A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS).
- Conditions
- Amyotrophic Lateral Sclerosis with Fused in Sarcoma mutationsMedDRA version: 21.1Level: PTClassification code 10002026Term: Amyotrophic lateral sclerosisSystem Organ Class: 10029205 - Nervous system disordersTherapeutic area: Diseases [C] - Nervous System Diseases [C10]
- Registration Number
- EUCTR2020-005522-28-BE
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 95
Inclusion Criteria for Part 1:
1.Must provide written informed consent
2.At the time of informed consent, a patient must be >= 10 years of age and have signs or symptoms consistent with an ALS disease process (in the opinion of the Investigator)
3.Genetic mutation in FUS confirmed by a testing laboratory that is Clinical Laboratory Improvement Amendments (CLIA) certified and, European Conformity (CE) marked, or equivalent. Mutations must be reviewed and approved by a Variant Classification Committee
4.Upright (sitting position) SVC is = 50% of predicted value (as adjusted for sex, age, and height) OR if SVC is < 50% of predicted value, must be 10 to 30 years of age (inclusive) at the time of informed consent AND had ALS symptom onset within 12 months before the time of informed consent
5. Able and willing to meet all study requirements (in the opinion of the Investigator), including travel to Study Center, procedures, assessments, and visits.
6.Participants taking edaravone, riluzole, Relyvrio (sodium phenylbutyrate/taurursodiol combination called Albrioza in Canada), sodium phenylbutyrate, or tauroursodeoxycholic acid [TUDCA, also known as taurursodiol or urosodiol]) must be on a stable dose for = 28 days prior to Day 1 and willing to continue on that dose throughout the duration of the study, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be
restarted during the study.
7. Satisfies the following:
a. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile
ii. post-menopausal
iii. abstinent*
or
iv. if engaged in sexual relations of childbearing potential, agree to use a highly effective contraceptive method from the time of signing the ICF until at least 40 Weeks after the last dose of Study Drug
b. Males must be abstinent*, surgically sterile (vasectomy with negative semen analysis at follow-up, or a surgically sterile non-pregnant female partner) or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective
contraceptive method must be used (refer to Section 6.3.1) from the time of signing the ICF until at least 40 weeks after the last dose of Study Drug
* Abstinence is only acceptable as true abstinence.
8.Stable concomitant medications and nutritional support for at least 1 month prior to Study Day 1. Concomitant medications or nutritional support that have not been stable for at least 1 month prior to Study Day 1 may be allowed per Investigator's Judgement.
9.Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the patient to be able to provide accurate information about the patient's cognitive and functional abilities throughout the study. In addition, a patient who is < 18 years old must have a trial partner (parent, caregiver, or other) who is reliable, competent, at least 18 years of age, and willing to accompany the patient to all trial visits.
Inclusion Criteria for Part 2:
1.Completed or was rescued from Part 1, or enrolled and received at least 1 dose of ION363 in the IIS. Patients from the IIS must provide written informed consent (and assent, if indicated per patient's age and institutional guidelines) (signed and dated) and any authorizations required by local law.
2. Satisfy the following:
a. Females: must be non-pregnant and non-lactating and either:
i. surgically sterile
ii. post-menopausal (defined as no menses for 12 months without
Exclusion Criteria for Part 1:
1.Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy
2.Any known genetic variant (other than those in the FUS gene) that is pathogenic or likely to be pathogenic for the ALS–frontotemporal dementia (FTD) spectrum of disease
3.Positive test result for:
a.Human immunodeficiency virus (HIV)
b.Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment
c.Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment
4.Clinically significant (CS) abnormalities in medical history (e.g., previous acute coronary syndrome within 3 months before Screening, major
surgery within 2 months before Screening) or physical examination
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
6. Uncontrolled hypertension (blood pressure [BP] > 160/100 mmHg).
7. Malignancy within 1 year before Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Patients with a history of other malignancies that have been treated with curative intent and which have not recurred within 6 months may also be eligible per Investigator judgment
8. Obstructive hydrocephalus
9. Presence of a functional ventriculoperitoneal shunt for the drainage of cerebrospinal fluid (CSF) or an implanted central nervous system (CNS) catheter
10. Known significant 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 (CT), subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or curvature, chiari malformation, obstructive hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome
11. Presence of significant cognitive impairment, not due to a developmental disability, based on the Mini-Mental State Examination (MMSE) (score of < 20) or an equivalent assessment, clinical dementia, and unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression, as determined by the Investigator
12. Concurrent participation in any other interventional clinical study
12. Concurrent participation in any other interventional clinical study
13. Previous or current treatment with an oligonucleotide (including small interfering RNA [siRNA], tofersen). This exclusion criterion does not apply to coronavirus disease 2019 (COVID-19) vaccinations, which are allowed.
14. Treatment with another investigational drug, biological agent, or device, including, but not limited to sodium phenylbutyrate, within 1 month before Screening, or 5 half-lives of investigational agent, whichever is longer
15. History of gene therapy or cell transplantation or any other experimental brain surgery
16. Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication that cannot be safely paused before and/or after an LP procedure according to local or institutional guidelines and/or Investigator determination after consultation with the appropriate treating physician. Low-dose aspiri
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method