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    Summary
    EudraCT Number:2016-003225-41
    Sponsor's Protocol Code Number:233AS102
    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:2021-06-14
    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 number2016-003225-41
    A.3Full title of the trial
    An Extension Study to Assess the Long-Term Safety, Tolerability, Pharmacokinetics, and Effect on Disease Progression of BIIB067 Administered to Previously Treated Adults with Amyotrophic Lateral Sclerosis Caused by Superoxide Dismutase 1 Mutation
    Estudio de extensión para evaluar la seguridad, la tolerabilidad, la farmacocinética y el efecto sobre la progresión de la enfermedad a largo plazo de BIIB067 administrado a adultos tratados previamente con esclerosis lateral amiotrófica causada por una mutación de la superóxido dismutasa 1
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-Term Evaluation of BIIB067
    Evaluación de BIIB067 a largo plazo
    A.4.1Sponsor's protocol code number233AS102
    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
    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.5.4Telephone number+3491 3107110
    B.5.5Fax number+3491 3107181
    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
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 in participants with ALS and confirmed superoxide dismutase 1 (SOD-1) mutation.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to evaluate the pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of BIIB067 administered to subjects with ALS and confirmed SOD1 mutation.
    El objetivo primario del estudio es evaluar la seguridad y la tolerabilidad
    a largo plazo de BIIB067 en sujetos con ALS y mutación confirmada de la
    la superóxido dismutasa 1 (SOD1).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Must have diagnosis of SOD1-ALS, and must have completed the End of Study Visit for either Parts A, B and/or C of Study 233AS101 (i.e., were not withdrawn).
    - If taking riluzole, must be receiving a stable dose for ≥30 days prior to Day 1
    - For female participants of childbearing potential must agree to practice effective contraception during the study and for 5 months after their last dose of study treatment.
    - Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
    - Participants from Study 233AS101 Parts A and B must have a washout ≥16 weeks between the last dose of study treatment received in Study 233AS101 and the first dose of BIIB067 received in the current Study 233AS102.
    - If taking edaravone, participant must have initiated edaravone ≥ 60 days (2 treatment cycles) prior to Day 1. Edaravone may not be administered on dosing days.
    - Tener diagnóstico de ELA-SOD1 y haber completado la visita de fin del
    estudio de las partes A, B o C del estudio 233AS101 (es decir, no haberse
    retirado).
    - En caso de estar en tratamiento con riluzol, la dosis debe haber
    permanecido estable durante ≥30 días antes del día 1 y preverse que
    dicha dosis permanezca estable hasta la visita final del estudio.
    - Las mujeres en edad fértil deben acceder a usar métodos
    anticonceptivos eficaces durante el estudio y durante los 5 meses
    posteriores a la última dosis del tratamiento del estudio.
    - Ser médicamente capaz de someterse a los procedimientos del estudio
    y de cumplir el calendario de visitas en el momento de la entrada en el
    estudio, según lo determine el investigador.
    - Los participantes de las partes A y B del estudio 233AS101 deben hacer
    un reposo farmacológico ≥16 semanas entre la última dosis del
    tratamiento del estudio recibida en el estudio 233AS101 y la primera
    dosis de BIIB067 recibida en el estudio 233AS102 actual.
    - En caso de estar en tratamiento con edaravona, el paciente debe haber
    comenzado a tomarla ≥60 días (2 ciclos de tratamiento) antes del día 1.
    No se puede tomar edaravona los días de administración de la dosis.
    E.4Principal exclusion criteria
    Key Exclusion Criteria:
    - History of allergies to a broad range of anaesthetics.
    - Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and could place a participant at an increased risk for bleeding during or after an LP procedure. These risks could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand’s disease, liver disease).
    - Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
    - Prior or current treatment with small interfering ribonucleic acid (RNA), stem cell therapy, or gene therapy.
    - Treatment with another investigational drug, biological agent (excluding BIIB067), or device within 1 month or 5 half-lives of study agent, whichever is longer.
    - Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.
    - Female subjects who are pregnant or currently breastfeeding.
    - Current enrollment in any other interventional study.
    - Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.

    NOTE: Other protocol defined Inclusion/Exclusion criteria may apply
    Criterios de exclusión principales:
    - Antecedentes de alergias a una amplia gama de anestésicos.
    - Presencia de riesgo de hemorragia aumentada o no controlada o riesgo
    de hemorragia que no se trata de manera óptima y podría aumentar el
    riesgo de que un participante experimente hemorragia durante o
    después de un procedimiento de PL. Estos riesgos podrían incluir, entre
    otros, factores anatómicos en o cerca del lugar de la PL (p. ej.,
    anomalías vasculares, neoplasias u otras anomalías) y trastornos
    subyacentes de la cascada de coagulación, la función plaquetaria o el
    recuento plaquetario (p. ej., hemofilia, enfermedad de Von Willebrand,
    hepatopatía).
    - Presencia de una derivación implantada para el drenaje del líquido
    cefalorraquídeo (LCR) o de un catéter de sistema nervioso central (SNC)
    implantado.
