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    Summary
    EudraCT Number:2020-004590-51
    Sponsor's Protocol Code Number:233AS303
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-09-01
    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 number2020-004590-51
    A.3Full title of the trial
    A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
    Ensayo en fase III, aleatorizado, controlado con placebo, con una preinclusión de evolución natural longitudinal y extensión abierta para evaluar BIIB067 iniciado en adultos clínicamente presintomáticos con una mutación de superóxido dismutasa 1 confirmada
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of BIIB067 When Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
    Un estudio de BIIB067 cuando se inicia en adultos clínicamente presintomáticos con una mutación confirmada de superóxido dismutasa 1
    A.3.2Name or abbreviated title of the trial where available
    ATLAS
    ATLAS
    A.4.1Sponsor's protocol code number233AS303
    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 Castella, 41
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28041
    B.5.3.4CountrySpain
    B.5.4Telephone number+34913107110
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code BIIB067 (ISIS666853)
    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 INNTofersen
    D.3.9.1CAS number 2088232-70-4
    D.3.9.2Current sponsor codeBIIB067 (ISIS 666853)
    D.3.9.3Other descriptive nameBIIB067
    D.3.9.4EV Substance CodeSUB179869
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.7
    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 typesecond-generation chimeric 2′ methoxyethyl mixed backbone antisense oligonucleotide (ASO) inhibitor of human SOD1 messenger ribonucleic acid (mRNA).
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntrathecal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Amyotrophic Lateral Sclerosis (ALS)
    Esclerosis Lateral Amiotrófica (ELA)
    E.1.1.1Medical condition in easily understood language
    Lou Gehrig's disease
    Enfermedad de Lou Gehrig
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10077024
    E.1.2Term Familial amyotrophic lateral sclerosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10002026
    E.1.2Term Amyotrophic lateral sclerosis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10052653
    E.1.2Term Amyotrophic lateral sclerosis gene carrier
    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 efficacy of BIIB067 when initiated in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF).
    El objetivo principal de este estudio es evaluar la eficacia de BIIB067 cuando se inicia en portadores adultos presintomáticos de una mutación de superóxido dismutasa 1 (SOD1) con neurofilamento (NF) elevado.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to evaluate the safety and tolerability of BIIB067 and to evaluate the effect of BIIB067 on pharmacodynamics (PD)/treatment response biomarkers.
    Los objetivos secundarios de este estudio son evaluar la seguridad y tolerabilidad de BIIB067 y evaluar el efecto de BIIB067 sobre los biomarcadores de farmacodinámica (PD) / respuesta al tratamiento.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Key Part A Inclusion Criteria:
    - Participants should have a protocol-defined rapidly progressive SOD1 mutation, confirmed by a central reader, or a SOD1 mutation that is adjudicated for inclusion by an external mutation adjudication committee.
    - Participants with plasma NfL level less than the protocol-defined threshold.
    - Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifested ALS).
    Criterios clave de inclusión de la Parte A:
    - Los participantes deben tener una mutación SOD1 de progresión rápida definida por el protocolo, confirmada por un lector central, o una mutación SOD1 adjudicada para su inclusión por un comité externo de adjudicación de mutaciones.
    - Participantes con niveles plasmáticos de NfL menor que el umbral definido por el protocolo.
    - Participantes clínicamente presintomáticos de ELA (es decir, no deben tener ELA clínicamente manifestada).
    E.4Principal exclusion criteria
    Key Part A Exclusion Criteria:
    - History or positive test result at screening for human immunodeficiency virus (HIV). The requirement for testing at Screening may be omitted if it is not permitted by local regulations.
    - Current hepatitis C infection (defined as positive Hepatitis C Virus (HCV) antibody and detectable HCV RNA). Participants with positive HCV antibody and undetectable HCV Ribonucleic Acid (RNA) are eligible to participate in the study (United States Centers for Disease Control and Prevention).
    - Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or anti-Hepatitis B Core antibody (HBc)). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-hepatitis B surface antibody (HBs) or vaccination (defined asnegative HBsAg, negative anti-HBc, and positive anti- HBs) are eligible to participate in the study.
    - History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study.
    - History of confounding neuromuscular or neurological disorder that is expected to have a progressive (i.e., worsening) course during the study, and/or is expected to be associated with elevations in NF, in the opinion of the Investigator.
    - Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding.
    - Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression ≤ 90 days of Screening, which in the opinion of the Investigator would interfere with the study procedures.
    - Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued or held for an LP procedure, if necessary, according to local or institutional guidelines and/or Investigator determination.
    - Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
    - Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment, biological agent, device, or approved therapy for investigational use. Participation in a noninterventional study focused on ALS natural history may be allowed at the discretion of the Investigator.

    NOTE: Other protocol defined Inclusion/Exclusion criteria will apply.
    Criterios Clave de Exclusión de la Parte A:
    - Historial o resultado positivo de la prueba de detección del virus de la inmunodeficiencia humana (VIH). El requisito de realizar pruebas en la selección puede omitirse si no está permitido por la regulación local.
    - Infección actual por hepatitis C (definida como anticuerpos positivos contra el virus de la hepatitis C (VHC) y ARN del VHC detectable). Los participantes con anticuerpos contra el VHC positivos y ácido ribonucleico (ARN) del VHC indetectable son elegibles para participar en el estudio (Centros para el Control y la Prevención de Enfermedades de los Estados Unidos).
