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    Summary
    EudraCT Number:2019-002663-10
    Sponsor's Protocol Code Number:232SM203
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-10-23
    Trial results View 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 number2019-002663-10
    A.3Full title of the trial
    Escalating Dose and Randomized, Controlled Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Nusinersen (BIIB058) in Participants With Spinal Muscular Atrophy
    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 number232SM203
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04089566
    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 AddressInnovation House, 70 Norden Road
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 4AY
    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.IMP: 2
    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 No
    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.3.1Product nameNusinersen
    D.3.2Product code ISIS 396443, BIIB058
    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 number12.0
    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.IMP: 3
    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 No
    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.3.1Product nameNusinersen
    D.3.2Product code ISIS 396443, BIIB058
    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 number10.0
    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.IMP: 4
    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 No
    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.3.1Product nameNusinersen
    D.3.2Product code ISIS 396443, BIIB058
    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 number5.6
    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 objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with spinal muscular atrophy (SMA), as measured by change in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) total score (Part B); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C).
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to examine the clinical efficacy of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A, B and C); to examine the effect of nusinersen administered intrathecally at higher doses to participants with SMA (Parts A and C); to examine the safety and tolerability of nusinersen administered intrathecally at higher doses to participants with SMA, to examine the effect of nusinersen administered intrathecally at higher doses compared to the currently approved dose in participants with SMA (Part B).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A, B and C: - Genetic documentation of 5q SMA (homozygous gene deletion, mutation, or compound heterozygote)

    Part A:
    - Onset of clinical signs and symptoms consistent with SMA at > 6 months (> 180 days) of age (i.e., later-onset SMA)
    - Age 2 to ≤ 15 years, inclusive, at the time of informed consent

    Part B:
    - Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset) should have age >1 week to ≤ 7 months (≤ 210 days) at the time of informed consent
    - Participants with SMA symptom onset > 6 months (> 180 days) of age (later onset):
    - Age 2 to < 10 years at the time of informed consent
    - Can sit independently but has never had the ability to walk independently
    - HFMSE score ≥ 10 and ≤ 54 at Screening

    Part C:
    - Currently on nusinersen treatment at the time of Screening, with the first dose being at least 1 year prior to Screening

    Part C Cohort 1:
    - Participants of any age (individuals ≥18 years of age at Screening must be ambulatory)

    Part C Cohort 2:
    - Participants ≥18 years of age at Screening (can be ambulatory or nonambulatory)
    - HFMSE total score ≥4 points at Screening
    - RULM entry item A score ≥3 points at Screening
    E.4Principal exclusion criteria
    Part A, B and C:
    - Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the Screening period
    - Presence of an implanted shunt for the drainage of CSF or of an implanted central nervous system (CNS) catheter
    - Hospitalization for surgery, pulmonary event, or nutritional support within 2 months prior to Screening or planned within 12 months after the participant’s first dose


    Part A:
    - Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
    - Medical necessity for a gastric feeding tube
    - Treatment with an investigational drug given for the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 (SMN2)-splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation

    Part B:
    - Treatment with an investigational drug including but not limited to the treatment of SMA, biological agent, or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening or anytime during the study; any prior or current treatment with any survival motor neuron-2 (SMN2)- splicing modifier or gene therapy; or prior antisense oligonucleotide treatment, or cell transplantation
    - Participants with SMA symptom onset > 6 months (> 180 days) of age(later onset)
    - Respiratory insufficiency, defined by the medical necessity for invasive or noninvasive ventilation for > 6 hours during a 24-hour period, at Screening
    - Medical necessity for a gastric feeding tube
    - Participants with SMA symptom onset ≤ 6 months (≤ 180 days) of age (infantile onset): Signs or symptoms of SMA present at birth or within the first week after birth

    Part C:
    - Concurrent or previous participation and/or administration of nusinersen in another clinical study
    - Concomitant or previous administration of any SMN2-splicing modifier (excluding nusinersen) or gene therapy, either in a clinical study or as part of medical care.
    - Concurrent or previous participation in any interventional investigational study for any other drug or device within 30 days or 5 half-lives of the agent, whichever is longer, prior to Screening

    NOTE: Other protocol defined Inclusion/Exclusion criteria may apply
    E.5 End points
    E.5.1Primary end point(s)
    Part B Infantile-onset SMA:

    1) Change from Baseline in CHOP-INTEND Total Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched Sham Control Group.

