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    Summary
    EudraCT Number:2014-001947-18
    Sponsor's Protocol Code Number:ISIS396443-CS4
    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:2015-02-09
    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 number2014-001947-18
    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 Later-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 en edad infantil con atrofia muscular espinal de inicio tardío
    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 later-onset Spinal Muscular Atrophy
    Ensayo clínico controlado para evaluar la eficacia y seguridad de ISIS 396443 en pacientes con atrofia muscular espinal de inicio tardío
    A.4.1Sponsor's protocol code numberISIS396443-CS4
    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 number+1760603-2684
    B.5.5Fax number+1760603-3891
    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 18.0
    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 later-onset SMA.
    Evaluar la eficacia de ISIS 396443 administrado por vía intratecal en pacientes con AME de inicio tardío.
    E.2.2Secondary objectives of the trial
    To examine the safety and tolerability of ISIS 396443 administered intrathecally to patients with later-onset SMA.
    Evaluar la seguridad y tolerabilidad de ISIS 396443 administrado por vía intratecal en pacientes con AME de inicio tardío.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Parent or guardian signed informed consent and, if indicated per subject?s age and institutional guidelines, subject has signed informed assent.
    2. Be medically diagnosed with spinal muscular atrophy (SMA)
    3. Have onset of clinical signs and symptoms consistent with SMA at > 6 months of age
    4. Be 2 to 12 years of age at screening
    5. Be able to sit independently, but has never had the ability to walk independently
    6. Have Motor Function Score (Hammersmith Functional Motor Scale ? Expanded) ? 10 and ? 54 at Screening
    7. Be able to complete all study procedures, measurements and visits and parent or guardian/subject has adequately supportive psychosocial circumstances, in the opinion of the Investigator
    8. Have estimated life expectancy > 2 years from screening, in the opinion of the Investigator
    9. Meet age-appropriate institutional criteria for use of anesthesia/sedation, if use is planned for study procedures
    10. For subjects who have reached reproductive maturity, satisfy study contraceptive requirements.
    Consentimiento informado firmado por el progenitor o tutor. Asentimiento informado del paciente firmado, en el caso de que sea pertinente en función de la edad del paciente y las pautas del centro.
    2. Documentación genética de AME 5q (deleción del gen homocigoto, mutación o heterocigoto compuesto)
    3. Primera aparición de signos y síntomas clínicos concordantes con AME a una edad de > 6 meses.
    4. Pacientes de ambos sexos de 2 a 12 años de edad.
    5. Paciente que puede sentarse sin asistencia, pero nunca ha podido caminar sin asistencia.
    6. Puntuación de la función motora (Escala de Hammersmith para la función motora, versión ampliada) ? 10 y ? 54 en la Selección.
    7. Paciente con capacidad para completar todos los procedimientos, las mediciones y las visitas del estudio, con un progenitor o tutor/paciente cuyas circunstancias psicosociales ofrecen un apoyo adecuado, a criterio del Investigador.
    8. Expectativa de vida > 2 años contados a partir de la selección, a criterio del investigador.
    9. Cumplimiento de los criterios institucionales apropiados para la edad en relación con el uso de anestesia/sedación, en el caso de que el uso de tales sustancias esté previsto para los procedimientos del estudio (según lo evaluado por el investigador del centro y el anestesista o el neumólogo).
    10. En el caso de los pacientes que, a criterio del investigador, hayan alcanzado la madurez sexual, el cumplimiento de uno de los siguientes criterios:
    Pacientes de sexo femenino: prueba de embarazo con resultado negativo en la selección y compromiso de usar métodos anticonceptivos adecuados durante el lapso del estudio. Los métodos anticonceptivos aceptables se limitan a abstinencia sexual, anticonceptivos de barrera, dispositivos anticonceptivos intrauterinos o productos hormonales autorizados.
    Pacientes de sexo masculino: abstinencia sexual durante el período establecido por el estudio.
    E.4Principal exclusion criteria
    1. Respiratory insufficiency, defined by the medical necessity for invasive or non-invasive ventilation for > 6 hours during a 24 hour period, at Screening
    2. Medical necessity for a gastric feeding tube, where the majority of feeds are given by this route, as assessed by the Site Investigator
    3. Severe contractures or severe scoliosis evident on X-ray examination at Screening
    4. Hospitalization for surgery (i.e., scoliosis surgery, other surgery), pulmonary event, or nutritional support within 2 months of screening or planned during the duration of the study
    5. Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period
    6. History of brain or spinal cord disease, including tumors, or abnormalities by MRI or CT that would interfere with the LP procedures or CSF circulation
    7. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter
    8. History of bacterial meningitis
    9. Dosing with ISIS 396443 in any previous clinical study
    10. Prior injury (e.g., upper or lower limb fracture) or surgical procedure which impacts the subject?s ability to perform any of the outcome measure testing required in the protocol and from which the subject has not fully recovered or achieved a stable baseline
    11. 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 inclusion
    12. Treatment with another investigational drug (e.g., oral albuterol/salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, etc.), biological agent, or device within 1-month of screening or 5 half-lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3-months of screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation
    13. Ongoing medical condition that according to the Site Investigator would interfere with the conduct and assessments of the study. Examples are medical disability (e.g., wasting or cachexia, severe anemia, etc.) that would interfere with the assessment of safety or would compromise the ability of the subject to undergo study procedures
    Insuficiencia respiratoria, definida como la necesidad médica de instaurar respiración mecánica invasiva o no invasiva durante > 6 horas en un período de 24 horas, en la selección.
    2. Necesidad médica de colocar una sonda nasogástrica para nutrición parenteral, que se utilizará para la mayor parte de la alimentación del paciente, según lo determinado por el investigador del centro.
    3. Presencia de contracturas importantes o escoliosis importante evidente en el examen radiológico en la selección.
    4. Hospitalización por intervención quirúrgica (p. ej., cirugía de escoliosis, otro tipo de cirugía), episodio pulmonar o soporte nutricional en los 2 meses previos a la selección o realización prevista dentro del período de realización del estudio.
    Presencia de infección no tratada o tratada inadecuadamente que requiere tratamiento antibiótico o antivírico sistémico en cualquier momento durante el período de selección.
    6. Antecedentes de enfermedad cerebral o de la médula espinal, incluidos tumores, o anomalías detectadas en la RM o en la TC que podrían interferir con los procedimientos de PL o con la circulación del LCR.
    7. Presencia de una derivación implantada para drenaje del LCR o un catéter implantado en el SNC.
    8. Antecedentes de meningitis bacteriana.
    9. Administración de ISIS 396443 en un estudio clínico anterior.
    10. Lesión (p. ej., fractura de extremidad superior o inferior) o procedimiento quirúrgico previo que repercute sobre la capacidad del paciente para realizar cualquiera de las pruebas de medidas de resultados requeridas en el protocolo y del/de la cual el paciente no se ha recuperado por completo o ha logrado un estado basal estable.
    11. Anomalías clínicamente significativas en los parámetros de hematología o de bioquímica clínica o del ECG, según lo determinado por el investigador del centro, presentes en la visita de selección, que harían que el paciente no fuera apto para su inclusión en el estudio.
    12. Tratamiento con otro medicamento (p. ej., albuterol/salbutamol oral, riluzol, carnitina, creatina, fenilbutirato sódico, etc.), medicamento biológico o dispositivo en fase de investigación en el mes previo a la selección o bien 5 semividas del medicamento en estudio, lo que implique el período más prolongado. Tratamiento con valproato o hidroxiurea en los 3 meses previos a la selección. Cualquier antecedente de terapia génica, terapia con oligonucleótidos antisentido o trasplante de células.
    13. Afección médica en curso que, a criterio del investigador del centro, interferiría con la realización del estudio y sus evaluaciones, entre ellas, discapacidades médicas (p. ej., emaciación o caquexia, anemia importante, etc.) que interferirían con la evaluación de la seguridad o que comprometerían la aptitud del paciente para ser sometido a los procedimientos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in HFMSE (Hammersmith Functional Motor Scale ? Expanded) score at 15 months
    Cambio respecto a la evaluación inicial en la escala HFMSE (Escala de Hammersmith para la función motora, versión ampliada (Hammersmith Functional Motor Scale ? Expanded) a los 15 meses
    E.5.1.1Timepoint(s) of evaluation of this end point
    15 months
    15 meses
    E.5.2Secondary end point(s)
    ? Proportion of subjects who achieve a 3 point increase from baseline in Hammersmith Functional Motor Scale ? Expanded (HFMSE) score at 15 months

