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-DE
- Lead Sponsor
- Ionis Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 77
Inclusion Criteria for Part 1:
1.Signs or symptoms consistent with an ALS disease process in the opinion of the Investigator
2.Participants in:
Cohort A must be, at the time of informed consent, 12 – 65 years of age, inclusive, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and if 30 to 65 years of age, inclusive, have an ALSFRS-R pre-study slope = 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset)
Cohort B must be, at the time of informed consent, > 30 years of age, with signs or symptoms consistent with an ALS disease process in the opinion of the Investigator and have an ALSFRS-R pre-study slope < 0.4 points per month (calculated as [48-Screening ALSFRS-R score]/time in months since symptom onset) if between the ages of 30-65, or > 65 years of age with no ALSFRS-R pre-study slope criterion
3.Confirmed genetic mutation in FUS in a clinical laboratory improvement amendments (CLIA) certified, CE-marked, or equivalent testing laboratory . Mutations must be reviewed and approved by a variant classification committee
4.Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height = 50 percentage (%) of predicted value
5.Participants taking edaravone, riluzole, AMX0035 (sodium phenylbutyrate/taurursodiol combination), sodium phenylbutyrate, or tauroursodeoxycholic acid [TUDCA, also known as taurursodiol or urosodiol]) must be on a stable dose for = 28 days prior to Screening
6. Females: a) 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.
6.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 Judment
7.Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at Screening. Participants < 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 participant to 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 participant's ongoing condition to respond to Study Center inquiries about the participant
Inclusion Criteria for Part 2:
1.Completed, or rescued from, Part 1, Enrolled and received at least 1 dose of ION363 in the Investigator-initiated Study
2. Satisfy the following:
a. Females: must be non-pregnant and n
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 ALS-associated mutations except FUS
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 of Screening, major surgery within 2 months of Screening) or physical examination, unless discussed and approved by the Sponsor Medical Monitor
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1
6. Uncontrolled hypertension (BP > 160/100 mm Hg)
7. Malignancy within 1 year of 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 no recurrence within 6 months may also be eligible per Investigator judgement
8. Obstructive hydrocephalus
9. Presence of a functional ventriculoperitoneal shunt for the drainage of CSF or an implanted 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, with either a score on the Mini-Mental State Examination (MMSE) < 20 or 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
13. Previous treatment with an oligonucleotide (including siRNA). This exclusion criterion does not apply to 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 of 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. Antiplatelet or anticoagulant therapy within the 14 days prior to Day 1 or anticipated use during the study, including but not limited to daily, low-dose aspirin (defined as = 150 mg/day), clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban
17. Clinically significant low platelet count (defined as < 100,000/mm3), coagulation tests, or laboratory abnormalities that would render a patient unsuitable for inclusion
18. Unwillingness to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator
19. Have any other condit
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