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    Summary
    EudraCT Number:2020-003492-18
    Sponsor's Protocol Code Number:232SM404
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-18
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2020-003492-18
    A.3Full title of the trial
    A Phase 4 Study of Nusinersen (BIIB058) Among Patients With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of Nusinersen Among Participants With Spinal Muscular Atrophy Who Received Onasemnogene Abeparvovec
    A.3.2Name or abbreviated title of the trial where available
    Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
    A.4.1Sponsor's protocol code number232SM404
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04488133
    A.5.4Other Identifiers
    Name:INDNumber:110011
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBiogen Idec Research Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiogen Idec Research Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiogen Idec Research Limited
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street Address5 Foundation Park, Roxborough Way
    B.5.3.2Town/ cityMaidenhead; Berkshire
    B.5.3.3Post codeSL6 3UD
    B.5.3.4CountryUnited Kingdom
    B.5.6E-mailclinicaltrials@biogen.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Spinraza
    D.2.1.1.2Name of the Marketing Authorisation holderBiogen Netherlands B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/12/976
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrathecal use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNusinersen
    D.3.9.1CAS number 125894-36-9
    D.3.9.2Current sponsor codeISIS 396443 (BIIB058)
    D.3.9.3Other descriptive nameNUSINERSEN SODIUM
    D.3.9.4EV Substance CodeSUB189898
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product type2′-O-(2-methoxyethyl) phosphorothioate antisense oligonucleotide
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Muscular Atrophy, Spinal
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy (SMA)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10041582
    E.1.2Term Spinal muscular atrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to evaluate the clinical outcomes following treatment with nusinersen in participants with spinal muscular atrophy (SMA) who previously received onasemnogene abeparvovec.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the safety and tolerability; clinical outcomes and pharmacodynamics (PD) of nusinersen treatment in participants with SMA who previously received onasemnogene abeparvovec.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion Criteria:
    - Genetic documentation of 5q SMA homozygous gene survival motor
    neuron 1 (SMN1) deletion or mutation, or compound heterozygous
    mutation
    - SMN2 copy number of ≥ 1
    - ≤ 36 months of age at the time of first nusinersen dose
    - Must have previously received onasemnogene abeparvovec per the
    approved label or local/regional regulations ≥ 2 months prior to first
    nusinersen dose
    - Must have suboptimal clinical status per the Investigator
    For Subgroups A and B:
    - < 300 days of age at the time of first nusinersen dose
    - SMN2 copy number of 2
    For Subgroup A:
    - SMA symptom onset ≤ 4 months (120 days) of age
    - Must have received intravenous (IV) onasemnogene abeparvovec at >6
    weeks to ≤ 6 months (43 days to 180 days) of age
    - Must have received IV onasemnogene abeparvovec after SMA symptom
    onset
    For Subgroup B:
    - Must have received IV onasemnogene abeparvovec at ≤ 6 weeks (42
    days) of age

    Note: other protocol defined Inclusion/Exclusion criteria may apply.
    E.4Principal exclusion criteria
    Key Exclusion Criteria:
    - Prior exposure to nusinersen
    - Ongoing severe or serious AEs related to onasemnogene abeparvovec
    - Treatment with an investigational drug, biological agent, or device
    within 30 days or 5 half-lives of the agent, whichever is longer, prior to
    study; any prior or current treatment with any survival motor neuron 2
    (SMN2)-directed splicing modifier; prior antisense oligonucleotide
    treatment or cell transplantation; gene therapy for the treatment of SMA
    other than onasemnogene abeparvovec. Note: treatment with
    onasemnogene abeparvovec as part of an investigational study is
    allowed
    For Subgroups A and B:
    - Weight-for-age is below the third percentile, based on WHO Child
    Growth Standards at the time of receiving onasemnogene abeparvovec.
    Adjustments for the gestational weight of premature babies enrolled in
    Subgroups A and B are allowed provided IV onasemnogene abeparvovec
    was dosed per the approved label or per local/regional regulations.

    Note: other protocol defined Inclusion/Exclusion criteria may apply.
    E.5 End points
    E.5.1Primary end point(s)
    Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to Day 778
    E.5.2Secondary end point(s)
    1) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    2) Number of Participants with Change from Baseline in Clinical Laboratory Parameters
    3) Number of Participants with Change from Baseline in Electrocardiograms (ECGs)
    4) Number of Participants with Change from Baseline in Vital Signs
    5) Number of Participants who Achieved Motor Milestones as Assessed by World Health Organization (WHO) Criteria
    6) Change from Baseline in Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score
    7) Change from Baseline in Hammersmith Functional Motor Scale - Expanded (HFMSE) Score
    8) Change from Baseline in Revised Upper Limb Module (RULM) Score
    9) Time to Death or Permanent Ventilation
    10) Change from Baseline in Cerebrospinal Fluid (CSF) levels of Neurofilament Light Subunit (NF-L)
    11) Change from Baseline in Plasma levels of NF-L
    E.5.2.1Timepoint(s) of evaluation of this end point
    For Items 1-9 and 11 up to day 778; for item 10 up to day 659
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Israel
    Japan
    United States
    Germany
    Italy
    Spain
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 49
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 43
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 49
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Nusinersen is an approved treatment, and continued use after completing study requirements will be at the discretion of the participant and Investigator through prescription/commercial sources.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-04-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-07
    P. End of Trial
    P.End of Trial StatusOngoing
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