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

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ClinicalTrials.gov Identifier: NCT04849741
Recruitment Status : Recruiting
First Posted : April 19, 2021
Last Update Posted : May 17, 2021
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

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 58 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 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
Estimated Study Start Date : May 2021
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : November 2025


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.




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 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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).

  9. Change From Baseline in Cerebrospinal Fluid (CSF) Glial Fibrillary Acid Protein (GFAP) Levels [ Time Frame: Baseline and Week 61 ]
  10. 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.

  11. 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.

  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 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.

  14. 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.

  15. 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.

  16. 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 ]


Information from the National Library of Medicine

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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
  6. History of gene therapy or cell transplantation or any other experimental brain surgery
  7. Obstructive hydrocephalus
  8. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter
  9. Known brain or spinal disease that would interfere with the 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04849741


Contacts
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Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com

Locations
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United States, California
Lucile Packard Children's Hospital Stanford Recruiting
Palo Alto, California, United States, 94304
Contact: Erika Shols    650-497-0873    eshols@stanford.edu   
United States, Illinois
IONIS Investigative Site Not yet recruiting
Chicago, Illinois, United States, 60611
United States, Massachusetts
IONIS Investigative Site Not yet recruiting
Boston, Massachusetts, United States, 02114
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Geraldine Liu    267-425-2063    liug@chop.edu   
United States, Texas
IONIS Investigative Site Not yet recruiting
Houston, Texas, United States, 77030
Canada, British Columbia
IONIS Investigative Site Not yet recruiting
Vancouver, British Columbia, Canada, V6H3N1
Canada, Quebec
McGill University Health Centre Recruiting
Montreal, Quebec, Canada, H3A 0G4
Contact    514-412-4400 ext 23380    bernardlab.neuropediatrics@mcgill.ca   
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
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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    Key Record Dates
Last Update Posted: May 17, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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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