    ? Proportion of subjects that achieve any new motor milestone at 15 months

    ? Number of motor milestones achieved per subject at 15 months

    ? Change from baseline in Upper Limb Module Test at 15 months

    ? Proportion of subjects that achieve standing alone at 15 months

    ? Proportion of subjects that achieve walking with assistance at 15 months
    - Proporción de pacientes que alcanzan un incremento de 3 puntos respecto de la evaluación inicial en la puntuación de la Escala de Hammersmith para la función motora (HFMSE), versión ampliada, a los 15 meses
    - Proporción de pacientes que alcanzan cualquier nuevo hito motriz a los 15 meses
    - Número de hitos motrices alcanzados por el paciente a los 15 meses
    - Cambio respecto de la evaluación inicial en la Prueba del módulo de extremidades superiores (Upper Limb Module Test) a los 15 meses
    - Proporción de pacientes que logran mantenerse de pie solos a los 15 meses.
    - Proporción de pacientes que logran caminar sin asistencia a los 15 meses
    E.5.2.1Timepoint(s) of evaluation of this end point
    15 months
    15 meses
    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 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
    Controlado mediante procedimiento simulado
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Canada
    France
    Germany
    Hong Kong
    Italy
    Japan
    Korea, Republic of
    Spain
    Sweden
    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 del 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 months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    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: 117
    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: 111
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 6
    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 No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 47
    F.4.2.2In the whole clinical trial 117
    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)
    At the end of participation in the trial, the study subjects will either be returned to their previously standard of care or they have the opportunity to participate in the open label extension study.
    TRas su participación en el estudio, los pacientes volverán a su tratamiento médico habitual o tendrán la posibilidad de participar en un estudio de extensión de diseño abierto.
    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 Decision2015-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-22
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