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FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)

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ClinicalTrials.gov Identifier: NCT04768972
Recruitment Status : Recruiting
First Posted : February 24, 2021
Last Update Posted : April 8, 2024
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Study Description
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Brief Summary:
The primary purpose of this study is to evaluate the efficacy of ION363 on clinical function and survival in carriers of fused in sarcoma mutations with amyotrophic lateral sclerosis (FUS-ALS).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: ION363 Drug: Placebo Phase 3

Detailed Description:
This is a multi-center, three-part study of ION363 in up to 95 participants. Part 1 will consist of participants who will be randomized in a 2:1 ratio to receive a multi-dose regimen of ION363 or placebo for a period of 60 weeks, followed by Part 2, in which participants will receive open-label ION363 for a period of 84 weeks. Participants may continue to receive open-label ION363 in Part 3 for up to 3 additional years or until ION363 becomes commercially available in the patient's country or until the Sponsor discontinues the ION363 development program, whichever occurs earlier.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 95 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 1-3 Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Intrathecally Administered ION363 in Amyotrophic Lateral Sclerosis Patients With Fused in Sarcoma Mutations (FUS-ALS)
Actual Study Start Date : June 14, 2021
Estimated Primary Completion Date : June 2026
Estimated Study Completion Date : March 2028

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: ION363
ION363 will be administered by lumbar intrathecal (IT) bolus injection every 12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period in Part 1; every 12 weeks for 84 weeks in the open-label extension treatment period (Part 2), with an additional loading dose administered 4 weeks after the first dose. Patients may continue to receive open-label ION363 every 12 weeks in Part 3 for up to 3 additional years or until ION363 becomes commercially available in the patient's country or until the Sponsor discontinues the development program, whichever occurs earlier.
 Drug: ION363
ION363 will be administered by IT bolus injection.
Placebo Comparator: Placebo
Placebo will be administered by lumbar IT bolus injection every12 weeks, with an additional loading dose at 4 weeks, over a 60-week double-blind treatment period (Part 1).
 Drug: Placebo
Placebo will be administered by IT bolus injection.


Outcome Measures
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Primary Outcome Measures :
  1. Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment [ Time Frame: Baseline, Day 505 in Part 1 ]
    Functional impairment to be measured by joint rank analysis of the combined assessment of: In-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score, time of rescue or discontinuation from Part 1 and entering Part 2 due to a deterioration in function, and ventilation assistance-free survival (VAFS). ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory function. The assessment will contain 12 questions scored from 0 (no function) to 4 (full function), with a total possible score of 48, which will indicate the highest level of function. ALSFRS-R will be a part of the combined assessment of joint rank analysis to assess efficacy in Part 1.


Secondary Outcome Measures :
  1. Change from Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 505 in Part 1 [ Time Frame: Baseline, Day 505 in Part 1 ]
    The ALSSQOL-R is a disease-specific 50-item assessment that measures the quality of life. Each item will be rated by the participant on a scale of 0 to 10, with 0 being the least desirable situation and 10 being the most desirable.

  2. Change from Baseline in the in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) [ Time Frame: Baseline, Day 505 in Part 1 ]
  3. Survival and Ventilation Assistance-Free Survival (VAFS) [ Time Frame: Up to Day 505 in Part 1 ]
  4. Change from Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1 [ Time Frame: Baseline, Day 505 in Part 1 ]
  5. Change from Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1 [ Time Frame: Baseline, Day 505 in Part 1 ]
  6. Change from Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF) to Day 505 [ Time Frame: Baseline, Day 505 in Part 1 ]
  7. Change from Baseline in FUS Concentration in Cerebrospinal Fluid (CSF) to Day 505 [ Time Frame: Baseline, Day 505 in Part 1 ]

Eligibility Criteria
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Ages Eligible for Study:   10 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for Part 1:

  1. Participants must be ≥10 years of age at the time of informed consent and have signs or symptoms consistent with an ALS disease (in the opinion of the Investigator).
  2. 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.
  3. Upright (sitting position) slow vital capacity (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.
  4. 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.
  5. 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 in consultation with the Sponsor Medical Monitor or designee.
  6. Females must not be pregnant or lactating. Males and females must be willing to following protocol-specified contraception requirements, or be surgically sterile, or be post-menopausal (females).
  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 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 rescued from, Part 1, or
  2. Enrolled and received at least 1 dose of ION363 in the Investigator-initiated study program
  3. Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator

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:

    1. Human immunodeficiency virus (HIV)
    2. Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment
    3. Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment
  4. Clinically significant 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. Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm Hg]).
  6. 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. Participants 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 judgement.
  7. Obstructive hydrocephalus
  8. Known significant brain or spinal disease that would interfere with the lumbar puncture (LP) process, CSF circulation or safety assessment, including tumors or abnormalities by magnetic resonance imaging (MRI) or computed tomography, subarachnoid hemorrhage, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis or curvature, Chiari malformation, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome.
  9. Concurrent participation in any other interventional clinical study.
  10. Previous or current treatment with an oligonucleotide (including small interfering RNA [siRNA], tofersen). This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed.
  11. Treatment with another investigational drug, biological agent, or device within 1 month before Screening, or 5 half-lives of investigational agent, whichever is longer.
  12. History of gene therapy or cell transplantation or any other experimental brain surgery.
  13. 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 aspirin (≤ 100 mg/day, administered as monotherapy) is permitted and may be continued through the LP procedure.
  14. Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the individual participating in or completing the study, in the opinion of the Investigator.
Contacts and Locations
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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): NCT04768972


Contacts
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Contact: Ionis Pharmaceuticals (844) 421-0104 ionisNCT04768972study@clinicaltrialmedia.com

Locations
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Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04768972    
Other Study ID Numbers: ION363-CS1
2020-005522-28 ( EudraCT Number )
First Posted: February 24, 2021    Key Record Dates
Last Update Posted: April 8, 2024
Last Verified: April 2024
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.:
Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations
Amyotrophic Lateral Sclerosis
Sarcoma Mutations
Additional relevant MeSH terms:
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Sarcoma
Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Pathologic Processes
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
 Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases