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    Summary
    EudraCT Number:2017-000266-29
    Sponsor's Protocol Code Number:AVXS-101-CL-302
    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:2020-06-09
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2017-000266-29
    A.3Full title of the trial
    Phase 3, Open Label, Single Arm, Single Dose Gene Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering AVXS 101 by Intravenous Infusion
    Sperimentazione clinica di fase 3 in aperto a braccio singolo di una terapia di sostituzione genica in dose singola per pazienti affetti da atrofia muscolare spinale di tipo 1 con una o due copie di SMN2 con somministrazione di AVXS-101 mediante infusione endovenosa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Single Dose Gene Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1
    Terapia di sostituzione genica in dose singola per pazienti affetti da atrofia muscolare spinale di tipo 1
    A.3.2Name or abbreviated title of the trial where available
    N/A
    N/A
    A.4.1Sponsor's protocol code numberAVXS-101-CL-302
    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 SponsorAVEXIS, 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 supportAvexis Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAvexis Inc
    B.5.2Functional name of contact pointSr. Global Trial Operations Manager
    B.5.3 Address:
    B.5.3.1Street Address2275 Half Day Road, Suite 200
    B.5.3.2Town/ cityBannockburn IL
    B.5.3.3Post code60015
    B.5.3.4CountryUnited States
    B.5.4Telephone number1 224 500 2097
    B.5.5Fax number1 224 500 2097
    B.5.6E-mailswilliamson630@avexis.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/3/15/1509
    D.3 Description of the IMP
    D.3.1Product nameAVXS-101 (previously known as scAAV9.CB.SMN)
    D.3.2Product code AVXS-101
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMP
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 1922968-73-7
    D.3.9.2Current sponsor codeAVXS-101
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number20000000000000 to 60000000000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    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 Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    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
    Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1
    Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1
    E.1.1.1Medical condition in easily understood language
    Patients with Spinal Muscular Atrophy Type 1
    Pazienti con Atrofia Muscolare Spinale di tipo 1
    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 20.1
    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
    Determine efficacy by demonstrating achievement of developmental milestone of sitting without support up to 18 months of age as defined by WHO Motor Developmental Milestones
    Determinazione dell’efficacia mediante la dimostrazione del conseguimento della tappa dello sviluppo relativa alla stazione seduta autonoma fino ai 18 mesi di età, come definito dalle Tappe dello sviluppo motorio dell’OMS
    E.2.2Secondary objectives of the trial
    Determine efficacy based on survival at 14 months of age. Survival is defined by the avoidance of combined endpoint of either (a) death or (b)
    permanent ventilation which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via non invasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation. Permanent ventilation, so defined, is considered a surrogate for death.
    Determinazione dell’efficacia sulla base della sopravvivenza ai 14 mesi di età. La sopravvivenza è definita dall’elusione di endpoint combinati di (a) decesso o (b) ventilazione permanente, definita da tracheostomia o dalla necessità di ≥16 ore di assistenza respiratoria al giorno (tramite dispositivi di assistenza respiratoria non invasivi) per ≥14 giorni consecutivi, in assenza di una patologia acuta reversibile, escludendo la ventilazione perioperatoria. La ventilazione permanente, così definita, è considerata un surrogato del decesso.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with SMA Type 1 as determined by the diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or
    point mutations) and one or two copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)]
    • Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion.
    • Patients must have a swallowing evaluation test performed prior to administration of gene replacement therapy.
    1. Pazienti affetti da SMA di tipo 1 come stabilito dalla diagnosi della SMA sulla base delle analisi relative alla mutazione del gene con mutazioni bialleliche di SMN1 (mutazioni puntiformi o delezioni) e una o due copie di SMN2 [inclusivo della nota mutazione modificatrice del gene SMN2 (c.859G>C)]
    2. I pazienti devono avere < 6 mesi (< 180 giorni) di età al momento dell’infusione di AVXS-101.
    3. I pazienti devono essere sottoposti a un test di valutazione della deglutizione prima della somministrazione della terapia di sostituzione genica.
    E.4Principal exclusion criteria
    • Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening
    - Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and dosing with confirmatory oximetry reading
    - Patients may be put on non-invasive ventilatory support for less than 12 hours per day at the discretion of their physician or trial staff.
    • Use or requirement of non-invasive ventilatory support for 12 or more hours daily in the two weeks prior to dosing.
    • Patient with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards [27] and is unwilling to use an alternative method to oral feeding.
    • Participation in recent SMA treatment clinical study (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product, or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this study. Oral β- agonists must be discontinued at least 30 days before gene therapy dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable.
    • Patient < 35 weeks gestational age at time of birth.
    1. Uso di dispositivi di assistenza respiratoria invasivi (tracheotomia con pressione positiva) o pulsossimetria <95% per misurare la saturazione allo screening
    a. La saturazione con pulsossimetro non deve diminuire ≥ quattro (4) punti percentuali tra lo screening e il dosaggio con lettura pulsossimetrica di conferma
    b. I pazienti possono utilizzare dispositivi di assistenza non invasivi per meno di 12 ore al giorno, a discrezione del medico o del personale della sperimentazione.
