Alexander DiseasePhase 3NCT04849741
A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)
A Phase 3 study testing zilganersen in people with Alexander Disease, run by Ionis Pharmaceuticals, Inc. at 13 sites in 8 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 65 years
- Conditions the study is for
- Alexander Disease
- What is being tested?
- zilganersen
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 54 participants
- Where
- 13 sitesin 8 countries
- Study dates
- 1 Jun 2021to Jul 2034
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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]
Show all 11Show fewer
- 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
Trial locations and contacts
13 sites in 8 countries.
13 sites in 8 countries
United States4 sites
Children's Hospital of Atlanta
Atlanta, Georgia, 30329
Massachusetts General Hospital
Boston, Massachusetts, 02114
Lucile Packard Children's Hospital Stanford
Palo Alto, California, 94304
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Italy2 sites
Ospedale dei Bambini Vittore Buzzi
Milan, 20154
Ospedale Pediatrico Bambino Gesù
Roma, 165
United Kingdom2 sites
University College London Hospitals NHS Foundation Trust
London, WC1N 3BG
Great Ormond Street Hospital for Children NHS Foundation Trust
London, WC1N 3JH
Australia1 site
Murdoch Children's Research Institute
Parkville, Victoria, 3052
Israel1 site
Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center
Tel Aviv, 6423906
Japan1 site
National Center of Neurology and Psychiatry
Tokyo, Kodaira-shi, 187-8551
Netherlands1 site
Amsterdam Universitair Medische Centra - Academisch Medisch Centrum
Amsterdam, North Holland, 1105 AZ
About this study
Official title: 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
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.
Read the 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.
- Conditions
- Alexander Disease
- Being tested
- zilganersen, Placebo
- Keywords
- AxD
- Medical subject headings
- Alexander Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
zilganersenDrug
Also called ION373
zilganersen will be administered by ITB injection.
PlaceboDrug
zilganersen-matching placebo will be administered by ITB injection.
| Study group | Role | What they receive |
|---|---|---|
| zilganersen | Experimental | 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, long-term and extended long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 469. Receives: Drug: zilganersen |
| Placebo | Placebo comparator | Matching placebo will be administered by ITB injection once every 12 weeks through Week 49. It will be followed by the open-label, long-term and extended long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 469. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change from Baseline in the 10-Meter Walk Test (10MWT)
10-Meter Walk Test (10MWT) is an assessment of gait speed.
Measured: Baseline and Week 61
Secondary outcomes (15)
Change From Baseline in Most Bothersome Symptom (MBS)
Measured: Baseline and Week 61
Change From Baseline in Patient Global Impression of Severity (PGIS) Score
Measured: Baseline and Week 61
Change From Baseline in Patient Global Impression of Change (PGIC) Score
Measured: Baseline and Week 61
Change From Baseline in Clinical Global Impression of Change (CGIC) Score
Measured: Baseline and Week 61
Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score
Measured: Baseline and Week 61
Change From Baseline in 9-Hole Peg Test (9HPT) Score
Measured: Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score
Measured: Baseline to Week 61
Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score
Measured: Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score
Measured: Baseline to Week 61
Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score
Measured: Baseline and Week 61
Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels
Measured: Baseline and Week 61
Change From Baseline in Clinical Global Impression of Severity (CGIS) Score
Measured: Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score
Measured: Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score
Measured: 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)
Measured: Baseline and Week 61
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2021
- Study start1 Jun 2021
- Primary completion22 Aug 2025
- Study completionJul 2034 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alexander DiseaseStudies of the same condition, open and under way.
- More trials run by Ionis Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 54 participants (actual)
Sponsor and investigators
- Lead sponsor
- Ionis Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04849741
- Sponsor's protocol ID
- ION373-CS1
- Other IDs
- 2024-510603-11-00
- Status last verified
- Aug 2026
- First submitted
- 16 Apr 2021
- Last updated
- 21 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.
- Expanded access
- Available
Study at a glance
From the registry record, last updated by the sponsor on 21 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT04849741
- Acronym / sponsor ID
- ION373-CS1
- Conditions
- Alexander Disease
- Keywords
- AxD
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 54 participants (actual)
- Lead sponsor
- Ionis Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 1 Jun 2021 (actual)
- Primary completion
- 22 Aug 2025 (actual)
- Study completion
- Jul 2034 (estimated)
- First posted
- 19 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| zilganersen | Experimental | Drug: zilganersenZilganersen 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, long-term and extended long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 469. |
| Placebo | Placebo comparator | Drug: PlaceboMatching placebo will be administered by ITB injection once every 12 weeks through Week 49. It will be followed by the open-label, long-term and extended long-term extension periods, where participants will receive zilganersen by ITB injection from Week 61 to Week 469. |
Who may qualify
- Ages
- 2 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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 (11 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| zilganersenAlso: ION373zilganersen will be administered by ITB injection. | Drug | zilganersen |
| Placebozilganersen-matching placebo will be administered by ITB injection. | Drug | Placebo |
Primary outcome
Percent Change from Baseline in the 10-Meter Walk Test (10MWT)
Time frame: Baseline and Week 61
10-Meter Walk Test (10MWT) is an assessment of gait speed.
15 secondary outcomes
Change From Baseline in Most Bothersome Symptom (MBS)
Time frame: Baseline and Week 61
Change From Baseline in Patient Global Impression of Severity (PGIS) Score
Time frame: Baseline and Week 61
Change From Baseline in Patient Global Impression of Change (PGIC) Score
Time frame: Baseline and Week 61
Change From Baseline in Clinical Global Impression of Change (CGIC) Score
Time frame: Baseline and Week 61
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
Change From Baseline in 9-Hole Peg Test (9HPT) Score
Time frame: Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score
Time frame: Baseline to Week 61
Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score
Time frame: Baseline to Week 61
Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score
Time frame: Baseline to Week 61
Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score
Time frame: Baseline and Week 61
Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels
Time frame: Baseline and Week 61
Change From Baseline in Clinical Global Impression of Severity (CGIS) Score
Time frame: Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score
Time frame: Baseline and Week 61
Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score
Time frame: 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)
Time frame: Baseline and Week 61
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Aug 2026.
- Individual participant dataSharing planned: Yes. Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
13 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing zilganersen in people with Alexander Disease, run by Ionis Pharmaceuticals, Inc. at 13 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 21 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United States, Italy, United Kingdom, Australia, Canada and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent Change from Baseline in the 10-Meter Walk Test (10MWT) (time frame: Baseline and Week 61). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2026.