Alexander Disease
Conditions
Keywords
AxD
Brief summary
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
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 during 5 treatment periods: 1) a 60-week double-blind treatment period; 2) a 60-week open-label treatment period; 3) a 120-week open-label, Long-Term Extension (LTE) period; 4) an open-label Extended Long-Term Extension Treatment Period (X-LTE) of up to 240 weeks; 5) 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 in the patient's country, or until the Sponsor discontinues the zilganersen development program, whichever occurs earlier.
Interventions
DRUGzilganersen
zilganersen will be administered by ITB injection.
DRUGPlacebo
zilganersen-matching placebo will be administered by ITB injection.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key 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 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) Key
Exclusion criteria
1. Clinically significant abnormalities in medical history or physical examination 2. Any 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. This exclusion does not apply to vaccines (both messenger ribonucleic acid \[mRNA\] and viral vector vaccines). 6. History of gene therapy or cell transplantation or any other experimental brain surgery \[ROW\] 7. Obstructive hydrocephalus 8. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter 9. Known brain or spinal disease that would interfere with the lumbar puncture (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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change from Baseline in the 10-Meter Walk Test (10MWT) | Baseline and Week 61 | 10-Meter Walk Test (10MWT) is an assessment of gait speed. |
Secondary
| Measure | 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 | Baseline and Week 61 |
| Change From Baseline in Patient Global Impression of Change (PGIC) Score | Baseline and Week 61 |
| Change From Baseline in Clinical Global Impression of Change (CGIC) Score | Baseline and Week 61 |
| Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score | Baseline and Week 61 |
| Change From Baseline in 9-Hole Peg Test (9HPT) Score | Baseline to Week 61 |
| Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score | Baseline to Week 61 |
| Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score | Baseline to Week 61 |
| Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score | Baseline to Week 61 |
| Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score | 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 | Baseline and Week 61 |
| Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score | Baseline and Week 61 |
| Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score | 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 |
Countries
Australia, Canada, Israel, Italy, Japan, Netherlands, United Kingdom, United States
Outcome results
None listed