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    Summary
    EudraCT Number:2021-003009-23
    Sponsor's Protocol Code Number:ION582-CS1
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-03-30
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2021-003009-23
    A.3Full title of the trial
    A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION582 in Patients with Angelman Syndrome
    Studio volto a valutare la sicurezza, la tollerabilità, la farmacocinetica e la farmacodinamica di ION582 somministrato per via intratecale in pazienti affetti dalla sindrome di Angelman
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This study is meant to evaluate the effects of a drug product called ION582 in patients with Angelman syndrome (genetic disorder that mainly affects the nervous system). This study will evaluate the safety, how the organism tolerates the drug product, how the product is metabolized by the organism and what are the effects of the product on the body.
    Questo studio ha lo scopo di valutare gli effetti di un prodotto farmaceutico chiamato ION582 in pazienti con sindrome di Angelman (disordine genetico che colpisce principalmente il sistema nervoso). Questo studio valuterà la sicurezza, come l'organismo tollera il prodotto farmaceutico, come il prodotto viene metabolizzato dall'organismo organismo e quali sono gli effetti del prodotto sul corpo.
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberION582-CS1
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT05127226
    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 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 pointIonis Clinical Trial Information
    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 number17606032302
    B.5.5Fax number17606032504
    B.5.6E-mailclinicaltrials@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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameION582
    D.3.2Product code [ION582]
    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.3.9.2Current sponsor codeION582
    D.3.9.4EV Substance CodeSUB235756
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 typeAntisense Oligonucleotide (ASO)
    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
    Angelman syndrome is a neurogenetic disorder caused by a loss of function of the maternally inherited UBE3A gene (chromosome 15) which codes for UBE3A ubiquitin protein ligase. AS presents early in life severe developmental delays (motor, language and cognitive functioning, seizures and ataxia with happy demeanor and sociability). It is a non-degenerative, life-long disorder resulting in complete dependence on a caregiver that generally remains clinically unchanged with a normal life expectancy.
    AS malattia neurogenetica causata da una perdita della funzionalità del gene UBE3A ereditato da madre (chr15) che codifica per la proteina ligasi dell'ubiquitina UBE3A. AS si presenta con gravi ritardi dello sviluppo (motorio, linguistico e cognitivo funzionamento, convulsioni e atassia con diminuizione della felicità e socievolezza). Disturbo non degenerativo, che dura tutta la vita e di conseguenza il paziente è dipendente da un caregiver che non cambia clinicamente la sua aspettativa di vita.
    E.1.1.1Medical condition in easily understood language
    Angelman syndrome is a genetic disorder that mainly affects the nervous system. Symptoms include severe intellectual disability and developmental disability with normal life expectancy.
    La AS è una malattia genetica che colpisce principalmente il sistema nervoso. I sintomi includono grave disabilità intellettiva e disabilità dello sviluppo con aspettativa di vita normale.
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10049004
    E.1.2Term Angelman's syndrome
    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 safety and tolerability of ascending dose-levels of multiple intrathecal bolus (ITB) administrations of ION582 in patients with Angelman syndrome (AS) based on incidence and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in vital signs and changes in clinical laboratory results.
    Per valutare la sicurezza e la tollerabilità di dosi crescenti di somministrazioni di boli intratecali multipli (ITB) di ION582 in pazienti con sindrome di Angelman (AS) in base all'incidenza e alla gravità degli eventi avversi emergenti dal trattamento (TEAE) e degli eventi avversi gravi (SAE) , cambiamenti nei segni vitali e cambiamenti nei risultati clinici di laboratorio.
    E.2.2Secondary objectives of the trial
    Secondary Objective: Characterize the pharmacokinetics (PK) in cerebrospinal fluid (CSF), plasma and urine of ascending dose-levels of multiple IT bolus administrations of ION582 in patients with AS.

    Exploratory Objective: To evaluate the effects of ION582 on AS biomarkers and clinical features
    including motor, language, cognitive functioning, sleep, and
    electroencephalogram (EEG) patterns in patients with AS.
    Obiettivi secondari: Caratterizzare la farmacocinetica (PK) nel liquido cerebrospinale (CSF), nel plasma e nelle urine di livelli crescenti di dose di somministrazioni multiple in bolo IT di ION582 in pazienti con AS.

