2'-O-(2-METHOXYETHYL)-D-RIBOSE ANTISENSE OLIGONUCLEOTIDE TARGETING GLIAL FIBRILLARY ACIDIC PROTEIN MESSENGER RIBONUCLEIC ACID for Alexander disease

Inclusion criteria

• {"criterion_text":"-Must have given written informed consent (and assent, if indicated per patient’s age and institutional guidelines) and any authorizations required by local law and be able to comply with all study requirements"}
• {"criterion_text":"-Patients who, in the opinion of the Investigator, have reached reproductive maturity, must satisfy 1 of the following: Females must be non-pregnant and non-lactating, and either: i. Surgically sterile (e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy) ii. Postmenopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause; in females ≤ 55 years of age not using hormonal contraception or hormonal replacement therapy, a high follicle stimulating hormone (FSH) level in the postmenopausal range for the laboratory involved will be used to confirm a postmenopausal state) iii. Abstinent* or iv. If engaged in sexual relations of childbearing potential, agree to use highly effective contraceptive methods (refer to Section 6.3.1) from the time of signing the informed consent form until at least 40 weeks after the last dose of Study Drug (ION373 or placebo) and agree to receive a pregnancy test at Screening, Day 1, every 12 weeks during the Double-Blind and Open-Label Treatment Periods, and at the last study visit Males must be abstinent*; surgically sterile (i.e., bilateral orchidectomy); or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method (refer to Section 6.3.1) must be used from the time of signing the informed consent form until at least 40 weeks after the last dose of Study Drug (ION373 or placebo). * Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of study participation) is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), withdrawal, and declaration of abstinence for the duration of a trial are not acceptable methods of contraception."}
• {"criterion_text":"-Clinical phenotype and brain imaging consistent with a diagnosis of AxD"}
• {"criterion_text":"-Documented genetic mutation in the GFAP gene"}
• {"criterion_text":"-Aged ≥ 2 to 65 years old at the time of informed consent (eligibility for main study) or aged < 2 years old at the time of informed consent (eligibility for the open-label sub study)"}
• {"criterion_text":"-If aged ≥ 2 and < 5 years old, must be able to sit with minimal assistance (using only own hands for support) for at least 10 seconds, or must be ambulatory (defined as able to complete the 10MWT in 5 minutes or less [assistive walking devices such as braces, canes, walkers permitted]); if aged ≥ 5 years old, must be ambulatory"}
• {"criterion_text":"-Stable medications, nutritional support and physical, occupational, speech, and respiratory therapy for at least 3 months prior to Screening"}
• {"criterion_text":"-Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, measurements and visits"}
• {"criterion_text":"-Patients < 18 years old at Screening must have a trial partner (parent, caregiver or other) who is reliable, competent and at least 18 years of age, is willing to accompany the patient to the trial visits and to be available to the Study Center by phone if needed, and who (in the opinion of the Investigator) is and will remain sufficiently knowledgeable of patient’s ongoing condition to respond to Study Center inquiries about the patient"}

Exclusion criteria

• {"criterion_text":"-Clinically significant abnormalities in medical history (e.g., previous acute coronary syndrome within 6 months of Screening, major surgery within 3 months of Screening) or physical examination"}
• {"criterion_text":"-Platelet count (defined as < 100,000/mm3 ) or any other clinically significant laboratory abnormalities that would render a patient unsuitable for inclusion"}
• {"criterion_text":"-History of bleeding diathesis or coagulopathy"}
• {"criterion_text":"-Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1"}
• {"criterion_text":"-Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator"}
• {"criterion_text":"-Any contraindication or unwillingness to undergo MRI (e.g., metal implants, claustrophobia, agitation or motor symptoms of a severity that precludes MRI scans)"}
• {"criterion_text":"-Known history of, or positive test for human immunodeficiency virus (HIV), hepatitis C or chronic hepatitis B"}
• {"criterion_text":"-Uncontrolled hypertension defined as: i. for patients < 13 years old, BP ≥ 95th percentile + 12 mmHg, or ≥ 140/90 mmHg, whichever is lower ii. for patients ≥ 13 years old, BP ≥ 140/90 mmHg"}
• {"criterion_text":"-Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix that has been successfully treated or benign pediatric tumors. Patients with a history of other malignancies that have been treated with curative intent and which have no recurrence within 5 years may also be eligible if approved by the Sponsor Medical Monitor"}
• {"criterion_text":"-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)"}
• {"criterion_text":"-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; or history of hypersensitivity to ION373 or its excipients; or history of hypersensitivity to any ASO. This exclusion does not apply to vaccines (both mRNA and viral vector vaccines)."}
• {"criterion_text":"-History of gene therapy or cell transplantation or any other experimental brain surgery"}
• {"criterion_text":"-Current obstructive hydrocephalus"}
• {"criterion_text":"-Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted CNS catheter"}
• {"criterion_text":"-Any condition that increases risk of meningitis unless patient is receiving appropriate prophylactic treatment"}
• {"criterion_text":"-Known brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, including tumors or abnormalities by MRI or computed tomography, subarachnoid hemorrhage, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome"}
• {"criterion_text":"-History of severe post-LP headache and/or blood patch"}
• {"criterion_text":"-Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks prior to Screening or planned during the study"}
• {"criterion_text":"-Recent history of, or current drug or alcohol abuse"}
• {"criterion_text":"-Antiplatelet or anticoagulant therapy within the 14 days prior to Screening or anticipated use during the study, including but not limited to aspirin (unless ≤ 81 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban"}
• {"criterion_text":"-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, such as the presence of a chronic condition which places the patient at higher risk from procedural sedation or anesthesia if this is deemed necessary by the Investigator for completion study procedures including the lumbar punctures and/or brain MRI scans"}