    Part A and C:
    2) Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    3) Number of Participants with Clinically Significant Shifts from Baseline in Clinical Laboratory Parameters
    4) Number of Participants with Clinically Significant Shifts from Baseline in Electrocardiograms (ECGs)
    5) Number of Participants with Clinically Significant Shifts from Baseline in Vital Signs
    6) Change from Baseline in Body Length/Height

    Part C Infantile-onset SMA:
    7) Change from Baseline in Head Circumference
    8) Change from Baseline in Chest Circumference
    9) Change from Baseline in Arm Circumference

    Part A and C Later-onset SMA:
    10) Change from Baseline in Ulnar Length

    Part A and C:
    11) Ratio of Weight for Age
    12) Ratio of Weight for Length

    Part C:
    13) Ratio of Head-to-chest Circumference

    Part A and C:
    14) Change from Baseline in Activated Partial Thromboplastin Time (aPTT)
    15) Change from Baseline in Prothrombin Time (PT)
    16) Change from Baseline in International Normalized Ratio (INR)
    17) Change in Urine Total Protein
    18) Change from Baseline in Neurological Examination Outcomes
    19) Percentage of Participants with a Postbaseline Platelet Count Below the Lower Limit of Normal on at least 2 Consecutive Measurements
    20) Percentage of Participants with a Postbaseline Corrected QT Interval Using Fridericia’s Formula (QTcF) of > 500 millisecond (msec) and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of > 60 msec
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part B Infantile-onset SMA:
    1) Baseline up to Day 183

    Part A and C:
    2) Screening up to Day 389
    3) Screening up to Day 302
    4) Screening up to Day 302
    5) Screening up to Day 302
    6) Baseline up to Day 302

    Part C Infantile-onset SMA:
    7) Baseline up to Day 302
    8) Baseline up to Day 302
    9) Baseline up to Day 302

