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

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ClinicalTrials.gov Identifier: NCT04856982
Recruitment Status : Recruiting
First Posted : April 23, 2021
Last Update Posted : February 16, 2024
Sponsor:
Information provided by (Responsible Party):
Biogen

Study Description
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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).

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation Drug: Tofersen Drug: Placebo Phase 3

Expanded Access : An investigational treatment associated with this study has been approved for sale to the public.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3 Randomized, Placebo-Controlled Trial With a Longitudinal Natural History Run-In and Open-Label Extension to Evaluate BIIB067 Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
Actual Study Start Date : May 17, 2021
Estimated Primary Completion Date : August 7, 2027
Estimated Study Completion Date : August 7, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
No Intervention: 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.
Experimental: 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.
 Drug: Tofersen
Administered as specified in the treatment arm
Other Names:
  • BIIB067
  • QALSODY

Drug: Placebo
Administered as specified in the treatment arm
Experimental: 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.
 Drug: Tofersen
Administered as specified in the treatment arm
Other Names:
  • BIIB067
  • QALSODY

Drug: Placebo
Administered as specified in the treatment arm
Experimental: 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.
 Drug: Tofersen
Administered as specified in the treatment arm
Other Names:
  • BIIB067
  • QALSODY


Outcome Measures
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Primary Outcome Measures :
  1. Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 24 Months of Part B Baseline [ Time Frame: Up to 24 months ]

Secondary Outcome Measures :
  1. Parts B and C: Time to Emergence of Clinically Manifest ALS [ Time Frame: Up to 5.6 years ]
  2. Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score [ Time Frame: 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.

  3. Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) [ Time Frame: Up to 5.6 years ]
  4. Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis [ Time Frame: 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.

  5. Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis [ Time Frame: Up to 5.6 years ]
  6. Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period [ Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years ]
  7. Parts B, C and D: Change from Baseline in Plasma NfL Concentrations [ Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years ]
  8. Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations [ Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Part A 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).

Key Part A 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.

NOTE: Other protocol defined Inclusion/Exclusion criteria will apply.

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): NCT04856982


Contacts
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Contact: US Biogen Clinical Trial Center 866-633-4636 clinicaltrials@biogen.com
Contact: Global Biogen Clinical Trial Center clinicaltrials@biogen.com

Locations
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Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT04856982    
Other Study ID Numbers: 233AS303
2020-004590-51 ( EudraCT Number )
First Posted: April 23, 2021    Key Record Dates
Last Update Posted: February 16, 2024
Last Verified: February 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on https://www.biogentrialtransparency.com/
URL: https://vivli.org/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
 Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases