A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

NCT ID: NCT04856982

Last Updated: 2025-03-07

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 158 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-17
• Study Completion Date: 2027-08-07

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).

Conditions

Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Part A: Natural History Run-in

Participants enrolled in Part A will undergo blood draws approximately once every 28 days to assess neurofilament light chain (NfL) levels.

Group Type: NO_INTERVENTION

No interventions assigned to this group

Part B: Randomized, Double-Blind, Placebo-Controlled

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.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm

Part C: Open-Label Extension

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.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm

Placebo

Intervention Type: DRUG

Administered as specified in the treatment arm

Part D: Open-Label Treatment

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.

Group Type: EXPERIMENTAL

Tofersen

Intervention Type: DRUG

Administered as specified in the treatment arm

Interventions

Tofersen

Administered as specified in the treatment arm

Intervention Type: DRUG

Placebo

Administered as specified in the treatment arm

Intervention Type: DRUG

Other Intervention Names

BIIB067; QALSODY

Eligibility Criteria

Inclusion Criteria

• 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).

Exclusion Criteria

• 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.
• 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).
• 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.
• 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.
• 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.
• 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.
• 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.

• 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.
• Use of off-label treatments for ALS.
• 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.
• 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.
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Biogen

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Biogen

Locations

HonorHealth Neurology

Scottsdale, Arizona, United States

University of California San Diego Medical Center

La Jolla, California, United States

California Pacific Medical Center Research Institute

San Francisco, California, United States

Holy Cross Hospital Phil Smith Neuroscience Institute

Fort Lauderdale, Florida, 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

Johns Hopkins Hospital

Baltimore, Maryland, United States

Massachusetts General Hospital

Charlestown, Massachusetts, United States

Washington University School of Medicine

St 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

UZ Leuven

Leuven, Flemish Brabant, Belgium

Hospital Sao Paulo

São Paulo, São Paulo, Brazil

University of Calgary

Calgary, Alberta, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Genge Partners Inc.

Montreal, Quebec, Canada

Groupe Hospitalier Pitie-Salpetriere

Paris, Paris, France

Universitaetsklinikum Ulm

Ulm, Baden-Wurttemberg, Germany

Medizinische Hochschule Hannover

Hanover, Lower Saxony, Germany

Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino

Torino, , Italy

Kagoshima University Hospital

Kagoshima, Kagoshima-ken, Japan

University of Tokyo Hospital

Bunkyō City, Tokyo-To, Japan

NeuroProtect Sp. z o.o.

Warsaw, Masovian Voivodeship, Poland

Hanyang University Seoul Hospital

Seoul, , South Korea

Hospital Universitari i Politecnic La Fe

Valencia, , Spain

University Hospital of Umea

Umeå, Västerbotten County, Sweden

University of Sheffield

Sheffield, South Yorkshire, United Kingdom

Countries

United States; Australia; Belgium; Brazil; Canada; France; Germany; Italy; Japan; Poland; South Korea; Spain; Sweden; United Kingdom

References

Benatar M, Wuu J, Andersen PM, Bucelli RC, Andrews JA, Otto M, Farahany NA, Harrington EA, Chen W, Mitchell AA, Ferguson T, Chew S, Gedney L, Oakley S, Heo J, Chary S, Fanning L, Graham D, Sun P, Liu Y, Wong J, Fradette S. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4. Epub 2022 May 18.

Reference Type: DERIVED

PMID: 35585374 (View on PubMed)

Related Links

http://www.alsATLASstudy.com

Disclaimer: Residents in the United States may click here to find out more about participation in this trial.

Other Identifiers

2020-004590-51

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

233AS303

Identifier Type: -

Identifier Source: org_study_id