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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
ION363
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations, Amyotrophic Lateral Sclerosis, Sarcoma Mutations

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria for Part 1:

  1. Participants in:

    Cohort A must be 12 - 65 years of age with signs or symptoms consistent with an ALS disease. If 30 to 65 years of age, 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> 30 years of age, with signs or symptoms consistent with an ALS disease process 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 years, inclusive, or > 65 years of age with no ALSFRS-R pre-study slope criterion

  2. 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.
  3. Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percent (%) of predicted value
  4. Participants taking edaravone must be on a stable dose for ≥ 28 days prior to Screening and riluzole 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 accompanied medications and nutritional support for at least 1 month prior to Study Day 1. Accompanied 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. 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, or
  2. Enrolled and received at least 1 dose of ION363 in the Investigator-initiated EAP 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 ALS-associated mutations except FUS
  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 (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
  5. Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm Hg])
  6. 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. Participants 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.
  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 (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
  9. Concurrent participation in any other interventional clinical study
  10. Previous treatment with an oligonucleotide (including small interfering RNA [siRNA]). This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed
  11. 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
  12. History of gene therapy or cell transplantation or any other experimental brain surgery
  13. 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

Sites / Locations

  • University of California San DiegoRecruiting
  • Stanford University Medical CenterRecruiting
  • Johns Hopkins UniversityRecruiting
  • Massachusetts General HospitalRecruiting
  • Washington University School of MedicineRecruiting
  • Columbia University Medical CenterRecruiting
  • The Ohio State University Wexner Medical CenterRecruiting
  • University of UtahRecruiting
  • UZ LeuvenRecruiting
  • Montreal Neurological InstituteRecruiting
  • Citta della Salute e della Scienza di Torino - Ospedale le MolinetteRecruiting
  • Hanyang University Seoul HospitalRecruiting
  • Universitair Medisch Centrum UtrechtRecruiting
  • King's College HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ION363

Placebo

Arm Description

ION363 will be administered by lumbar intrathecal (IT) bolus injection with 1 dose every 4-12 weeks, after a loading dose at 4 weeks, over a 61-week double-blind treatment period in Part 1 and every 12 weeks for 85 weeks in the open-label extension treatment period, aside from a loading dose administered 4 weeks after the first dose in Part 2.

Placebo will be administered by lumbar IT bolus injection with 1 dose every 4-12 weeks over a 61-week double-blind treatment period.

Outcomes

Primary Outcome Measures

Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment
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. 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

Change From Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 505 in Part 1
The ALSSQOL-R is a disease-specific 50-item assessment that measures the quality of life (QoL). 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.
Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory. 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
Survival
Change From Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1
Change From Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1
Change From Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF) to Day 505

Full Information

First Posted
February 22, 2021
Last Updated
September 14, 2023
Sponsor
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT04768972
Brief Title
A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)
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)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 14, 2021 (Actual)
Primary Completion Date
June 2026 (Anticipated)
Study Completion Date
March 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary purpose of this study is to evaluate the clinical efficacy of ION363 on clinical function and survival in carriers of fused in sarcoma mutations with amyotrophic lateral sclerosis (FUS-ALS).
Detailed Description
This is a multi-center, three-part study of ION363 in up to 77 participants. Part 1 will consist of participants that 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 ION363 for a period of 80 weeks.Participants who have completed Part 2 are eligible to participate in Part 3 and continue to receive ION363 for an additional 156 weeks. Treatment extension period was added to allow patients who complete Part 2 to continue to receive ION363 until the drug may become commercially available.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations, Amyotrophic Lateral Sclerosis, Sarcoma Mutations

