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    Summary
    EudraCT Number:2014-001947-18
    Sponsor's Protocol Code Number:ISIS396443-CS4
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-12
    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 ConcernedItaly - Italian Medicines Agency
    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
    Studio di fase 3 randomizzato, in doppio cieco, controllato con procedura fittizia per valutare l'efficacia e la sicurezza clinica di ISIS 396443 somministrato per via intratecale a pazienti con atrofia muscolare spinale ad esordio tardivo
    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
    Studio clinico controllato per valutare l'efficacia e la sicurezza di ISIS 396443 in pazienti con atrofia muscolare spinale ad esordio tardivo
    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 type2สน-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 Muscolare spinale (SMA)
    E.1.1.1Medical condition in easily understood language
    Spinal Muscular Atrophy (SMA)
    Atrofia Muscolare spinale (SMA)
    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.
    Valutare l'efficacia di ISIS 396443 somministrato per via intratecale a pazienti con SMA ad esordio tardivo
    E.2.2Secondary objectives of the trial
    To examine the safety and tolerability of ISIS 396443 administered intrathecally to patients with later-onset SMA.
    Valutare la sicurezza e la tollerabilità di ISIS 396443 somministrato per via intratecale a pazienti con SMA ad esordio tardivo.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    . 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
    1. Consenso informato firmato dal genitore o dal tutore e assenso informato firmato dal soggetto, se previsto in base all'età del soggetto e alle linee guida dell'istituto
    2. Avere una diagnosi medica di atrofia muscolare spinale (SMA)
    3. Insorgenza di segni clinici e sintomi compatibili con SMA a > 6 mesi di età
    4. Avere un'età compresa fra 2 e 12 anni allo screening
    5. Essere capace di stare seduto autonomamente, ma non essere mai stato capace di camminare da solo
    6. Punteggio funzionale motorio [Scala funzionale motoria di Hammersmith – espansa] ≥ 10 e ≤ 54 allo screening
    7. Aver completato tutte le procedure, le misurazioni e le visite dello studio e, secondo l'opinione dello sperimentatore, il genitore o il tutore/soggetto può fare affidamento su un contesto psicosociale di supporto adeguato
    8. Attesa di vita stimata > 2 anni dallo screening, secondo l'opinione dello sperimentatore
    9. Soddisfare i criteri dell'istituto correlati all'età per l'utilizzo dell'anestesia/sedazione, ove detto utilizzo sia previsto per le procedure dello studio
    10. I soggetti che hanno raggiunto l'età fertile, devono soddisfare le richieste di utilizzo di anticoncezionali come previsto dallo studio.
    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.
    1. Insufficienza respiratoria, definita come necessità medica di ventilazione invasiva o non invasiva per > 6 ore nelle 24 ore, allo screening
    2. Necessità medica di una sonda gastrica per nutrizione, dove l'alimentazione viene per lo più somministrata attraverso questa via, secondo valutazione dello sperimentatore del centro
    3. Gravi contratture o scoliosi grave evidenziate da radiografia allo screening
    4. Ricovero per intervento chirurgico (ovvero intervento per scoliosi o di altro tipo), evento polmonare o supporto nutrizionale entro 2 mesi dallo screening o in programma durante lo svolgimento dello studio
    5. Presenza di un'infezione attiva non trattata o trattata in modo inadeguato che richiede terapia antivirale sistemica o terapia antimicrobica in qualsiasi momento durante il periodo di screening
    6. Anamnesi di malattia al cervello o al midollo spinale, inclusi tumori o anomalie evidenziate da MRI o CT che interferirebbe con le procedure di LP o la circolazione del CSF
    7. Presenza di uno shunt impiantato per il drenaggio del CSF o di un catetere CNS impiantato
    8. Anamnesi di meningite batterica
    9. Somministrazione di ISIS 396443 in qualsiasi studio clinico precedente
    10. Lesione pregressa (es. frattura di arto superiore o inferiore) o intervento chirurgico che compromette la capacità del soggetto di eseguire i test di misura degli esiti richiesti dal protocollo e dal quale il soggetto non si è ancora completamente ripreso o non ha raggiunto condizioni stabili.
    11. Anomalie clinicamente significative dei parametri ematologici o chimico-clinici o dell'ECG, secondo valutazione dello sperimentatore del centro, alla visita di screening, che renderebbero il soggetto non idoneo all'inclusione
    12. Trattamento con un altro farmaco sperimentale (es. albuterolo/salbutamolo per via orale, riluzolo, carnitina, creatina, fenilbutirrato di sodio, etc.), agente biologico, o dispositivo entro 1 mese dallo screening o 5 emivite dell'agente in studio, a seconda di quale periodo sia maggiore Trattamento con valproato o idrossiurea entro 3 mesi dallo screening. Anamnesi di terapia genica, terapia con oligonucleotidi antisenso o trapianto di cellule
    13. Patologia concomitante che secondo lo sperimentatore del centro potrebbe interferire con lo svolgimento e le valutazioni dello studio Ne è esempio la disabilità medica (es. deperimento o cachessia, anemia grave, etc.) che interferirebbe con la valutazione della sicurezza o comprometterebbe la capacità del soggetto di sottoporsi alle procedure dello studio.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in HFMSE (Hammersmith Functional Motor Scale – Expanded) score at 15 months
    Variazione del punteggio HFMSE (Scala funzionale motoria di Hammersmith – espansa) rispetto al basale a 15 mesi
    E.5.1.1Timepoint(s) of evaluation of this end point
    15 months
    15 mesi
    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
    - Proporzione dei soggetti che raggiungono un incremento di 3 punti rispetto al basale nel punteggio HFMSE (Scala funzionale motoria di Hammersmith – espansa) a 15 mesi - Proporzione dei soggetti che raggiungono qualsiasi nuova tappa motoria a 15 mesi - Numero di tappe motorie raggiunte per soggetto a 15 mesi - Variazione rispetto al basale del test ULM (Upper Limb Module) a 15 mesi - Proporzione dei soggetti che raggiungono la posizione eretta in autonomia a 15 mesi - Proporzione dei soggetti che acquisiscono la deambulazione assistita a 15 mesi
    E.5.2.1Timepoint(s) of evaluation of this end point
    15 months
    15 mesi
    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
    Procedura Fittizia controllata
    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 EEA16
    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
    LVLS
    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 months2
    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.1.1.1In 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 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.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    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.
    Alla fine della partecipazione alla sperimentazione, i soggetti coinvolti nello studio potranno sia tornare al loro precedente trattamento standard sia avranno l'opportunità di partecipare ad uno studio di estensione in aperto
    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 Decision2015-02-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-02-20
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