    Part A and C Later-onset SMA:
    10) Baseline up to Day 302

    Part A and C:
    11) Baseline up to Day 302
    12) Baseline up to Day 302

    Part C:
    13) Baseline up to Day 302

    Part A and C:
    14) Baseline up to Day 269
    15) Baseline up to Day 269
    16) Baseline up to Day 269
    17) Baseline up to Day 302
    18) Baseline up to Day 302
    19) Baseline up to Day 302
    20) Baseline up to Day 302
    E.5.2Secondary end point(s)
    Part B Infantile-onset SMA
    21) Percentage of Hammersmith Infant Neurological Examination
    (HINE) Section 2 Motor Milestone Responders for Nusinersen 50/28mg
    Treatment Group Versus CS3B Matched Sham Control Group
    22) Change from Baseline in HINE Section 2 Motor Milestones Total
    Score for Nusinersen 50/28mg Treatment Group Versus CS3B Matched
    Sham Control Group
    23) Change from Baseline in Plasma Concentration of Neurofilament
    Light Chain (NF-L) for Nusinersen 50/28mg Treatment Group Versus
    CS3B Matched Sham Control Group
    24) Change from Baseline in CHOP-INTEND Total Score for Nusinersen
    50/28mg Treatment Group Versus 12/12mg Active Control Group
    25) Change from Baseline in HINE Section 2 Motor Milestones Total
    Score for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active
    Control Group
    26) Change from Baseline in Plasma Concentration of NF-L for
    Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control
    Group
    27) Time to Death or Permanent Ventilation for Nusinersen 50/28mg
    Treatment Group Versus CS3B Matched Sham Control Group
    28) Time to Death (Overall Survival) for Nusinersen 50/28mg Treatment
    Group Versus CS3B Matched Sham Control Group
    29) Time to Death or Permanent Ventilation for Nusinersen 50/28mg
    Treatment Group Versus 12/12mg Active Control Group
    30) Time to Death (Overall Survival) for Nusinersen 50/28mg Treatment
    Group Versus 12/12mg Active Control Group
    Part B Later-onset SMA:
    31) Change from Baseline in Hammersmith Functional Motor Scale
    Expanded (HFMSE) Score for Nusinersen 50/28mg Treatment Group
    Versus 12/12mg Active Control Group
    32) Change from Baseline in Revised Upper Limb Module (RULM) Score
    for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active
    Control Group
    33) Total Number of New World Health Organization (WHO) Motor
    Milestones for Nusinersen 50/28mg Treatment Group Versus 12/12mg
    Active Control Group
    34) Change from Baseline in Assessment of Caregiver Experience with
    Neuromuscular Disease (ACEND) for Nusinersen 50/28mg Treatment
    Group Versus 12/12mg Active Control Group
    35) Change from Baseline in Pediatric Quality of Life Inventory™
    (PedsQL) for Nusinersen 50/28mg Treatment Group Versus 12/12mg
    Active Control Group
    36) Change from Baseline in Cerebral Spinal Fluid (CSF) Concentration of
    NF-L for Nusinersen 50/28mg Treatment Group Versus 12/12mg Active
    Control Group
    37) Change from Baseline in Plasma Concentration of NF-L for
    Nusinersen 50/28mg Treatment Group Versus 12/12mg Active Control
    Group
    Part B:
    38) Number of Participants with AEs and SAEs
    39) Number of Participants with Clinically Significant Shifts from
    Baseline in Clinical Laboratory Parameters
    40) Number of Participants with Clinically Significant Shifts from
    Baseline in ECGs
    41) Number of Participants with Clinically Significant Shifts from
    Baseline in Vital Signs
    42) Change from Baseline in Body Length/Height
    Part B Infantile-onset SMA:
    43) Change from Baseline in Head Circumference
    44) Change from Baseline in Chest Circumference
    45) Change from Baseline in Arm Circumference
    Part B Later-onset SMA:
    46) Change from Baseline in Ulnar Length
    Part B:
    47) Ratio of Weight for Age
    48) Ratio of Weight for Length
    49) Ratio of Head-to-chest Circumference
    50) Change from Baseline in aPTT
    51) Change from Baseline in PT
    52) Change from Baseline in INR
    53) Change in Urine Total Protein
    54) Change from Baseline in Neurological Examination Outcomes
    55) Percentage of Participants with a Postbaseline Platelet Count Below
    the Lower Limit of Normal on at least 2 Consecutive Measurements
    56) Percentage of Participants with a Postbaseline QTcF of > 500 msec
    and an Increase from Baseline to Any Postbaseline Timepoint in QTcF of
    > 60 msec
    Part A, B and C:
    57) Number of Hospitalizations
    58) Duration of Hospitalizations
    59) Clinical Global Impression of Change (CGIC)
    60) Number of Participants with Serious Respiratory Events
    Part B Infantile-onset SMA:
    61) Percentage of Time on Ventilation
    Parts A, B and C:
    62) Ventilator Use
    Parts A and B:
    63) Change from Baseline in the Parent Assessment of Swallowing
    Ability (PASA) Scale
    Part B: Infantile SMA-onset:
    64) Change from baseline in CSF concentration of NF-L
    Part A and C:
    65) Change from Baseline in HFMSE Score
    66) Change from Baseline in RULM Score
    67) Total Number of New WHO Motor Milestones
    68) Change from Baseline in ACEND
    69) Change from Baseline in PedsQL™
    Part C:
    70) Change from Baseline in CHOP-INTEND Total Score
    71) Change from Baseline in HINE Section 2 Motor Milestones Total
    Score
    E.5.2.1Timepoint(s) of evaluation of this end point
    BL=Baseline; SC=Screening
    Part B Infantile-onset SMA
    21-23) BL to Day 183
    24 & 25) BL to Day 302
    26) BL to Day 29
    27 & 28) SC to Day 183
    29 & 30) SC to Day 399
    Part B Later-onset SMA
    31-37) BL to Day 302
    Part B
    38) SC to Day 399
    39) SC to Day 302
    40) Day 1 to Day 302
    41) SC to Day 302
    42) BL to Day 302
    Part B Infantile-onset SMA
    43-45) BL to Day 302
    Part B Later-onset SMA
    46) BL to Day 302
    Part B
    47-49) BL to Day 302
    50-52) BL to Day 279
    53-56) BL to Day 302
    Part A, B & C
    57 & 58) Day 1 to Day 302
    59) Day 302
    60) SC to Day 302
    Part B Infantile-onset SMA
    61) SC to Day 302
    Parts A, B & C
    62) SC to Day 302
    Parts A & B
    63) BL to Day 302
    Part B-Infantile SMA-onset
    64) BL to Day 302
    Part A & C
    65-69) BL to Day 302
    Part C
    70 & 71) BL to Day 302
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    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 Yes
    E.8.1.7.1Other trial design description
    Sequential Assignment: Part A - Open Label. Part B - Double Blind. Part C - Open Label
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Part B only - commercial Spinraza
    E.8.2.4Number of treatment arms in the trial4
    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 Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Chile
    Colombia
    Taiwan
    Australia
    Brazil
    Canada
    China
    Israel
    Japan
    Korea, Republic of
    Lebanon
    Mexico
    Russian Federation
    Saudi Arabia
    United Kingdom
    United States
    Estonia
    France
    Germany
    Greece
    Hungary
    Ireland
    Italy
    Latvia
    Netherlands
    Poland
    Spain
    Türkiye
    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 years2
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days7
    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: 121
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 12
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 63
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 39
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 7
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 37
    F.4.2.2In the whole clinical trial 145
    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)
    in addition to standard of care, subjects may be able to enter an extension study.
    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 Decision2020-11-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-02-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2024-05-30
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