- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04849741
A Study to Evaluate the Safety and Efficacy of ION373 in Patients With Alexander Disease (AxD)
A Phase 1-3, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered Zilganersen (ION373) in Patients With Alexander Disease
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a Phase 1-3, multi-center, double-blind, placebo-controlled, multiple-ascending dose (MAD) study in approximately 73 patients with AxD. Participants will be randomized in a 2:1 ratio to receive zilganersen (ION373) or matching placebo for a 60-week double-blind treatment period; then all participants will receive zilganersen for a 60-week open-label treatment period followed by a 120-week open-label, long-term extension period, and a 28-week post-treatment follow-up period. Multiple dose cohorts will be evaluated in the study. Cohorts will be enrolled sequentially. The initial participants in each dose cohort must be at least 8 years of age at the time of Screening.
The study will include an optional open-label sub-study in participants <2 years of age at some sites.
Treatment extension period was added to provide continued access to open label zilganersen for patients completing the main study and sub-study until the drug may be commercially available.
Study Type
Enrollment (Estimated)
Phase
- Phase 3
Contacts and Locations
Study Contact
- Name: Ionis Pharmaceuticals
- Phone Number: (844) 514-7157
- Email: ionisNCT04849741study@clinicaltrialmedia.com
Study Locations
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Victoria
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Parkville, Victoria, Australia, 3052
- Recruiting
- Murdoch Children's Research Institute
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Quebec
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Montreal, Quebec, Canada, H3A 0G4
- Recruiting
- McGill University Health Centre
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Tel Aviv, Israel, 6423906
- Recruiting
- Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center
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Milan, Italy, 20154
- Recruiting
- Ospedale dei Bambini Vittore Buzzi
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Roma, Italy, 165
- Recruiting
- Ospedale Pediatrico Bambino Gesù
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Kodaira-shi
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Tokyo, Kodaira-shi, Japan, 187-8551
- Recruiting
- National Center of Neurology and Psychiatry
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Noord-Holland
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Amsterdam, Noord-Holland, Netherlands, 1105 AZ
- Recruiting
- Amsterdam Universitair Medische Centra - Academisch Medisch Centrum
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London, United Kingdom, WC1N 3BG
- Recruiting
- University College London Hospitals NHS Foundation Trust
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London, United Kingdom, WC1N 3JH
- Recruiting
- Great Ormond Street Hospital For Children NHS Foundation Trust
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California
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Palo Alto, California, United States, 94304
- Recruiting
- Lucile Packard Children's Hospital Stanford
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Georgia
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Atlanta, Georgia, United States, 30329
- Recruiting
- Children's Hospital of Atlanta
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Recruiting
- Massachusetts General Hospital
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Pennsylvania
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Philadelphia, Pennsylvania, United States, 19104
- Recruiting
- Children's Hospital of Philadelphia
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Key Inclusion Criteria:
- Clinical phenotype and brain imaging consistent with a diagnosis of Alexander disease
- Documented genetic mutation in the GFAP gene
- Aged ≥ 2 to 65 years old at the time of informed consent
- Able and willing to meet all study requirements, including travel to Study Center, procedures, measurements and visits
- Patients < 18 years old at Screening must have a trial partner (parent, caregiver or other)
Key Exclusion Criteria:
- Clinically significant abnormalities in medical history or physical examination
- Any clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion
- Any contraindication or unwillingness to undergo MRI
- 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)
- 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. This exclusion does not apply to vaccines (both messenger ribonucleic acid [mRNA] and viral vector vaccines).
- History of gene therapy or cell transplantation or any other experimental brain surgery [ROW]
- Obstructive hydrocephalus
- Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
- Known brain or spinal disease that would interfere with the lumbar puncture (LP) process, CSF circulation or safety assessment.
- Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: zilganersen
Zilganersen will be administered by intrathecal bolus (ITB) injection once every 12 weeks through Week 49.
The 60-week double-blind treatment period will be followed by the open-label and long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 229.
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zilganersen will be administered by ITB injection.
Other Names:
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Placebo Comparator: Placebo
Matching placebo will be administered by ITB injection once every 12 weeks through Week 49.
It will be followed by the open-label and long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 229.
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zilganersen-matching placebo will be administered by ITB injection.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Percent Change from Baseline in the 10-Meter Walk Test (10MWT)
Time Frame: Baseline and Week 61
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Baseline and Week 61
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change From Baseline in Most Bothersome Symptom (MBS)
Time Frame: Baseline and Week 61
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Baseline and Week 61
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Change From Baseline in Patient Global Impression of Severity (PGIS) Score
Time Frame: Baseline and Week 61
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The PGIS questionnaire captures the participant's rating of the severity of his/her global health status associated with AxD on a 5-point ordinal scale.
