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    Summary
    EudraCT Number:2020-000976-40
    Sponsor's Protocol Code Number:ION373-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:2021-08-02
    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 number2020-000976-40
    A.3Full title of the trial
    A Phase 1-3, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of
    Intrathecally Administered ION373 in Patients with Alexander Disease
    Studio di Fase 1-3, in doppio cieco, randomizzato, controllato con placebo, per valutare l’efficacia, la sicurezza, la farmacocinetica e la farmacodinamica di ION373 somministrato per via intratecale in pazienti affetti da malattia di Alexander
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION373 in Patients with
    Alexander Disease
    Studio per valutare l’efficacia, la sicurezza, la farmacocinetica e la farmacodinamica di ION373 somministrato per via intratecale in pazienti affetti da malattia di Alexander
    A.3.2Name or abbreviated title of the trial where available
    NA
    NA
    A.4.1Sponsor's protocol code numberION373-CS1
    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 Court
    B.5.3.2Town/ cityCarlsbad
    B.5.3.3Post codeCA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number0017609319200
    B.5.5Fax number0017606032504
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/19/2206
    D.3 Description of the IMP
    D.3.1Product nameION373
    D.3.2Product code [ION373]
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntratracheal use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNION373
    D.3.9.1CAS number 2305355-56-8
    D.3.9.2Current sponsor codeION373
    D.3.9.3Other descriptive name2'-O-(2-METHOXYETHYL)-D-RIBOSE ANTISENSE OLIGONUCLEOTIDE TARGETING GLIAL FIBRILLARY ACIDIC PROTEIN MESSENGER RIBONUCLEIC ACID
    D.3.9.4EV Substance CodeSUB198712
    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
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboIntratracheal use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alexander Disease
    Malattia di Alexander
    E.1.1.1Medical condition in easily understood language
    Alexander Disease
    Malattia di Alexander
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    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 efficacy of ION373 in improving or stabilizing gross motor function in patients with Alexander disease
    Valutare l’efficacia di ION373 nel miglioramento o nella stabilizzazione della funzione grosso-motoria in pazienti affetti da malattia di Alexander
    E.2.2Secondary objectives of the trial
    To further evaluate the efficacy of ION373 in improving or stabilizing disease manifestations across the full range of affected domains (gross
    and fine motor, communication, swallowing, autonomic and/or other gastrointestinal functions, nutritional/growth status) in patients with Alexander disease
    Valutare ulteriormente l’efficacia di ION373 nel miglioramento o nella stabilizzazione delle manifestazioni della malattia nell’intero range dei domini interessati (funzioni grosso-motoria e motoria fine, di comunicazione, deglutizione, autonoma e/o altre funzioni gastrointestinali, stato nutrizionale/della crescita) in pazienti affetti da malattia di Alexander.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Clinical phenotype and brain imaging consistent with a diagnosis of Alexander disease
    2.Documented genetic mutation in the GFAP gene
    3.Aged > o = 2 to 65 years old at the time of informed consent
    4.Able and willing to meet all study requirements, including travel to Study Center, procedures, measurements and visits
    5.Patients < 18 years old at Screening must have a trial partner (parent, caregiver or other)
    1. Fenotipo clinico e diagnostica per immagini del cervello coerenti con una diagnosi di malattia di Alexander
    2. Mutazione genetica documentata a livello del gene GFAP
    3. Età compresa tra >o= 2 e 65 anni al momento del consenso informato
    4. Essere in grado di, e disposti a, soddisfare tutti i requisiti dello studio incluso recarsi al centro dello studio e sottoporsi a procedure, misurazioni e visite
    5. I pazienti di età < 18 anni allo Screening devono avere un accompagnatore per la sperimentazione (genitore, persona che si prende cura di loro o altro)
    E.4Principal exclusion criteria
    1.Clinically significant abnormalities in medical history or physical examination
    2.Platelet count or any other clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion
    3.Any contraindication or unwillingness to undergo MRI
    4.Treatment with another investigational drug, biological agent, or device within 1 month of Screening, or 5 half-lives of investigational
    agent, whichever is longer; concurrent participation in any other clinical study (including observational and non-interventional studies)
    5.Previous treatment with an oligonucleotide (including small interfering ribonucleic acid [siRNA]) within 4 months of Screening if single dose
    received, or within 12 months of Screening if multiple doses received received or history of hypersensitivity to ION373 or its excipients or history of
    hypersensitivity to any ASO
    6.History of gene therapy or cell transplantation or any other experimental brain surgery
    7.Obstructive hydrocephalus
    8.Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
    9.known brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment.
