A Study to Evaluate the Safety and Efficacy of ION373 in Patients With Alexander Disease (AxD)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of zilganersen (ION373) in improving or stabilizing gross motor function across the full range of affected domains in patients with AxD.

Detailed Description
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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.

Official Title
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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

Conditions
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Alexander Disease

Intervention / Treatment
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* Drug: zilganersen
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: zilganersen<br>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. | Drug: zilganersen<br>* zilganersen will be administered by ITB injection.<br>* Other names: ION373;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* zilganersen-matching placebo will be administered by ITB injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change from Baseline in the 10-Meter Walk Test (10MWT) |  | Baseline and Week 61 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Most Bothersome Symptom (MBS) |  | Baseline and Week 61 | 
| Change From Baseline in Patient Global Impression of Severity (PGIS) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in Patient Global Impression of Change (PGIC) Score | The PGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale. | Baseline and Week 61 | 
| Change From Baseline in Clinical Global Impression of Change (CGIC) Score | The CGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale. | Baseline and Week 61 | 
| Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in 9-Hole Peg Test (9HPT) Score | 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. | Baseline to Week 61 | 
| Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score | 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. | Baseline to Week 61 | 
| Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score | 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. | Baseline to Week 61 | 
| Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score | 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. | Baseline to Week 61 | 
| Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels |  | Baseline and Week 61 | 
| Change From Baseline in Clinical Global Impression of Severity (CGIS) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score | 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. | Baseline and Week 61 | 
| Change From Baseline in Body Weight Percentile (for participants < 18 years old at screening) or body weight (for participants ≥ 18 years old at screening) |  | Baseline and Week 61 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AxD