Primary endpoints

• {"endpoint_text":"-Percent change from Baseline to Week 61 in the 10MWT in patients who are in Stratum 1.","definition_or_measurement_approach":"Percent change from baseline to Week 61 measured using the 10-Meter Walk Test (10MWT) in patients in Stratum 1."}

Secondary endpoints

• {"endpoint_text":"-Change from Baseline to Week 61 or value at Week 61 for the following: • Patients' self-identified most bothersome symptom (based on a Likert scale for change; all patients) • PedsQL Generic Core Scales (all patients) • Patient Global Impression of Severity (PGIS; all patients) • Patient Global Impression of Change (PGIC; all patients) • Clinical Global Impression of Change (CGIC; all patients)","definition_or_measurement_approach":"Change from baseline to Week 61 or absolute value at Week 61 for listed patient-reported outcomes and clinician global impression measures."}
• {"endpoint_text":"-Change from Baseline to Week 61 or value at Week 61 for the following: • Gross Motor Function Measure-88, Dimensions C, D and E (GMFM-88, Dimensions C-E; patients < 5 years old at Screening) or 10MWT (patients ≥ 5 years old at Screening) • 9-Hole Peg Test (9HPT; patients ≥ 8 years old at Screening) • Vineland-3 Motor Skills Domain (patients < 8 years old at Screening) • PedsQL Gastrointestinal Symptoms Scales (all patients)","definition_or_measurement_approach":"Age-specific motor function assessments (GMFM-88 or 10MWT), 9HPT for eligible ages, Vineland-3 motor domain for younger patients, and PedsQL GI symptom scales."}
• {"endpoint_text":"-Change from Baseline to Week 61 or value at Week 61 for the following: Vineland-3 Adaptive Behavior Composite (ABC) Score (patients < 18 years old at Screening) • Composite Autonomic Symptom Score 31 (COMPASS-31; patients ≥ 18 years old at Screening) • CSF GFAP levels (all patients) • Clinical Global Impression of Severity (CGIS; all patients)","definition_or_measurement_approach":"Change from baseline to Week 61 for adaptive behavior (Vineland-3), autonomic symptom score (COMPASS-31), laboratory biomarker CSF GFAP levels, and clinician global severity rating."}
• {"endpoint_text":"-Change from Baseline to Week 61 or value at Week 61 for the following: • Alexander Disease Patient Domain Impression of Severity (AxD-PDIS; all patients) •Alexander Disease Patient Domain Impression of Change (AxD-PDIC; all patients) • Body weight percentile (for patients < 18 years old at Screening) or body weight (for patients ≥ 18 years old at Screening","definition_or_measurement_approach":"Patient domain impressions (AxD-PDIS, AxD-PDIC) and body weight measures (percentile or absolute) assessed at Week 61 or change from baseline."}

Netherlands

Earliest CTIS Part Ii Submission Date

09-05-2024

Latest Decision Or Authorization Date

12-03-2025

Processing Time Days

307

Number Of Sites

1

Number Of Participants

6

Italy

Earliest CTIS Part Ii Submission Date

09-05-2024

Latest Decision Or Authorization Date

24-04-2025

Processing Time Days

350

Number Of Sites

2

Number Of Participants

9

Primary sponsor

Full Name

Ionis Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

medical monitoring support

Name

PPD Development LP

Responsibilities

PK, CSF and Plasma GFAP

Name

Pharmaceutical Product Development LLC

Responsibilities

safety reporting

Third parties

• {"country":"United States","full_name":"Biologics Development Services LLC","duties_or_roles":"GFAP's NFL","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"CSF Albumin and IgG Day 1","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Quest Diagnostics Nichols Institute Inc.","duties_or_roles":"BIORAD MULTISPOT HIV-1/2 ANTIBODY DIFFERENTIATION TEST, QUALITATIVE RNA","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Invicro LLC","duties_or_roles":"Central MRI Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"Holter (cardiac monitoring services)","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Chillibean Limited","duties_or_roles":"video services for clinical assessments","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"IRT","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sitero LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"medical monitoring support","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Precision For Medicine Inc.","duties_or_roles":"Biomarker analysis (IP10 and FDF15)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"PK, CSF and Plasma GFAP","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Pharmaceutical Product Development LLC","duties_or_roles":"safety reporting","organisation_type":"Pharmaceutical company"}