    10.Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during
    the study
    11.Have any other conditions, which, in the opinion of the Investigator would make the patient unsuitable for inclusion, or could interfere with
    the patient participating in or completing the study
    1. Anomalie clinicamente significative nell’anamnesi o all’esame obiettivo
    2. Conta piastrinica o qualsiasi altra anomalia di laboratorio clinicamente significativa che renderebbe un paziente non idoneo all’inclusione
    3. Qualsiasi controindicazione o riluttanza a sottoporsi alla risonanza magnetica
    4. Trattamento con altro agente biologico, dispositivo o farmaco sperimentale nel mese precedente allo Screening o nelle 5 emivite precedenti all’agente sperimentale, a seconda di quale sia il periodo più lungo; partecipazione concomitante a qualsiasi altro studio clinico (inclusi studi osservazionali e non interventistici)
    5. Precedente trattamento con oligonucleotide (incluso un piccolo acido ribonucleico interferente [siRNA]) nei 4 mesi precedenti allo Screening, se è stata somministrata una dose singola, o nei 12 mesi precedenti allo Screening, se sono state somministrate più dosi oppure anamnesi di ipersensibilità a ION373 o ai suoi eccipienti; oppure anamnesi di ipersensibilità a qualsiasi oligonucleotide antisenso (ASO)
    6. Anamnesi di terapia genica o trapianto di cellule o qualsiasi altro intervento chirurgico sperimentale al cervello
    7. Idrocefalo ostruttivo
    8. Presenza di shunt ventricolo-peritoneale funzionale per il drenaggio di LCS o catetere impiantato a livello del sistema nervoso centrale (SNC)
    9. Malattia cerebrale o spinale nota che interferirebbe con la procedura di puntura lombare (LP), la circolazione del LCS o la valutazione della sicurezza
    10. Ospedalizzazione per qualsiasi procedura medica o chirurgica maggiore, che preveda anestesia generale, nelle 12 settimane precedenti allo Screening o che sia programmata nel corso dello studio
    11. Presenza di altre condizioni che, secondo l’opinione dello sperimentatore, renderebbero il soggetto non idoneo all’inclusione o potrebbero interferire con la partecipazione da parte del soggetto allo studio o con il suo completamento dello stesso
    E.5 End points
    E.5.1Primary end point(s)
    Percent change from Baseline to Week 61 in the 10MWT in patients who are in Stratum 1.
    Variazione percentuale rispetto al Basale alla Settimana 61 nel 10MWT in pazienti che si trovano nello Strato 1.