    2. L’uso o la prescrizione di dispositivi di assistenza respiratoria non invasivi per 12 ore o più al giorno nelle due settimane precedenti al dosaggio.
    3. Paziente con sintomi di aspirazione sulla base di un test di deglutizione o il cui peso per età scende al di sotto del 3° percentile secondo le Tabelle di crescita infantile dell’Organizzazione mondiale della sanità (OMS) [27] e che non è disposto a utilizzare un metodo alternativo all’alimentazione per via orale.
    4. La partecipazione alla sperimentazione clinica relativa al trattamento della SMA (fatta eccezione per gli studi osservazionali di coorte o per gli studi non interventistici) o la ricezione di composti, prodotti o terapie sperimentali o commerciali, somministrati allo scopo di trattare la SMA (come, ad esempio, nusinersen o acido valproico), in qualunque momento precedente allo screening per la presente sperimentazione. I β-antagonisti per via orale devono essere interrotti almeno 30 giorni prima del dosaggio della terapia genetica. L’albuterol inalato, prescritto in maniera specifica a scopi di controllo della respirazione (broncodilatatore) è accettabile e non rappresenta una controindicazione in alcun momento precedente allo screening in relazione alla presente sperimentazione.
    5. Paziente con età gestazionale al momento della nascita < 35 settimane
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of symptomatic SMA Type 1 patients who are homozygous negative for SMN1 exon 7 and have two copies of SMN2 without the
    SMN2 genetic modifier that achieve the ability to sit without support for at least 10 seconds up to and including the 18 months of age trial visit.
    Sitting without support is defined by the World Health Organization Multicentre Growth Reference Trial (WHO MGRS), confirmed by video recording, as a patient who sits up straight with head erect for at least 10 seconds; child does not use arms or hands to balance body or support position.
    Percentuale dei pazienti affetti da SMA sintomatica di tipo 1 che risultano essere omozigoti negativi per l’esone 7 di SMN1 e presentano due coppie di SMN2 senza il modificatore genetico SMN2 che permette il conseguimento dell’abilità motoria di stare seduti autonomamente per almeno 10 secondi fino a e comprese la visita di sperimentazione a 18 mesi. Stare seduti autonomamente è definito dalla Sperimentazione di riferimento multicentrico sulla crescita dell’Organizzazione mondiale della sanità (WHO MGRS) e confermato da registrazioni video come un paziente che è in grado di sedere dritto e con la testa eretta per almeno 10 secondi; i bambini non usano le braccia o le mani per trovare l’equilibrio o sostenere la posizione.
    E.5.1.1Timepoint(s) of evaluation of this end point
    18 months
    18 mesi
    E.5.2Secondary end point(s)
    Survival at 14 months of age amongst symptomatic SMA Type 1 patients who are homozygous negative for SMN1 exon 7 and have two copies of SMN2 without the SMN2 genetic modifier. Survival is defined by the avoidance of the combined endpoint of either (a) death or (b) permanent ventilation, which is defined by tracheostomy or by the requirement of ≥ 16 hours of respiratory assistance per day (via noninvasive ventilatory support) for ≥ 14 consecutive days in the absence of an acute reversible illness, excluding perioperative ventilation.
    Permanent ventilation, so defined, is considered a surrogate for death.
    Sopravvivenza a 14 mesi di età tra i pazienti affetti da SMA sintomatica di tipo 1 che risultano essere omozigoti negativi per l’esone 7 di SMN1 e presentano due coppie di SMN2 senza il modificatore genetico SMN2. La sopravvivenza è definita dall’elusione di endpoint combinati di (a) decesso o (b) ventilazione permanente, definita da tracheostomia o dalla necessità di ≥ 16 ore di assistenza respiratoria al giorno (tramite dispositivi di assistenza respiratoria non invasivi) per ≥ 14 giorni consecutivi, in assenza di una patologia acuta reversibile, escludendo la ventilazione perioperatoria. La ventilazione permanente, così definita, è considerata un surrogato del decesso
    E.5.2.1Timepoint(s) of evaluation of this end point
    14 months
    14 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 No
    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 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 Information not present in EudraCT
    E.8.1.6Cross over Information not present in EudraCT
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    In aperto, braccio singolo, dose singola
    Open-label, single-arm, single-dose
    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 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 concerned5
    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 No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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 months6
    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 months6
    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: 1
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Yes
    F.1.1.2.1Number of subjects for this age range: 2
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 27
    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 No
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women Information not present in EudraCT
    F.3.3.4Nursing women Information not present in EudraCT
    F.3.3.5Emergency situation Information not present in EudraCT
    F.3.3.6Subjects incapable of giving consent personally Information not present in EudraCT
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    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 the End of Trial visit, eligible patients will be asked to rollover into the long-term follow up trial.
    After the End of Trial visit, eligible patients will be asked to rollover into the long-term follow up trial.
    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 Decision2018-04-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-21
    P. End of Trial
    P.End of Trial StatusCompleted
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