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    Summary
    EudraCT Number:2015-001870-16
    Sponsor's Protocol Code Number:ISIS396443-CS11
    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:2016-02-03
    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 number2015-001870-16
    A.3Full title of the trial
    An Open-label Extension Study for Patients with Spinal Muscular Atrophy who Previously Participated in Investigational Studies of ISIS 396443
    Estudio de extensión abierto para pacientes con atrofia muscular espinal que han participado previamente en estudios experimentales de ISIS 396443
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An extension study for patients with Spinal Muscular Atrophy who participated to the previous ISIS 396443 studies
    Estudio de extensión para pacientes con atrofia muscular espinal que han participado previamente en estudios de ISIS 396443
    A.4.1Sponsor's protocol code numberISIS396443-CS11
    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 SponsorIonis 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 supportIonis Pharmaceuticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIonis 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 number(+) 391708 86 00
    B.5.5Fax number+17606033891
    B.5.6E-mailmbuck@ionisph.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 (AME)
    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 18.1
    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 evaluate the long-term safety and tolerability of ISIS 396443 administered intrathecally to patients with SMA who previously participated in investigational studies of ISIS 396443.
    Evaluar la seguridad y tolerabilidad a largo plazo de ISIS 396443 administrado intratecalmente (i.t.) a pacientes con AME que participaron previamente en estudios experimentales de ISIS 396443
    E.2.2Secondary objectives of the trial
    To examine the long-term efficacy of ISIS 396443 administered intrathecally to patients with SMA who previously participated in investigational studies of ISIS 396443.
    Examinar la eficacia a largo plazo de ISIS 396443 administrado intratecalmente a pacientes con AME que participaron previamente en estudios experimentales de ISIS 396443.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subjects must meet all of the following criteria at Screening to be eligible:
    1.Signed informed consent of parent or guardian. Signed informed assent of subject, if indicated per subject?s age and institutional guidelines
    2.Completion of the index study in accordance with the study protocol within preceding 12 weeks
    Los pacientes deben cumplir todos los criterios que se indican a continuación en la selección para considerarlos idóneos para el estudio:
    1. Consentimiento informado firmado del padre/madre o tutor legal. Asentimiento informado firmado del paciente, si lo indican la edad del paciente y las pautas institucionales.
    2. Finalización del estudio índice conforme al protocolo del estudio en las 12 semanas previas.
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria are not eligible for the study:
    1.Have any new condition or worsening of existing condition which in the opinion of the Investigator would make the subject unsuitable for enrollment, or could interfere with the subject participating in or completing the study
    2.Clinically significant abnormalities in hematology or clinical chemistry parameters or ECG, as assessed by the Site Investigator, at the Screening visit that would render the subject unsuitable for participation in the study
    3.Subject?s parent or legal guardian is not willing or able to meet standard of care guidelines (including vaccinations and respiratory syncytial virus prophylaxis if available), nor provide nutritional and respiratory support throughout the study
    4.Treatment with another investigational agent, biological agent, or device within one month of Screening, or 5 half-lives of study agent, whichever is longer
    Los pacientes que satisfagan cualquiera de los siguientes criterios no reúnen los requisitos del estudio:
    1. Tienen una enfermedad nueva o presentan empeoramiento de la afección existente que, según opinión del investigador, haría que el paciente no sea idóneo para inscribirse en el estudio, o podría interferir con la participación del paciente en el estudio o la terminación del mismo.
    2. Anomalías clínicamente importantes en los parámetros hematológicos o bioquímicos o ECG, según evalúe el investigador del centro, en la visita de selección que harían que el paciente no sea idóneo para participar en el estudio.
    3. El padre/la madre o el tutor legal del paciente no está dispuesto o es incapaz de cumplir las directrices del tratamiento estándar (incluidas las vacunas y el tratamiento profiláctico del virus sincitial respiratorio, si está disponible) o de proporcionar soporte nutricional y respiratorio durante todo el estudio.
