Study disclosed to Participating Site and/or Investigator in this Study as confidential and shall not disclose personal identity information to any third parties or use any information for any purpose other than the performance of the Study. The collection, processing and disclosure of personal data is subject to compliance with applicable per(Directive 95/46/EC and Belgian law of 8-12-1992.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2020
    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
    Belgium: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    15
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All 16 patients received intrathecal administrations of 12 mg of nusinersen following the standard of care dosing schedule, for a study duration of 14 months.

    Pre-assignment
    Screening details
    		 Inclusion criteria for the prospective study evaluating treatment with nusinersen were as follows: genetically confrmed 5q SMA, adult age at the time of enrolment (≥18 years), patients with SMA type 3 or 4, the use of an adequate contraceptive by female patients for the whole duration of the study and patients’ written informed consent.

    Pre-assignment period milestones
    Number of subjects started
    		 16
    Number of subjects completed
    		 16

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

    Arms
    Arm title
    		 treated patients (all)
    Arm description
    		 all included patients are treated with nusinersen, therefore there is only one arm
    Arm type
    		 Experimental

    Investigational medicinal product name
    nusinersen (Spinraza)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intrathecal use
    Dosage and administration details
    The treatment with nusinersen (Spinraza®) is done by intrathecal injection, using a standard lumbar puncture needle, in sterile conditions. Prior to injection of 5 ml nusinersen intrathecally, first 5 ml of cerebrospinal fluid (CSF) is being tapped, in order to compensate for the 5 ml of medication that will be injected, in order to keep the same total CSF volume. This is done following the normal standard-of-care procedures.

    Number of subjects in period 1
    		treated patients (all)
    Started
    16
    Completed
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial period
    Reporting group description
    		 Sixteen adult SMA type 3 and 4 patients participated in a prospective, observational study to examine the effectiveness and safety of intrathecal nusinersen (Spinraza®) treatment in adult SMA patients.

    Reporting group values
    		 overall trial period Total
    Number of subjects
    		 16 16
    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)
    		 15 15
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 10 10

    End points

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    End points reporting groups
    Reporting group title
    treated patients (all)
    Reporting group description
    		 all included patients are treated with nusinersen, therefore there is only one arm

    Primary: Efficacy of nusinersen treatment - grip strength R hand

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    End point title
    		 Efficacy of nusinersen treatment - grip strength R hand [1]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    9 ± 7.76
    Attachments
    		 Statistics and Results published
    No statistical analyses for this end point

    Primary: Efficacy of nusinersen treatment - grip strength L hand

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    End point title
    		 Efficacy of nusinersen treatment - grip strength L hand [2]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    8.19 ± 8.78
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: MRC sum score

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    End point title
    		 MRC sum score [3]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    15
    Units: sum score
        arithmetic mean (standard deviation)
    39.4 ± 8.4
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: 6MWD

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    End point title
    		 6MWD [4]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: metre
        arithmetic mean (standard deviation)
    303 ± 211
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: HFMSE

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    End point title
    		 HFMSE [5]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: score
        arithmetic mean (standard deviation)
    29.4 ± 19.9
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: RULM

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    End point title
    		 RULM [6]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: score
        arithmetic mean (standard deviation)
    28.2 ± 8.41
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: FVC

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    End point title
    		 FVC [7]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    Notes
    [7] - 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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: litre(s)
        arithmetic mean (standard deviation)
    4.12 ± 1.20
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: PEF

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    End point title
    		 PEF [8]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    Notes
    [8] - 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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: litre(s)
        arithmetic mean (standard deviation)
    7.34 ± 1.94
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Primary: ActivLim

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    End point title
    		 ActivLim [9]
    End point description
    End point type
    Primary
    End point timeframe
    study duration of 14 months for all patients
    Notes
    [9] - 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: see attached document for results
    End point values
    		 treated patients (all)
    Number of subjects analysed
    16
    Units: score
        arithmetic mean (standard deviation)
    1.44 ± 2.59
    Attachments
    		 Statistics and results published
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from start of the study (first visit of first included patient) until end of the study (last visit of last included patient)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23
    Reporting groups
    Reporting group title
    all included patients
    Reporting group description
    		 -

    Serious adverse events
    		 all included patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 all included patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 16 (37.50%)
         occurrences all number
    28
    Post-puncture headache
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    11
    Dizziness
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 16 (50.00%)
         occurrences all number
    45
    Agitation
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    22
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 16 (18.75%)
         occurrences all number
    12
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 16 (75.00%)
         occurrences all number
    72
    Myalgia
         subjects affected / exposed
    7 / 16 (43.75%)
         occurrences all number
    21
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences all number
    25

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32935160
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