Clinical trial NCT04849741: A Study to Evaluate the Safety and Efficacy of Zilganersen (ION373) in Patients With Alexander Disease (AxD)
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
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
Phase: PHASE3
Conditions: Alexander Disease
Keywords: AxD
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-04-19
Enrollment: 73
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Percent Change from Baseline in the 10-Meter Walk Test (10MWT)
timeFrame: Baseline and Week 61
Secondary outcomes:
measure: Change From Baseline in Most Bothersome Symptom (MBS)
timeFrame: Baseline and Week 61
measure: Change From Baseline in Patient Global Impression of Severity (PGIS) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Patient Global Impression of Change (PGIC) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Clinical Global Impression of Change (CGIC) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in 9-Hole Peg Test (9HPT) Score
timeFrame: Baseline to Week 61
measure: Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score
timeFrame: Baseline to Week 61
measure: Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score
timeFrame: Baseline to Week 61
measure: Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score
timeFrame: Baseline to Week 61
measure: Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels
timeFrame: Baseline and Week 61
measure: Change From Baseline in Clinical Global Impression of Severity (CGIS) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score
timeFrame: Baseline and Week 61
measure: Change From Baseline in Body Weight Percentile (for participants < 18 years old at screening) or body weight (for participants ≥ 18 years old at screening)
timeFrame: Baseline and Week 61
Other outcomes:
measure: Change From Baseline in Pediatrics Quality of Life Inventory (PedsQL) Generic Core Scales Score
timeFrame: Baseline and Week 61
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford
state: California
city: Atlanta
country: United States
facility: Children's Hospital of Atlanta
state: Georgia
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Parkville
country: Australia
facility: Murdoch Children's Research Institute
state: Victoria
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Tel Aviv
country: Israel
facility: Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center
city: Milan
country: Italy
facility: Ospedale dei Bambini Vittore Buzzi
city: Roma
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Tokyo
country: Japan
facility: National Center of Neurology and Psychiatry
state: Kodaira-shi
city: Amsterdam
country: Netherlands
facility: Amsterdam Universitair Medische Centra - Academisch Medisch Centrum
state: Noord-Holland
city: London
country: United Kingdom
facility: University College London Hospitals NHS Foundation Trust
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children NHS Foundation Trust
Study officials:
References: