A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)
- Registration Number
- NCT04849741
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- 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. For information on enrollment to the sub-study, please call or email the below central contact:
Telephone: (844) 514-7157 Email: ionisNCT04849741study@clinicaltrialmedia.com
- 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 in the patient's country, or until the Sponsor discontinues the zilganersen development program, whichever occurs earlier.
Recruitment & Eligibility
- Status
- ENROLLING_BY_INVITATION
- Sex
- All
- Target Recruitment
- 73
- 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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description zilganersen 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. Placebo 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.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method Change From Baseline in Most Bothersome Symptom (MBS) Baseline and Week 61 Change From Baseline in 9-Hole Peg Test (9HPT) 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 Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score Baseline and 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 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 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
Trial Locations
- Locations (13)
University College London Hospitals NHS Foundation Trust
🇬🇧London, United Kingdom
Children's Hospital of Atlanta
🇺🇸Atlanta, Georgia, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Ospedale Pediatrico Bambino Gesù
🇮🇹Roma, Italy
Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv, Israel
McGill University Health Centre
🇨🇦Montreal, Quebec, Canada
National Center of Neurology and Psychiatry
🇯🇵Tokyo, Kodaira-shi, Japan
Amsterdam Universitair Medische Centra - Academisch Medisch Centrum
🇳🇱Amsterdam, Noord-Holland, Netherlands
Murdoch Children's Research Institute
🇦🇺Parkville, Victoria, Australia
Great Ormond Street Hospital for Children NHS Foundation Trust
🇬🇧London, United Kingdom
Lucile Packard Children's Hospital Stanford
🇺🇸Palo Alto, California, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Ospedale dei Bambini Vittore Buzzi
🇮🇹Milan, Italy