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    Summary
    EudraCT Number:2013-004422-29
    Sponsor's Protocol Code Number:ISIS396443-CS3B
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-08
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-004422-29
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Sham-Procedure Controlled Study to Assess the Clinical Efficacy and Safety of ISIS 396443 Administered Intrathecally in Patients with Infantile-onset Spinal Muscular Atrophy
    Estudio de fase 3, aleatorizado, a doble ciego, controlado con procedimiento simulado para evaluar la eficacia clínica y la seguridad de ISIS 396443 administrado por vía intratecal en pacientes con atrofia muscular espinal de inicio en edad infantil
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A controlled clinical study to assess the effectiveness and safety of ISIS 396443 in patients with infantile-onset Spinal Muscular Atrophy
    Estudio controlado para evaluar la eficacia clínica y la seguridad de ISIS 396443 en pacientes con atrofia muscular espinal de inicio en edad infantil
    A.4.1Sponsor's protocol code numberISIS396443-CS3B
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/082/2014
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorIsis Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    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 supportIsis Pharmaceuticals
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIsis Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointMatt R. Buck
    B.5.3 Address:
    B.5.3.1Street Address2855 Gazelle Ct.
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post code92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number011760603-2684
    B.5.5Fax number011760603-3891
    B.5.6E-mailmbuck@isisph.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 nameSurvival of Motor Neuron 2 (SMN2) Splicing Modulator Antisense Oligonucleotide
    D.3.2Product code ISIS 396443
    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 INNISIS 396443
    D.3.9.1CAS number 1258984-36-9
    D.3.9.2Current sponsor codeISIS 396443
    D.3.9.3Other descriptive nameISIS 396443
    D.3.9.4EV Substance CodeSUB130563
    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?-MOE 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
    Spinal Muscular Atrophy (SMA)
    Atrofia Muscular Espinal
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy (SMA)
    Atrofia Muscular Espinal
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    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
    To examine the clinical efficacy of ISIS 396443 administered intrathecally to patients with infantile-onset SMA.
    Examinar la eficacia clínica de ISIS 396443 administrado por vía intratecal a pacientes con SMA de inicio en edad infantil
    E.2.2Secondary objectives of the trial
    To examine the safety and tolerability of ISIS 396443 administered intrathecally to patients with infantile-onset SMA.
    Examinar la seguridad y tolerabilidad de ISIS 396443 administrado por vía intratecal a pacientes con SMA de inicio en edad infantil
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    ? Be 7 months (210 days) of age or younger at screening
    ? Be born between 37 and 42 weeks
    ? Be medically diagnosed with spinal muscular atrophy (SMA) and have SMN2 Copy # of 2
    ? Be able to follow all study procedures
    ? Reside within 9 hours ground travel each way, for the duration of the study
    ? Meet additional study-related criteria
    . Body weight ? 3rd percentile for age using appropriate country-specific guidelines
    . Genetic documentation of 5q SMA homozygous gene deletion, homozygous mutation, or compound heterozygote
    . Ser ?7 meses (210 días) de edad en el momento de la selección.
    . Edad gestacional de 37 a 42 semanas
    . Ser diagnosticado con atrofia muscular espinal y tener Cantidad de copias de SMN2 = 2
    .Poder completar todos los procedimientos del estudio
    . Residir a una distancia que no supere, aproximadamente, las 9 horas de viaje en trasporte terrestre hasta un centro del estudio
    . Cumplir los criterios adicionales del estudio.
    . Peso corporal ?3.er percentil de edad utilizando guías adecuadas específicas para el país
    . Documentación genética de la deleción del gen homocigota 5q SMA, mutación homocigota o heterocigota compuesta
    E.4Principal exclusion criteria
    . Hypoxemia (O2 saturation awake <96% or O2 saturation asleep <96%, without ventilation support) during screening evaluation
    . Signs or symptoms of SMA present at birth or within the first week after birth
    .Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
    .History of brain or spinal cord disease that would interfere with the LP procedures, CSF circulation, or safety assessments
    .Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
    .Subject?s caregiver is not willing to continue to meet standard of care guidelines for care (including vaccinations and RSV prophylaxis if available), nutritional and respiratory support throughout the duration of the study
    .Clinically significant abnormalities in hematology or clinical chemistry parameters, as assessed by the Site Investigator, at screening that would render the subject unsuitable for inclusion
    . Hipoxemia (saturación de O2 despierto <96 % o saturación de O2 dormido <96 %, sin apoyo ventilatorio con aire ambiente) durante la evaluación de selección
    . Signos o síntomas de SMA presentes al momento del nacimiento o en el plazo de la primera semana después del nacimiento
    . Presencia de una infección activa no tratada o tratada inadecuadamente que requiere terapia antiviral o antimicrobiana sistémica en cualquier momento durante el período de selección.
    . Antecedente de enfermedad cerebral o medular que interferirían con los procedimientos de PL, circulación del LCR o evaluaciones de la seguridad.
    . Presencia de una derivación implantada para el drenaje de LCR o de un catéter implantado en el sistema nervioso central (SNC)
    . El cuidador del sujeto no desea continuar cumpliendo los estándares de las guías de cuidados para el cuidado (incluye las vacunaciones y la profilaxis contra RSV, si estuviera disponible), la nutrición y el soporte respiratorio durante todo el estudio
    . Alteraciones clínicamente significativas en los parámetros de hematología o química clínica, según lo evaluado por el investigador del centro, en la selección, que provocaría que el sujeto fuera inadecuado para la inclusión
    E.5 End points
    E.5.1Primary end point(s)
    Time to death or permanent ventilation [?16 hours ventilation/day continuously for >21 days in the absence of an acute reversible event OR tracheostomy]
    Tiempo hasta la muerte o la ventilación permanente [?16 horas de ventilación/día continuamente durante >21 días en ausencia de un acontecimiento agudo reversible (Apéndice E) O traqueostomía]
    E.5.1.1Timepoint(s) of evaluation of this end point
    13 Months
    13 Meses
    E.5.2Secondary end point(s)
    ? Change from baseline in CHOP-INTEND infant motor function scale at 13 months
    ? Change from baseline in motor milestones at 13 months
    ? Percent of subjects not requiring permanent ventilation over 13 months
    ? Survival rate over 13 months
    ? Time to death or permanent ventilation in the subgroups of subjects below the study median disease duration
    ? Time to death or permanent ventilation in the subgroups of subjects above the study median disease duration
    ? Cambio con respecto al inicio en la escala de función motora del lactante CHOP-INTEND a los 13 meses
    ? Cambio con respecto al inicio en los hitos de la motricidad a los 13 meses
    ? Porcentaje de sujetos que no requieren ventilación permanente a los 13 meses
    ? Tasa de supervivencia a los 13 meses
    ? Tiempo hasta la muerte o la ventilación permanente en los subgrupos de sujetos por debajo de la mediana de la duración de la enfermedad en el estudio
    ? Tiempo hasta la muerte o la ventilación permanente en los subgrupos de sujetos por encima de la mediana de la duración de la enfermedad en el estudio
    E.5.2.1Timepoint(s) of evaluation of this end point
    13 months
    13 months
    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 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 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 Yes
    E.8.2.3.1Comparator description
    Justificación de los procedimientos simulados
    Sham-Procedure Controlled
    E.8.2.4Number of treatment arms in the trial2
    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 EEA6
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Spain
    Sweden
    Taiwan
    United Kingdom
    United States
    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
    Última visita Último paciente.
    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 days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    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 Yes
    F.1.1Number of subjects for this age range: 111
    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: 3
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 108
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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
    Newborns, Infant´s and toddlers aged unable to provide informed consent. Before a subject?s participation in the trial, the Investigator will be required to obtain written informed consent from the parent(s) or legal guardian(s).
    Neonatos y niños incapaces de proporcionar el consentimiento informado. Antes de la participación del sujeto en es estudio el investigador solicitará el consentimiento informado por escrito de los padres o tutores.
    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 38
    F.4.2.2In the whole clinical trial 111
    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)
    After completion of (Day 394 visit) treatment, eligible subjects may elect to receive ISIS 396443 in an Open Label (OLE) study, pending study approval by IRB or IEC and the appropriate regulatory authority.
    Tras completar el tratamiento (visita del día 394), los sujetos elegibles pueden optar por recibir ISIS 396443 en un estudio abierto (OLE), pendiente de aprobación por los CEIC y la autoridad competente.
    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 Decision2015-01-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-11-21
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