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Baseline and Week 61
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Change From Baseline in Patient Global Impression of Change (PGIC) Score
Time Frame: Baseline and Week 61
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The PGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale.
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Baseline and Week 61
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Change From Baseline in Clinical Global Impression of Change (CGIC) Score
Time Frame: Baseline and Week 61
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The CGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale.
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Baseline and Week 61
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Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score
Time Frame: Baseline and Week 61
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The GMFM-88 is a standardized observational instrument to measure change in gross motor function over time in children with developmental disabilities consisting of 88 items scored on a 4-point ordinal scale grouped in 5 dimensions.
Dimensions C (crawling and kneeling), D (standing) and E (walking, running & jumping) will be assessed.
The goal total score is the average of the dimension scores expressed as a percentage of the maximum score for that dimension.
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Baseline and Week 61
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Change From Baseline in 9-Hole Peg Test (9HPT) Score
Time Frame: Baseline to Week 61
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The 9HPT is a simple test of manual dexterity that records the time required for the participant to accurately place and remove nine pegs into a pegboard.
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Baseline to Week 61
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Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score
Time Frame: Baseline to Week 61
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The Vineland-3 is a standardized measure used to quantify adaptive behaviors necessary for socialization, communication and daily functioning.
Items are scored on a 0-2 scale rating the consistency of independent completion of the assessed skill.
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Baseline to Week 61
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Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score
Time Frame: Baseline to Week 61
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The PedsQL GI Symptoms Scales captures gastrointestinal symptoms on 10 scales and 58 items: Stomach Pain and Hurt Scale (6 items), Stomach Discomfort When Eating Scale (5 items), Food and Drink Limits Scale (6 items), Trouble Swallowing Scale (3 items), Heartburn and Reflux Scale (4 items), Nausea and Vomiting Scale (4 items), Gas and Bloating Scale (7 items), Constipation Scale (14 items), Blood in Poop Scale (2 items) and Diarrhea Scale (7 items).
Higher scores indicate few symptoms and better GI-specific health-related quality of life.
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Baseline to Week 61
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Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score
Time Frame: Baseline to Week 61
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The Vineland-3 is a standardized measure used to quantify adaptive behaviors necessary for socialization, communication and daily functioning.
The Core Adaptive Behavior Scores encompass 3 domains of behavior: communication, daily living and socialization.
Items are scored on a 0-2 scale rating the consistency of independent completion of the assessed skill.
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Baseline to Week 61
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Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score
Time Frame: Baseline and Week 61
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COMPASS-31 is a 31-question participant-reported assessment that measures autonomic symptoms across 6 weighted domains on a 100-point scale: orthostatic intolerance (40 points), vasomotor (5 points), secretomotor (15 points), gastrointestinal (25 points), bladder (10 points), and pupillomotor (15 points).
A higher score indicates worse autonomic dysfunction.
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Baseline and Week 61
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Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels
Time Frame: Baseline and Week 61
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Baseline and Week 61
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Change From Baseline in Clinical Global Impression of Severity (CGIS) Score
Time Frame: Baseline and Week 61
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The CGIS questionnaire captures the clinician's rating of the severity of the participant's global health status associated with AxD on a 5-point ordinal scale.
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Baseline and Week 61
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Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score
Time Frame: Baseline and Week 61
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The AxD-PDIS questionnaire captures the participant's rating of the severity of specific disease symptoms including gross and fine motor problems, GI problems, language or speech problems and other cognitive problems.
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Baseline and Week 61
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Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score
Time Frame: Baseline and Week 61
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The AxD-PDIC questionnaire captures the participant's rating of improvement or decline in specific disease symptoms including gross and fine motor problems, GI problems, language or speech problems and other cognitive problems.
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Baseline and Week 61
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Change From Baseline in Body Weight Percentile (for participants < 18 years old at screening) or body weight (for participants ≥ 18 years old at screening)
Time Frame: Baseline and Week 61
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Baseline and Week 61
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Change From Baseline in Pediatrics Quality of Life Inventory (PedsQL) Generic Core Scales Score
Time Frame: Baseline and Week 61
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The generic core scale is a global health-related quality of life assessment reflecting physical (8 items), emotional (5 items), social (5 items) and school/work functioning (5 items).
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Baseline and Week 61
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Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Demyelinating Diseases
- Genetic Diseases, Inborn
- Neurodegenerative Diseases
- Metabolism, Inborn Errors
- Heredodegenerative Disorders, Nervous System
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Leukoencephalopathies
- Hereditary Central Nervous System Demyelinating Diseases
- Alexander Disease
Other Study ID Numbers
- ION373-CS1
- 2020-000976-40 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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