    - Infección actual por hepatitis B (definida como positiva para el antígeno de superficie de la hepatitis B (HBsAg) y / o el anticuerpo anti-Hepatitis B Core (HBc)). Participantes con inmunidad a la hepatitis B por una infección natural previa (definida como HBsAg negativo, anti-HBc positivo y anticuerpo de superficie antihepatitis B (HBs) positivo o vacunación (definida como HBsAg negativo, anti-HBc negativo y anti-HBs positivo) son elegibles para participar en el estudio.
    - Antecedentes de reacción de hipersensibilidad sistémica al tofersen, a los excipientes contenidos en la formulación y, en su caso, a cualquier agente de diagnóstico que deba administrarse durante el estudio.
    - Historia de trastorno neuromuscular o neurológico de confusión que se espera que tenga un curso progresivo (es decir, empeoramiento) durante el estudio, y / o se espera que esté asociado con elevaciones en la NF, en opinión del investigador.
    - Presencia de riesgo de hemorragia aumentada o incontrolada y / o riesgo de hemorragia que, si no se maneja de manera óptima, podría colocar a un participante en un mayor riesgo de hemorragia intraoperatoria o posoperatoria.
    - Deterioro cognitivo significativo, demencia clínica o enfermedad psiquiátrica inestable, incluida psicosis, ideación suicida, intento de suicidio o depresión mayor no tratada ≤ 90 días de selección, que en opinión del investigador interferiría con los procedimientos del estudio.
    - Necesidad anticipada, en opinión del investigador, de la administración de cualquier medicamento antiplaquetario o anticoagulante (p. Ej., Clopidogrel) que no se puede continuar o mantener de forma segura para un procedimiento de LP, si es necesario, de acuerdo con las pautas locales o institucionales y / o la determinación del investigador .
    - Tratamiento con otro medicamento en investigación (incluidos medicamentos en investigación para ELA a través de programas de uso compasivo), agente biológico o dispositivo dentro de 1 mes o 5 vidas medias del agente del estudio, lo que sea más largo. Específicamente, no se permite ningún tratamiento previo con micro ARN interferentes, terapia con células madre o terapia génica.
    - Inscripción actual o plan para inscribirse en cualquier estudio clínico intervencionista en el que se haya aprobado un tratamiento, agente biológico, dispositivo o terapia en investigación para uso en investigación. La participación en un estudio no intervencionista centrado en la historia natural de la ELA puede permitirse a discreción del investigador.

    NOTA: Se aplicarán otros criterios de inclusión / exclusión definidos por el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Parts B and C: Percentage of Participants with Emergence of Clinically Manifested ALS Within 12 Months of Part B Baseline
    Partes B y C: Porcentaje de participantes con aparición de ELA clínicamente manifestada dentro de los 12 meses posteriores al inicio de la Parte B
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 1 year
    Hasta 1 año
    E.5.2Secondary end point(s)
    1. Parts B and C: Percentage of Participants with Emergence of Clinically Manifested ALS Within 2 Years of Part B Baseline
    2. Parts B and C: Time to Emergence of Clinically Manifested ALS
    3. Parts B and C: Change in Revised ALS Functional Rating Scale (ALSFRS-R) Total Score
    4. Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC)
    5. Parts B and C: Percentage of Participants with Ventilation Assistance-free Survival (VAFS)
    6. Parts B and C: Percentage of Participants with Overall Survival
    7. Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period
    8. Parts B, C and D: Change from Baseline in Plasma NfL Concentrations
    9. Parts B, C and D: Change in Total Cerebrospinal Fluid (CFL) SOD1 Concentrations
    1. Partes B y C: Porcentaje de participantes con aparición de ELA clínicamente manifestada dentro de 2 años al inicio de la parte B
    2. Partes B y C: tiempo de aparición de la ELA clínicamente manifestada
    3. Partes B y C: Cambio en la puntuación total de la Escala de calificación funcional revisada de ALS (ALSFRS-R)
    4. Partes B y C: cambio con respecto al valor inicial en el porcentaje de capacidad vital lenta prevista (CVS)
    5. Partes B y C: Porcentaje de participantes con supervivencia sin asistencia de ventilación (VAFS)
    6. Partes B y C: porcentaje de participantes con supervivencia general
    7. Partes B, C y D: número de participantes con eventos adversos (EA) y eventos adversos graves (AAG) durante el período de tratamiento
    8. Partes B, C y D: cambio con respecto al valor inicial en las concentraciones plasmáticas de NfL
    9. Partes B, C y D: cambio en las concentraciones totales de líquido cefalorraquídeo (CFL) SOD1
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part B, C and D: Up to 2 years
    Parte B, C y D: hasta 2 años
    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 No
    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 Yes
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part A: Natural History Run-in: blood draws approx. every 28 days to access NfL levels
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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
    Brazil
    Canada
    Japan
    Korea, Republic of
    Russian Federation
    United States
    Belgium
    Bulgaria
    France
    Germany
    Italy
    Poland
    Spain
    Sweden
    United Kingdom
    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
    The end of study is last protocol-specified contact with the last participant.
    El final del estudio es el último contacto especificado por el protocolo con el último participante
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 105
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 45
    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 state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 150
    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)
    none
    ninguno
    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 Decision2021-05-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-05
    P. End of Trial
    P.End of Trial StatusOngoing
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