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    Summary
    EudraCT Number:2021-001294-23
    Sponsor's Protocol Code Number:232SM303
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-12-20
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2021-001294-23
    A.3Full title of the trial
    A Phase 3b Study to Evaluate Higher Dose Nusinersen (BIIB058) in Patients with Spinal Muscular Atrophy Previously Treated with Risdiplam
    Estudio de fase IIIb para evaluar una dosis más alta de nusinersén (BIIB058) en pacientes con atrofia muscular espinal tratados previamente con risdiplam
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Higher Dose (HD) Nusinersen (BIIB058) in Participants with Spinal Muscular Atrophy Previously Treated with Risdiplam
    Estudio para evaluar una dosis más alta de nusinersén (BIIB058) en pacientes con atrofia muscular espinal tratados previamente con risdiplam
    A.4.1Sponsor's protocol code number232SM303
    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 pointBiogen España
    B.5.3 Address:
    B.5.3.1Street AddressPaseo de la Castellana, 41
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28046
    B.5.3.4CountrySpain
    B.5.4Telephone number+34919107110
    B.5.5Fax number+34913107181
    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 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: 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 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
    Atrofia Muscular Espinal
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy (SMA)
    Atrofia Muscular Espinal (AME)
    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 motor function following treatment with HD nusinersen in participants with spinal muscular atrophy (SMA) previously treated with risdiplam.
    El objetivo principal de este estudio es evaluar la función motora después del tratamiento con dosis más áltas de nusinersén en participantes con atrofia muscular espinal (AME) tratados previamente con risdiplam.
    E.2.2Secondary objectives of the trial
    The secondary objective of this study is to evaluate the safety and tolerability of HD nusinersen in participants with SMA previously treated with risdiplam.
    El objetivo secundario de este estudio es evaluar la seguridad y tolerabilidad de dosis más altas de nusinersén en participantes con AME tratados previamente con risdiplam.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Inclusion Criteria:
    - Genetic documentation of 5q SMA homozygous survival motor neuron-1 (SMN1) gene deletion or mutation or compound heterozygous mutation.
    - Diagnosis of later-onset SMA with symptom onset at age >6 months.
    - Aged ≥5 to ≤39 years at the time of informed consent for nusinersen-naïve participants.
    - Aged ≥18 to ≤39 years at time of informed consent for nusinersen-experienced participants.
    - Body weight >20 kg.
    - Received oral risdiplam per the approved label or per the managed access program as follows
    Nusinersen-naive participants must have had prior treatment with risdiplam for ≥6 months and ≤12 months before enrollment.
    Nusinersen-experienced participants must have stopped nusinersen for ≥16 months and have been on risdiplam for ≥12 months and ≤18 months before enrollment.
    - Able to perform the age-appropriate functional assessments in the study.
    - RULM entry item A score ≥3.
    - RULM total score ≥5 and ≤30 at Screening.
    - Nonambulatory, defined as not able to walk 15 feet (4.57 meters) independently without support.
    - Willing to stop risdiplam treatment.
    - Willing and able to start treatment with nusinersen.

    NOTE: Other protocol defined Inclusion criteria may apply.
    Criterios de inclusión principales:
    - Documentación genética de la deleción o mutación, o de la mutación heterocigótica compuesta del gen de supervivencia de
    las neuronas motoras 1 (SMN1) en la región cromosómica 5Q en la AME.
    - Diagnóstico de AME de inicio tardío con inicio de los síntomas a una edad de >6 meses.
    - Tener entre #5 y #39 años de edad en el momento del consentimiento informado para participantes sin tratamiento previo con nusinersén.
    - Tener entre #18 y #39 años de edad en el momento del consentimiento informado para participantes con tratamiento previo con nusinersén.
    - Peso corporal >20 kg.
    - Haber recibido risdiplam por vía oral según la ficha técnica aprobada o según el programa de acceso gestionado, de la siguiente manera: Los participantes sin tratamiento previo con nusinersén deben haber recibido tratamiento previo con risdiplam durante #6 meses y #12 meses antes de la inscripción. Los participantes con tratamiento previo con nusinersén deben haber dejado de tomar nusinersén
    durante #16 meses y haber recibido risdiplam durante #12 meses y #18 meses antes de la inscripción.
    - Tener capacidad de realizar las evaluaciones funcionales adecuadas para la edad en el estudio.
    - Puntuación del elemento A de entrada RULM #3.
    - Puntuación total RULM #5 y #30 en la selección.
    - No ambulatorio, definido como incapaz de caminar 4,57 metros (15 pies) de forma independiente y
    sin apoyo.
    - Estar dispuesto a interrumpir el tratamiento con risdiplam.
    - Estar dispuesto y ser capaz de iniciar el tratamiento con nusinersén.