    - Tratamiento previo o actual con ácido ribonucleico (ARN) pequeño de
    interferencia, tratamiento con células madre o tratamiento génico.
    - Tratamiento con otro fármaco en investigación, fármaco biológico
    (excepto BIIB067) o dispositivo en el plazo de 1 mes o 5 semividas del
    fármaco del estudio, lo que dure más.
    - Necesidad actual o prevista, en opinión del investigador, de un sistema
    de electroestimulación diafragmática (SED) durante el periodo del
    estudio.
    - Mujeres que estén embarazadas o en periodo de lactancia.
    - Inscripción actual en cualquier otro estudio intervencionista.
    - Uso actual o reciente (en el plazo de 1 mes), o necesidad prevista, en
    opinión del investigador, de cobre (II) (diacetil-bis [N4-
    metiltiosemicarbazona]) o pirimetamina.
    NOTA: Podrán aplicarse otros criterios de inclusión/exclusión definidos
    en el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    - Number of participants experiencing AEs and serious adverse events (SAEs)
    Número de participantes que experimenten AA y acontecimientos
    adversos graves (AAG)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to Week 248
    Hasta la semana 248
    E.5.2Secondary end point(s)
    - PK parameter of BIIB067 in plasma: Maximum observed concentration (Cmax)
    - PK parameter of BIIB067 in plasma: Time to reach the maximum observed concentration (Tmax)
    - PK parameter of BIIB067 in plasma: Area under the concentration-time curve from time 0 to infinity (AUCinf)
    - PK parameter of BIIB067 in plasma: Area under the concentration-time curve from time 0 to time of the last measurable (AUClast)
    - PK parameter of BIIB067 in plasma: Apparent terminal elimination half-life (t½)
    - PK parameter of BIIB067 in CSF: Apparent terminal elimination half-life (t½)
    - Change from Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Score
    - Change from Baseline in Slow Vital Capacity (SVC)
    - Change from Baseline in Handheld Dynamometry (HHD) MegaScore and Individual Muscle Strength
    - Overall Survival
    - Ventilation Assistance-Free Survival (VAFS)
    - PD Parameter of BIIB067 in CSF: Change in Baseline in Total SOD1
    - PD Parameter of BIIB067 in CSF: Change from Baseline in Total Phosphorylated Axonal Neurofilament Heavy Chain (p-NHF)
    - PD Parameter of BIIB067 in Plasma: Change from Baseline in Total p-NHF
    (Cmáx).
    - Parámetro FC de BIIB067 en plasma: tiempo hasta alcanzar la
    concentración máxima observada (Tmáx).
    - Parámetro FC de BIIB067 en plasma: área bajo la curva de
    concentración-tiempo desde el momento 0 hasta infinito (ABCinf).
    - Parámetro FC de BIIB067 en plasma: área bajo la curva de
    concentración-tiempo desde el momento 0 hasta la última cuantificable
    (ABCúlt).
    - Parámetro FC de BIIB067 en plasma: semivida de eliminación terminal
    aparente (t½).
    - Parámetro FC de BIIB067 en LCR: semivida de eliminación terminal
    aparente (t½).
    - Cambio con respecto al inicio en la puntuación de la escala de
    valoración funcional de la ELA revisada (ALSFRS-R).
    - Cambio con respecto al inicio en la capacidad vital lenta (CVL).
    - Cambio con respecto al inicio en la Megapuntuación mediante
    dinamometría manual (HHD) y fuerza muscular individual.
    - Supervivencia global.
    - Supervivencia sin ventilación asistida (SSVA).
    - Parámetro FD de BIIB067 en LCR: cambio en el inicio en SOD1 total.
    - Parámetro FD de BIIB067 en LCR: cambio con respecto al inicio en los
    niveles de la cadena pesada del neurofilamento axonal fosforilada (PNHF)
    total.
    - Parámetro FD de BIIB067 en plasma: cambio con respecto al inicio en
    p-NHF total
    E.5.2.1Timepoint(s) of evaluation of this end point
    Up to Week 248
    Hasta la semana 248
    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 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) 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) 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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    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
    Canada
    Israel
    Japan
    New Zealand
    United States
    European Union
    United Kingdom
    E.8.7Trial has a data monitoring committee No
    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 subject, last telephone contact (approximately 24 hours after the Final or Early Termination [Week 248]) visit. The last Maintenance Dose Visit for a subject will occur at Week 236, OR when the last subject enrolled has had their Week 92 Maintenance Dose Visit, whichever occurs first.
    El final del estudio es la última visita mediante contacto telefónico
    (aproximadamente 24 horas después del final o de la finalización
    anticipada [semana 248]) del último sujeto. La última visita de dosis de
    mantenimiento de un sujeto tendrá lugar en la semana 236 O cuando el
    último sujeto inscrito haya tenido su visita de dosis de mantenimiento
    de la semana 92, lo que ocurra primero
    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 months2
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    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: 146
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 37
    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 state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 183
    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 Decision2021-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-24
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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