    4. El tratamiento con otro fármaco en fase de investigación, fármaco biológico o dispositivo en el mes previo a la selección o 5 semividas del fármaco del estudio, el período que sea más largo.
    E.5 End points
    E.5.1Primary end point(s)
    ? Time to death or permanent ventilation (tracheostomy OR ? 16 hours ventilation/day continuously for > 21 days in the absence of an acute reversible event)
    - Período de tiempo hasta el fallecimiento o respiración mecánica permanente (traqueostomía O respiración mecánica?16 horas al día continuamente durante >21 días sin un acontecimiento agudo reversible)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 1 through End of Study Visit
    Día 1 por visita final de estudio
    E.5.2Secondary end point(s)
    ? Survival rate
    ? Proportion of subjects not requiring permanent ventilation
    ? Change from baseline in CHOP INTEND
    ? Change from baseline in HFMSE (Hammersmith Functional Motor Scale ? Expanded)
    ? Proportion of subjects that achieve any new motor milestone
    ? Number of motor milestones achieved per subject
    ? Proportion of subjects that achieve standing alone
    ? Proportion of subjects that achieve walking with assistance
    ? Change from baseline in Upper Limb Module Test
    ? Change from baseline in CSF SMN protein concentration
    ? Change from baseline in PedsQL (Pediatric Quality of Life Inventory)
    ? Change from baseline in Assessment of Caregiver Experience with Neuromuscular Disease (ACEND)
    ? Clinical Global Impression - Improvement
    ? Disease-related hospitalizations and adverse events
    -Tasa de supervivencia
    -Proporción de pacientes que no requieren respiración mecánica permanente
    -Cambio en la puntuación CHOP INTEND con respecto al valor inicial.
    -Puntuación total HFMSE (Escala motriz funcional de Hammersmith ? ampliada)
    -Proporción de pacientes que logran cualquier nuevo hito motriz.
    -Número de hitos del desarrollo motriz conseguidos por paciente.
    -Proporción de pacientes que logran ponerse de piel por ellos mismos.
    -Proporción de pacientes que consiguen andar con ayuda.
    -Cambio en la prueba del módulo de las extremidades superiores respecto al inicio
    -Cambios de la concentración de proteína SMN en el LCR respecto al inicio.
    -Cambio en el Inventario pediátrico de calidad de vida (PedsQL) respecto al inicio
    -Cambio en la Evaluación de la experiencia del cuidador en la enfermedad neurovascular (Assessment of Caregiver Experience with Neuromuscular Disease, ACEND) respecto al inicio
    -Impresión clínica global ? Escala de mejoría de la enfermedad
    -Acontecimientos adversos e ingresos hospitalarios relacionados con la enfermedad.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 1 through End of Study Visit
    Día 1 por visita final de estudio
    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) 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 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 Yes
    E.8.1.7.1Other trial design description
    The study is an open label extension with a blinded loading period
    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
    Sham-Procedure Controlled
    E.8.2.4Number of treatment arms in the trial5
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA14
    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
    Canada
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Spain
    Sweden
    Taiwan
    Turkey
    United Kingdom
    United States
    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
    LVLS
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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: 274
    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) Yes
    F.1.1.4.1Number of subjects for this age range: 111
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 130
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 33
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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
    For very young children, parents or legal representative consent will be requested
    Consentimiento de padres o representante legal será requerido para niños muy pequeños.
    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 72
    F.4.2.2In the whole clinical trial 274
    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)
    Patient may be offered the opportunity to continue to receive ISIS 396443. This may occur via early access, extension of the treatment period, enrollment in another open label extension study. Patients may continue to receive treatment via one of these mechanisms until ONE of the following is met: ISIS 396443 is commercially available or is rejected in the local country. Sponsor terminates access to ISIS 396443 for reasons including safety issues or emergent data
    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 Decision2016-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-03
    P. End of Trial
    P.End of Trial StatusOngoing
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