    NOTA: Podrán aplicarse otros criterios de inclusión definidos en el protocolo.
    E.4Principal exclusion criteria
    Key Exclusion Criteria:
    - Any major illness within 1 month before the Screening examination or within 1 week prior to Screening and up to first dose administration.
    - 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 catheter.
    - History of bacterial meningitis, viral encephalitis, or hydrocephalus.
    - Ongoing medical condition that according to the Investigator would interfere with the conduct and assessments of the study. An example is a medical disability (e.g., wasting or cachexia, severe anemia, and respiratory parameters) that would interfere with the assessment of safety or would compromise the ability of the participant to undergo study procedures.
    - Participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study. - Treatment with an investigational drug, 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 gene therapy for the treatment of SMA.

    NOTE: Other protocol defined Exclusion criteria may apply.
    Criterios de exclusión principales:
    - Cualquier enfermedad grave en el mes anterior a la exploración de selección o en la semana anterior a la selección y hasta la administración de la primera dosis.
    - Presencia de una infección activa sin tratar o tratada de forma inadecuada que requiere un tratamiento antimicrobiano o antivírico sistémico en cualquier momento durante el periodo de selección.
    - Presencia de una derivación implantada para el drenaje del líquido cefalorraquídeo (LCR) o de un catéter del sistema nervioso central implantado.
    - Antecedentes de meningitis bacteriana, encefalitis vírica o hidrocefalia.
    - Afecciones médicas en curso que, de acuerdo con el investigador, podrían interferir con la realización y las evaluaciones del estudio. Un ejemplo es una discapacidad médica (p. ej., pérdida o caquexia, anemia grave y parámetros respiratorios) que podría interferir en la evaluación de la seguridad o comprometer la capacidad del participante para someterse a los procedimientos del estudio.
    - Participantes que estén embarazadas o actualmente en periodo de lactancia y aquellas cuya intención sea quedarse embarazadas
    durante el estudio.
    - Tratamiento con un fármaco, agente biológico o dispositivo en investigación en los 30 días o 5 semividas del fármaco, lo que dure más, antes de
    la selección o en cualquier momento durante el estudio; cualquier tratamiento previo o actual con tratamiento génico para el tratamiento de la AME.

    NOTA: Podrán aplicarse otros criterios de exclusión definidos en el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Change in Total Revised Upper Limb Module (RULM) Score
    Cambio en la puntuación total del módulo de extremidades superiores revisado
    (RULM).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to Day 855
    Hasta el día 855.
    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, Electrocardiogram (ECG), Vital Signs and Pulse Oximetry
    1) Número de participantes con acontecimientos adversos (AA) y acontecimientos adversos graves (AAG).
    2) Número de participantes con cambio con respecto al inicio en los parámetros analíticos clínicos, electrocardiograma (ECG), constantes vitales y oximetría del pulso.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) Up to Day 855
    2) Up to Day 855
    1) Hasta el día 855.
    2) Hasta el día 855.
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    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 EEA5
    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
    Australia
    Belgium
    Brazil
    Canada
    Germany
    Japan
    Poland
    Spain
    Switzerland
    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
    UVUS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days22
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days22
    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: 135
    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) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 60
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 40
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 35
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children of 6 years or older or Adults of 18 years or older who lack the capacity to provide consent due to underlying disease conditions including but not limited to SMA.
    Niños de 6 años o más o Adultos de 18 años o más que carecen de la capacidad para dar su consentimiento debido a enfermedades subyacentes incluída mas no limitada a la AME.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 135
    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)
    Following completion of this study, all eligible participants may elect to enroll in a separate long-term extension study, pending study approval by ethics committees and the appropriate
    regulatory authorities.
    Después de la finalización de este estudio, todos los participantes elegibles pueden optar a ser incluidos en un nuevo estudio de extensión a largo plazo, siempre que se cuente con la aprobación de dicho estudio por parte del comité de ética y las correspondientes autoridades regulatorias.
    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 Decision2022-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-03-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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