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline, Weeks 13, 25, 37, 49, 61, 73, 85, 97, 109, 121
    basale, settimane 13, 25, 37, 49, 61, 73, 85, 97, 109, 121
    E.5.2Secondary end point(s)
    Key Secondary Endpoints:
    Change from Baseline to Week 61 or value at Week 61 for the following:
    • Patients' self-identified most bothersome symptom (based on a Likert scale for change; all patients)
    • PedsQL Generic Core Scales (all patients)
    • Patient Global Impression of Severity (PGIS; all patients)
    • Patient Global Impression of Change (PGIC; all patients)
    • Clinical Global Impression of Change (CGIC; all patients)
    Other Secondary Endpoints:
    Change from Baseline to Week 61 or value at Week 61 for the following:
    • Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E; patients < 5 years old at Screening) or
    10MWT (patients > o = 5 years old at Screening)
    • 9-Hole Peg Test (9HPT; patients > o = 8 years old at Screening)
    • Vineland-3 Motor Skills Domain (patients < 8 years old at Screening)
    • PedsQL Gastrointestinal Symptoms Scales (all patients)
    • Vineland-3 Adaptive Behavior Composite (ABC) Score (patients < 18 years old at Screening)
    • Composite Autonomic Symptom Score 31 (COMPASS-31; patients > o = 18 years old at Screening)
    • CSF GFAP levels (all patients)
    • Clinical Global Impression of Severity (CGIS; all patients)
    • Alexander Disease Patient Domain Impression of Severity (AxD-PDIS; all patients)
    •Alexander Disease Patient Domain Impression of Change (AxD-PDIC; all patients)
    • Body weight percentile (for patients < 18 years old at Screening) or body weight (for patients > o = 18 years old at Screening
    Principali endpoint secondari:
    Variazione rispetto al Basale alla Settimana 61 o valore alla Settimana 61 per quanto segue:
    • Sintomo identificato dai pazienti stessi come il più fastidioso (basato su una scala Likert per la variazione; tutti i pazienti)
    • Scale di base generiche PedsQ (tutti i pazienti)
    • Patient Global Impression of Severity (PGIS; tutti i pazienti)
    • Patient Global Impression of Change (PGIC; tutti i pazienti)
    • Clinical Global Impression of Change (GCIC; tutti i pazienti)
    Altri endpoint secondari:
    Variazione rispetto al Basale alla Settimana 61 o valore alla Settimana 61 per quanto segue:
    • Misura-88 della funzione grosso-motoria, dimensioni C, D ed E (GMFM 88, dimensioni C-E; pazienti di età < 5 anni allo Screening) o 10MWT (pazienti di età > o = 5 anni allo Screening)
    • Test dei 9 pioli (9HPT; pazienti di età > o = 8 anni allo Screening)
    • Dominio delle capacità motorie Vineland-3 (pazienti di età < 8 anni allo Screening)
    • Scale PedsQL di valutazione dei sintomi gastrointestinali (tutti i pazienti)
    • Punteggio composito del comportamento adattativo (ABC) Vineland-3 (pazienti di età < 18 anni allo Screening)
    • Punteggio composito 31 dei sintomi autonomici (COMPASS-31; pazienti di età > o = 18 anni allo Screening)
    • Livelli di GFAP nel LCS (tutti i pazienti)
    • Clinical Global Impression of Severity (CGIS; tutti i pazienti)
    • Patient Domain Impression of Severity - malattia di Alexander (AxD-PDIS; tutti i pazienti)
    • Patient Domain Impression of Change - malattia di Alexander (AxD-PDIC; tutti i pazienti)
    • Percentile di peso corporeo (per pazienti di età < 18 anni allo Screening) o peso corporeo (per pazienti di età> o = 18 anni allo Screening)
    E.5.2.1Timepoint(s) of evaluation of this end point
    baseline, Weeks 13, 25, 37, 49, 61, 73, 85, 97, 109, 121
    basale, settimane 13, 25, 37, 49, 61, 73, 85, 97, 109, 121
    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 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) Yes
    E.7.1.1First administration to humans Yes
    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) Yes
    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 Yes
    E.8.2.3Other No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Australia
    Canada
    Israel
    Japan
    United States
    Italy
    Netherlands
    United Kingdom
    Argentina
    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
    LPLV
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    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 years4
    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.1.1.1In 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: 16
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 13
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 13
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 13
    F.4.2.2In the whole clinical trial 42
    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)
    Standard of care
    cura standard
    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 Decision2021-10-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-06-09
    P. End of Trial
    P.End of Trial StatusOngoing
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