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    Summary
    EudraCT Number:2020-000976-40
    Sponsor's Protocol Code Number:ION373-CS1
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-02-12
    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 ConcernedNetherlands - Competent Authority
    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
    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
    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
    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 code CA 92010
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 760 931 9200
    B.5.5Fax number+1 760 603 2504
    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 IMPIntrathecal use
    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 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 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 placeboIntrathecal use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alexander Disease
    E.1.1.1Medical condition in easily understood language
    Alexander Disease
    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 22.1
    E.1.2Level PT
    E.1.2Classification code 10083059
    E.1.2Term Alexander disease
    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
    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
    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 ≥ 2 to 65 years old at the time of informed consent (eligibility for main study) or aged < 2 years old at the time informed consent was obtained (eligibility for the open-label sub-study)
    4.Able and willing to meet all study requirements (in the opinion of the Investigator), 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) who is reliable, competent and at least 18 years of age, is willing to accompany the patient to the trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of patient's ongoing condition to respond to Study Center inquiries about the patient
    6.If aged ≥ 2 and < 5 years old, must be able to sit with minimal assistance (using only own hands for support) for at least 10 seconds, or must be ambulatory (defined as able to complete the 10MWT in 5 minutes or less [assistive walking devices such as braces, canes, walkers permitted]); if aged ≥ 5 years old, must be ambulatory
    7. Stable medications, nutritional support and physical, occupational and, speech, and respiratory therapy for at least 3 months prior to Screening
    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 or history of hypersensitivity to ION373 or its excipients or history of hypersensitivity to any ASO. This exclusion does not apply to vaccines (both mRNA and viral vector vaccines).
    6.History of gene therapy or cell transplantation or any other experimental brain surgery
    7.Current 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
    12. History of gene therapy or cell transplantation or any other experimental brain surgery
    13. Current obstructive hydrocephalus
    14. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
    15. Any condition that increases risk of meningitis unless patient is receiving appropriate prophylactic treatment
    16. Known brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including tumors or abnormalities by MRI or computed tomography, subarachnoid hemorrhage, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome
    17. History of severe post-LP headache and/or blood patch
    18. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
    19. Recent history of, or current drug or alcohol abuse
    20. Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or anticipated use during the study, including but not limited to aspirin (unless ≤ 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
    21. 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, such as the presence of a chronic condition which places the patient at higher risk from procedural sedation or anesthesia if this is deemed necessary by the Investigator for completion study procedures including the lumbar punctures and/or brain MRI scans
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    baseline, Weeks 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 ≥ 5 years old at Screening)
    • 9-Hole Peg Test (9HPT; patients ≥ 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
    ≥ 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 ≥ 18 years old at Screening
    E.5.2.1Timepoint(s) of evaluation of this end point
    baseline, Weeks 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 concerned2
    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 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
    Israel
    Japan
    United Kingdom
    United States
    Italy
    Netherlands
    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
    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.1.1Number of subjects for this age range: 29
    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) Yes
    F.1.1.3.1Number of subjects for this age range: 2
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 13
    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 Yes
    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 state5
    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
    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 Decision2021-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-04
    P. End of Trial
    P.End of Trial StatusOngoing
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