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
77 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
ION363
Arm Type
Experimental
Arm Description
ION363 will be administered by lumbar intrathecal (IT) bolus injection with 1 dose every 4-12 weeks, after a loading dose at 4 weeks, over a 61-week double-blind treatment period in Part 1 and every 12 weeks for 85 weeks in the open-label extension treatment period, aside from a loading dose administered 4 weeks after the first dose in Part 2.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo will be administered by lumbar IT bolus injection with 1 dose every 4-12 weeks over a 61-week double-blind treatment period.
Intervention Type
Drug
Intervention Name(s)
ION363
Intervention Description
ION363 will be administered by IT bolus injection.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo will be administered by IT bolus injection.
Primary Outcome Measure Information:
Title
Change from Baseline (Day 1) through Study Day 505 in Part 1 in functional impairment
Description
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. 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.
Time Frame
Baseline, Day 505 in Part 1
Secondary Outcome Measure Information:
Title
Change From Baseline in Amyotrophic Lateral Sclerosis Specific Quality of Life - Revised (ALSSQOL-R) Score to Day 505 in Part 1
Description
The ALSSQOL-R is a disease-specific 50-item assessment that measures the quality of life (QoL). 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.
Time Frame
Baseline, Day 505 in Part 1
Title
Change from Baseline in in-clinic Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
Description
ALSFRS-R measures functional disease severity. The scale measures four functional domains, bulbar function, gross motor skills, fine motor skills, and respiratory. 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
Time Frame
Baseline, Day 505 in Part 1
Title
Survival
Time Frame
Up to Day 505 in Part 1
Title
Change From Baseline in In-clinic Slow Vital Capacity (SVC) to Day 505 in Part 1
Time Frame
Baseline, Day 505 in Part 1
Title
Change From Baseline in Handheld Dynamometry (HHD) to Day 505 in Part 1
Time Frame
Baseline, Day 505 in Part 1
Title
Change From Baseline in Neurofilament Light (NfL) Concentration in Cerebrospinal Fluid (CSF) to Day 505
Time Frame
Baseline, Day 505 in Part 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria for Part 1: Participants in: Cohort A must be 12 - 65 years of age with signs or symptoms consistent with an ALS disease. If 30 to 65 years of age, 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> 30 years of age, with signs or symptoms consistent with an ALS disease process 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 years, inclusive, or > 65 years of age with no ALSFRS-R pre-study slope criterion 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. Upright (sitting position) slow vital capacity (SVC) as adjusted for sex, age, and height ≥ 50 percent (%) of predicted value Participants taking edaravone must be on a stable dose for ≥ 28 days prior to Screening and riluzole 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 Stable accompanied medications and nutritional support for at least 1 month prior to Study Day 1. Accompanied 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. 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: Completed, or rescued from, Part 1, or Enrolled and received at least 1 dose of ION363 in the Investigator-initiated EAP program Patient meeting Criteria #1-2 is otherwise suitable for study participation, in the opinion of the Investigator Exclusion Criteria for Part 1: Requiring permanent ventilation (> 22 hours of mechanical ventilation [invasive or noninvasive] per day for > 21 consecutive days) and/or tracheostomy Any known ALS-associated mutations except FUS Positive test result for: Human immunodeficiency virus (HIV) Hepatitis C (HCV), unless previously treated and has been serum/plasma HCV RNA negative for at least 6 months after the end of treatment Hepatitis B (HBV) by HBV surface antigen test, unless currently on nucleotide/nucleoside analogue treatment 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 Uncontrolled hypertension (blood pressure [BP] > 160/100 millimeters of mercury [mm Hg]) 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. Participants 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. Obstructive hydrocephalus 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 (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 Concurrent participation in any other interventional clinical study Previous treatment with an oligonucleotide (including small interfering RNA [siRNA]). This exclusion criterion does not apply to COVID-19 vaccinations, which are allowed 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 History of gene therapy or cell transplantation or any other experimental brain surgery 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ionis Pharmaceuticals
Phone
(844) 421-0104
Email
ionisNCT04768972study@clinicaltrialmedia.com
Facility Information:
Facility Name
University of California San Diego
City
La Jolla
State/Province
California
ZIP/Postal Code
92037
Country
United States
Individual Site Status
Recruiting
Facility Name
Stanford University Medical Center
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Individual Site Status
Recruiting
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21205
Country
United States
Individual Site Status
Recruiting
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Individual Site Status
Recruiting
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Individual Site Status
Recruiting
Facility Name
The Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Individual Site Status
Recruiting
Facility Name
UZ Leuven
City
Leuven
State/Province
VL-Brabant
ZIP/Postal Code
3000
Country
Belgium
Individual Site Status
Recruiting
Facility Name
Montreal Neurological Institute
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 2B4
Country
Canada
Individual Site Status
Recruiting
Facility Name
Citta della Salute e della Scienza di Torino - Ospedale le Molinette
City
Torino
ZIP/Postal Code
10126
Country
Italy
Individual Site Status
Recruiting
Facility Name
Hanyang University Seoul Hospital
City
Seoul
ZIP/Postal Code
4763
Country
Korea, Republic of
Individual Site Status
Recruiting
Facility Name
Universitair Medisch Centrum Utrecht
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Individual Site Status
Recruiting
Facility Name
King's College Hospital
City
London
ZIP/Postal Code
SE5 9RT
Country
United Kingdom
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
35246398
Citation
Codron P, Cassereau J, Vourc'h P. InFUSing antisense oligonucleotides for treating ALS. Trends Mol Med. 2022 Apr;28(4):253-254. doi: 10.1016/j.molmed.2022.02.006. Epub 2022 Mar 1.
Results Reference
derived

Learn more about this trial

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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