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

• ClinicalTrials.gov Identifier: NCT04849741
• Recruitment Status: Recruiting
• First Posted: April 19, 2021
• Last Update Posted: January 9, 2023
• Sponsor: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Ionis Pharmaceuticals, Inc.

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Alexander Disease	Drug: ION373; Drug: Placebo	Phase 3

Detailed Description:

This is a Phase 1-3, multi-center, double-blind, placebo-controlled, multiple-ascending dose (MAD) study in up to 73 patients with AxD. Participants will be randomized in a 2:1 ratio to receive ION373 or matching placebo for a 60-week double-blind treatment period; then all participants will receive ION373 for a 60-week open-label treatment 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 73 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 1, 2021
• Estimated Primary Completion Date: February 2024
• Estimated Study Completion Date: November 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: ION373; ION373 will be administered by intrathecal bolus (ITB) injection once every 12 weeks through Week 109.	Drug: ION373; ION373 will be administered by ITB injection.
Placebo Comparator: Placebo; Matching placebo will be administered by ITB injection once every 12 weeks through Week 109.	Drug: Placebo; ION373-matching placebo will be administered by ITB injection.

Outcome Measures

Primary Outcome Measures :

1. Percent Change from Baseline in the 10-Meter Walk Test (10MWT) [ Time Frame: Baseline and Week 61 ]

Secondary Outcome Measures :

1. Change From Baseline in Most Bothersome Symptom (MBS) [ Time Frame: Baseline and Week 61 ]
2. Change From Baseline in Patient Global Impression of Severity (PGIS) Score [ Time Frame: Baseline and Week 61 ]
   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.
3. Change From Baseline in Patient Global Impression of Change (PGIC) Score [ Time Frame: Baseline and Week 61 ]
   The PGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale.
4. Change From Baseline in Clinical Global Impression of Change (CGIC) Score [ Time Frame: Baseline and Week 61 ]
   The CGIC questionnaire captures the participant's rating of improvement or decline in his/her global health status on a 5-point ordinal scale.
5. 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 ]
   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.
6. Change From Baseline in 9-Hole Peg Test (9HPT) Score [ Time Frame: Baseline to Week 61 ]
   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.
7. Change From Baseline in Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) Motor Skills Domain Score [ Time Frame: Baseline to Week 61 ]
   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.
8. Change From Baseline in Pediatrics Quality of Life Inventory Gastrointestinal Symptoms Scale (PedsQL GI) Score [ Time Frame: Baseline to Week 61 ]
   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.
9. Change From Baseline in Vineland Adaptive Behavior Composite, Third Edition (Vineland-3 ABC) Score [ Time Frame: Baseline to Week 61 ]
   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.
10. Change From Baseline in Composite Autonomic Symptom Score 31 (COMPASS-31) Score [ Time Frame: Baseline and Week 61 ]
    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.
11. Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels [ Time Frame: Baseline and Week 61 ]
12. Change From Baseline in Clinical Global Impression of Severity (CGIS) Score [ Time Frame: Baseline and Week 61 ]
    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.
13. Change From Baseline in Alexander Disease Patient Domain Impression of Severity (AxD-PDIS) Score [ Time Frame: Baseline and Week 61 ]
    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.
14. Change From Baseline in Alexander Disease Patient Domain Impression of Change (AxD-PDIC) Score [ Time Frame: Baseline and Week 61 ]
    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.
15. 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 ]

Other Outcome Measures:

1. Change From Baseline in Pediatrics Quality of Life Inventory (PedsQL) Generic Core Scales Score [ Time Frame: Baseline and Week 61 ]
   The generic core scale is a global health-related quality of life assessment reflecting physical (8 items), emotional (5 items), social (5 items) and school/work functioning (5 items).

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: Ionis Pharmaceuticals; (844) 514-7157; ionisNCT04849741study@clinicaltrialmedia.com

Locations

United States, California

Lucile Packard Children's Hospital Stanford; Recruiting

Palo Alto, California, United States, 94304

United States, Georgia

Children's Hospital of Atlanta; Recruiting

Atlanta, Georgia, United States, 30329

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Australia, Victoria

Murdoch Children's Research Institute; Recruiting

Parkville, Victoria, Australia, 3052

Canada, British Columbia

British Columbia Children's Hospital; Recruiting

Vancouver, British Columbia, Canada, V6H3N1

Canada, Quebec

McGill University Health Centre; Recruiting

Montreal, Quebec, Canada, H3A 0G4

Israel

Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center; Recruiting

Tel Aviv, Israel, 6423906

Italy

Ospedale dei Bambini Vittore Buzzi; Recruiting

Milan, Italy, 20154

Ospedale Pediatrico Bambino Gesù; Recruiting

Roma, Italy, 165

Japan

National Center of Neurology and Psychiatry; Recruiting

Tokyo, Kodaira-shi, Japan, 187-8551

Netherlands

Amsterdam Universitair Medische Centra - Academisch Medisch Centrum; Recruiting

Amsterdam, Noord-Holland, Netherlands, 1105 AZ

United Kingdom

University College London Hospitals NHS Foundation Trust; Recruiting

London, United Kingdom, WC1N 3BG

Great Ormond Street Hospital for Children NHS Foundation Trust; Recruiting

London, United Kingdom, WC1N 3JH

Sponsors and Collaborators

Ionis Pharmaceuticals, Inc.

More Information

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04849741
• Other Study ID Numbers: ION373-CS1; 2020-000976-40 ( EudraCT Number )
• First Posted: April 19, 2021
• Last Update Posted: January 9, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Ionis Pharmaceuticals, Inc.:

AxD

Additional relevant MeSH terms:

Alexander Disease; Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Leukoencephalopathies; Demyelinating Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Metabolic Diseases