    Obiettivi esplorativi: Per valutare gli effetti di ION582 sui biomarcatori AS e sulle caratteristiche cliniche inclusi motori, linguaggio, funzionamento cognitivo, sonno e pattern dell'elettroencefalogramma (EEG) nei pazienti con AS.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Participant has a documented and certified diagnosis of Angelman syndrome (AS) (ubiquitin-protein ligase E3A [UBE3A] deletion or UBE3A mutation)
    2. Male or female between the ages of 2-50 years of age, with signed informed consent from parent(s) or legal guardian(s)
    3. Currently receiving stable standard of care treatments such as, stable doses of anti-epileptic medication, behavioural management medications, sleep medications, gabapentin, cannabidiol, and including
    special diets, supplements or nutritional support for at least 3 months prior to first dose.
    4. Follow good study practice and not participate in the sharing of personal or study information on social media platforms, such as any website or social media site (e.g., Facebook, Instagram, Twitter, YouTube, etc.) until notified that the study is completed.
    1. Il partecipante ha una diagnosi documentata e certificata di sindrome di Angelman (AS) (delezione ubiquitina-proteina ligasi E3A [UBE3A] o mutazione UBE3A)
    2. Uomo o donna di età compresa tra 2 e 50 anni, con il consenso informato firmato da parte dei genitori o tutori legali
    3. Attualmente riceve trattamenti di cura standard stabili come dosi stabili di farmaci antiepilettici, farmaci per la gestione del comportamento, farmaci per dormire, gabapentin, cannabidiolo e inclusi diete speciali, integratori o supporto nutrizionale per almeno 3 mesi prima della prima dose.
    4. Seguire le buone pratiche di studio e non partecipare alla condivisione di informazioni personali o di studio su piattaforme di social media, come qualsiasi sito Web o sito di social media (ad es. Facebook, Instagram, Twitter, YouTube, ecc.) fino a quando non viene notificato che lo studio è completato.
    E.4Principal exclusion criteria
    1. Has documented molecular AS confirmation of paternal uniparental disomy (UPD) or imprinting defect (ID).
    2. Any clinically significant (CS) cardiovascular, endocrine, hepatic, renal, pulmonary, gastrointestinal, neurologic, malignant, metabolic, psychiatric, or other condition that, in the judgment of the Investigator, will pose a safety risk, will make the patient unsuitable for participation in, and/or unable to complete the study procedures. Has poorly controlled seizures as determined by the Investigator or has documented Status Epilepticus in the past 6 months that could pose a safety risk while on study.
    3. Known bone, spine, bleeding, or other disorder that exposes the patient to risk of injury or unsuccessful lumbar puncture. Previous treatment with an oligonucleotide (including small interfering ribonucleic acid, antisense oligonucleotide [ASOs]). COVID-19 vaccinations are allowed.
    4. Any prior use of gene therapy. Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participant taking part in or completing the study.
    1. conferma di AS molecolare di disomia uniparentale paterna (UPD) o difetto di imprinting (ID).
    2. Qualsiasi condizione clinicamente significativa (CS) cardiovascolare, endocrina, epatica, renale, polmonare, gastrointestinale, neurologica, maligna, metabolica, psichiatrica o di altra natura che, a giudizio dello sperimentatore, rappresenterà un rischio per la sicurezza, renderà il paziente non idoneo a partecipare e/o impossibilitato a completare le procedure di studio. Ha crisi epilettiche scarsamente controllate come determinato dallo sperimentatore o ha documentato Status Epilepticus negli ultimi 6 mesi che potrebbero rappresentare un rischio per la sicurezza durante lo studio.
    3. Ossa, colonna vertebrale, sanguinamento o altri disturbi noti che espongono il paziente al rischio di lesioni o puntura lombare non riuscita. Precedente trattamento con un oligonucleotide (incluso acido ribonucleico piccolo interferente, oligonucleotide antisenso [ASO]). Sono consentite le vaccinazioni COVID-19.
    4. Qualsiasi uso precedente di terapia genica. Avere qualsiasi altra condizione che, a giudizio dello sperimentatore, renderebbe il partecipante inadatto all'inclusione o potrebbe interferire con il partecipante che prende parte o completa lo studio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be the assessment of patient safety and
    tolerability of ION582 by determining the incidence and severity of the
    below parameters:
    • TEAEs, SAEs and changes in concomitant medications
    • Physical examination and standard neurological assessment
    • Vital signs (body temperature, heart rate [HR], blood pressure [BP],
    weight)
    • Electrocardiograms (ECGs)
    • CSF safety labs (cell counts, protein, glucose)
    • Laboratory tests (clinical chemistry, hematology, urinalysis)
    L'endpoint primario sarà la valutazione della sicurezza del paziente e
    tollerabilità di ION582 determinando l'incidenza e la gravità del
    sotto i parametri:
    • TEAE, SAE e cambiamenti nei farmaci concomitanti
    • Esame obiettivo e valutazione neurologica standard
    • Segni vitali (temperatura corporea, frequenza cardiaca [FC], pressione sanguigna [BP],
    peso)
    • Elettrocardiogrammi (ECG)
    • Laboratori di sicurezza del liquido cerebrospinale (conta cellulare, proteine, glucosio)
    • Esami di laboratorio (chimica clinica, ematologia, analisi delle urine)
    E.5.1.1Timepoint(s) of evaluation of this end point
    throughout the study
    durante tutto lo studio
    E.5.2Secondary end point(s)
    Pharmacokinetic parameters of ION582 will be evaluated through the
    collection of CSF, plasma and urine samples.
    ION582 concentration in CSF will be summarized.
    Plasma maximum concentration (Cmax), area under the curve (AUC),
    elimination half-life and trough and post-distribution ION582 levels will be assessed, where appropriate and possible.
    Amount of ION582 excreted in urine, percent of dose excreted, and renal
    clearance (if possible) following first dose will be summarized, as
    appropriate.
    I parametri farmacocinetici di ION582 saranno valutati attraverso il
    raccolta di campioni di liquido cerebrospinale, plasma e urina.
    Verrà riassunta la concentrazione di ION582 nel liquido cerebrospinale.
    Concentrazione massima plasmatica (Cmax), area sotto la curva (AUC),
    L'emivita di eliminazione ei livelli minimi e post-distribuzione di ION582 saranno valutati, ove appropriato e possibile.
    Quantità di ION582 escreto nelle urine, percentuale della dose escreta e renale
    sarà riassunta la clearance (se possibile) dopo la prima dose, come
    adeguata.
    E.5.2.1Timepoint(s) of evaluation of this end point
    CSF and plasma samples will be collected pre-dose on each dosing day
    (day 1, 29 and 85) for PK analyses.
    Additional plasma samples will be collected on Study Day 1 (1, 3, and 6
    hours post-ITB injection), Study Day 2 (24 hours post-ITB injection),
    and Study Days 113, 169, and 309 (any 1 time point during the visit).
    Urine will be collected for 24 hours on Day 1 starting at the time of
    dosing, only for patients in Cohorts D and E and if they are able.
    I campioni di liquido cerebrospinale e plasmatico verranno raccolti prima della dose in ogni giorno di somministrazione
    (giorno 1, 29 e 85) per analisi farmacocinetiche.
    Ulteriori campioni di plasma saranno raccolti il ¿¿giorno di studio 1 (1, 3 e 6
    ore dopo l'iniezione di ITB), giorno di studio 2 (24 ore dopo l'iniezione di ITB),
    e giornate di studio 113, 169 e 309 (ogni 1 punto temporale durante la visita).
    L'urina verrà raccolta per 24 ore il giorno 1 a partire dal momento del
    dosaggio, solo per i pazienti nelle coorti D ed E e se in grado.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase1-2a
    Fase
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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
    in aperto
    open
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 EEA12
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Canada
    Israel
    United States
    France
    Germany
    Italy
    United Kingdom
    Netherlands
    Spain
    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 months0
    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 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.1.1.1In 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: 14
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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.3.3.6.1Details of subjects incapable of giving consent
    Patient's LAR must sign the consent form before any screening tests or
    assessments are performed. Due to the severity of the disease, which
    significantly limits the patient's ability to provide assent, patient assent
    will not be requested.
    La LAR del paziente deve firmare il modulo di consenso prima di qualsiasi test di screening o
    si eseguono valutazioni. A causa della gravità della malattia, che
    limita significativamente la capacità del paziente di fornire il consenso, il consenso de
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state3
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 22
    F.4.2.2In the whole clinical trial 44
    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)
    NONE
    NESSUNO
    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 Decision2022-06-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-09-08
    P. End of Trial
    P.End of Trial StatusOngoing
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