A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
- Conditions
- Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation
- Interventions
- Drug: Placebo
- Registration Number
- NCT04856982
- Lead Sponsor
- Biogen
- Brief Summary
The primary objective of this study is to evaluate the efficacy of tofersen in presymptomatic adult carriers of a superoxide dismutase 1 (SOD1) mutation with elevated neurofilament (NF). The secondary objectives of this study are to evaluate the safety and tolerability tofersen and to evaluate the effect of tofersen on pharmacodynamics (PD)/treatment response biomarkers when initiated prior to versus at the time of emergence of clinically manifest amyotrophic lateral sclerosis (ALS).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 158
- Participants should have a protocol-defined rapidly progressive SOD1 mutation, confirmed by a central reader, or a SOD1 mutation that is approved for inclusion by an external mutation adjudication committee.
- Participants with plasma NfL level less than the protocol-defined threshold.
- Participants who are clinically presymptomatic for ALS (i.e., must not have clinically manifest ALS).
Key Part A
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History or positive test result at screening for human immunodeficiency virus (HIV). The requirement for testing at Screening may be omitted if it is not permitted by local regulations.
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Current hepatitis C infection (defined as positive Hepatitis C Virus (HCV) antibody and detectable HCV RNA). Participants with positive HCV antibody and undetectable HCV Ribonucleic Acid (RNA) are eligible to participate in the study (United States Centers for Disease Control and Prevention).
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Current hepatitis B infection (defined as positive for hepatitis B surface antigen (HBsAg) and/or anti-Hepatitis B Core antibody (HBc)). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-hepatitis B surface antibody (HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti- HBs) are eligible to participate in the study.
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History of systemic hypersensitivity reaction to tofersen, the excipients contained in the formulation, and if appropriate, any diagnostic agents to be administered during the study.
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History of confounding neuromuscular or neurological disorder that is expected to have a progressive (i.e., worsening) course during the study, and/or is expected to be associated with elevations in NF, in the opinion of the Investigator.
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Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that if not managed optimally could place a participant at an increased risk for intraoperative or postoperative bleeding.
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Significant cognitive impairment, clinical dementia, or unstable psychiatric illness, including psychosis, suicidal ideation, suicide attempt, or untreated major depression
≤ 90 days of screening, which in the opinion of the Investigator would interfere with the study procedures.
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Treatment with riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol (also known as ursodoxicoltaurine). If the participant has been on riluzole, edaravone, and/or sodium phenylbutyrate/taurursodiol, the medication(s) must be discontinued for at least 5 half-lives prior to Screening.
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Use of off-label treatments for ALS.
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Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs), biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering RNA, stem cell therapy, or gene therapy is allowed.
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Anticipated need, in the opinion of the Investigator, for administration of any antiplatelet or anticoagulant medication (e.g., clopidogrel) that cannot be safely continued or held for an LP procedure, if necessary, according to local or institutional guidelines and/or Investigator determination.
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Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment, biological agent, device, or approved therapy for investigational use. Participation in a noninterventional study focused on ALS natural history may be allowed at the discretion of the Investigator.
NOTE: Other protocol defined Inclusion/Exclusion criteria will apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Part B: Randomized, Double-Blind, Placebo-Controlled Tofersen Participants from Part A who meet the protocol-defined NfL threshold and remain presymptomatic may be eligible to participate in Part B. During Part B, participants will receive tofersen 100 milligram (mg) or placebo via intrathecal (IT) injection on Days 1, 15, 29, and every 28 days thereafter for up to approximately 5.6 years. Part C: Open-Label Extension Placebo Participants from Part B who develop clinically manifest ALS may be eligible to participate in Part C. During Part C, participants who received placebo in Part B will receive tofersen 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter up to the final maintenance dost visit. Participants who received tofersen during Part B will receive tofersen 100 mg on Days 1, 29, and every 28 days thereafter up to the final maintenance dost visit, with a dose of placebo on Day 15 to maintain the study blind. The combined duration of Part B and Part C is up to approximately 5.6 years. Part D: Open-Label Treatment Tofersen Participants from Part A who develop clinically manifest ALS prior to randomization in Part B may be eligible to participate in Part D. During Part D, participants will receive tofersen100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years. Part B: Randomized, Double-Blind, Placebo-Controlled Placebo Participants from Part A who meet the protocol-defined NfL threshold and remain presymptomatic may be eligible to participate in Part B. During Part B, participants will receive tofersen 100 milligram (mg) or placebo via intrathecal (IT) injection on Days 1, 15, 29, and every 28 days thereafter for up to approximately 5.6 years. Part C: Open-Label Extension Tofersen Participants from Part B who develop clinically manifest ALS may be eligible to participate in Part C. During Part C, participants who received placebo in Part B will receive tofersen 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter up to the final maintenance dost visit. Participants who received tofersen during Part B will receive tofersen 100 mg on Days 1, 29, and every 28 days thereafter up to the final maintenance dost visit, with a dose of placebo on Day 15 to maintain the study blind. The combined duration of Part B and Part C is up to approximately 5.6 years.
- Primary Outcome Measures
Name Time Method Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 24 Months of Part B Baseline Up to 24 months
- Secondary Outcome Measures
Name Time Method Parts B and C: Time to Emergence of Clinically Manifest ALS Up to 5.6 years Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score Up to 5.6 years The ALSFRS-R measures 4 functional domains: respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 to 4, for a total possible score of 48, with higher scores representing better function.
Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations Parts B and C: Up to 5.6 years and Part D: Up to 2 years Parts B, C and D: Change from Baseline in Plasma NfL Concentrations Parts B and C: Up to 5.6 years and Part D: Up to 2 years Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) Up to 5.6 years Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis Up to 5.6 years Permanent ventilation is defined as ≥22 hours of invasive or non-invasive mechanical ventilation per day for ≥21 consecutive days.
Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis Up to 5.6 years Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period Parts B and C: Up to 5.6 years and Part D: Up to 2 years
Trial Locations
- Locations (29)
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
California Pacific Medical Center Research Institute
🇺🇸San Francisco, California, United States
University of Miami School of Medicine
🇺🇸Miami, Florida, United States
The Emory Clinic
🇺🇸Atlanta, Georgia, United States
Northwestern Medicine
🇺🇸Chicago, Illinois, United States
Groupe Hospitalier Pitie-Salpetriere
🇫🇷Paris cedex 13, Paris, France
Medizinische Hochschule Hannover
🇩🇪Hannover, Niedersachsen, Germany
Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
🇮🇹Torino, Italy
NeuroProtect Sp. z o.o.
🇵🇱Warszawa, Mazowieckie, Poland
University of Sheffield
🇬🇧Sheffield, South Yorkshire, United Kingdom
HonorHealth Neurology
🇺🇸Scottsdale, Arizona, United States
Holy Cross Hospital Phil Smith Neuroscience Institute
🇺🇸Fort Lauderdale, Florida, United States
Johns Hopkins Hospital
🇺🇸Baltimore, Maryland, United States
Massachusetts General Hospital
🇺🇸Charlestown, Massachusetts, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Austin Neuromuscular Center
🇺🇸Austin, Texas, United States
Macquarie University
🇦🇺Sydney, New South Wales, Australia
Sunnybrook Health Sciences Centre
🇨🇦Toronto, Ontario, Canada
Hanyang University Seoul Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
UZ Leuven
🇧🇪Leuven, Flemish Brabant, Belgium
Hospital Sao Paulo
🇧🇷São Paulo, Sao Paulo, Brazil
University of Calgary
🇨🇦Calgary, Alberta, Canada
Genge Partners Inc.
🇨🇦Montréal, Quebec, Canada
Kagoshima University Hospital
🇯🇵Kagoshima-shi, Kagoshima-Ken, Japan
University of Tokyo Hospital
🇯🇵Bunkyo-ku, Tokyo-To, Japan
Universitaetsklinikum Ulm
🇩🇪Ulm, Baden Wuerttemberg, Germany
University Hospital of Umea
🇸🇪Umeå, Västerbotten County, Sweden