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

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

Tracking Information

• First Submitted Date: April 20, 2021
• First Posted Date: April 23, 2021
• Last Update Posted Date: February 16, 2024
• Actual Study Start Date: May 17, 2021
• Estimated Primary Completion Date: August 7, 2027 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 15, 2024): 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 ]
• Original Primary Outcome Measures (submitted: April 20, 2021): Parts B and C: Percentage of Participants with Emergence of Clinically Manifested ALS Within 1 Year of Part B Baseline [ Time Frame: Up to 1 year ]

Current Secondary Outcome Measures (submitted: February 15, 2024)

• Parts B and C: Time to Emergence of Clinically Manifest ALS [ Time Frame: Up to 5.6 years ]
• 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.
• Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) [ Time Frame: 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 [ 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.
• Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years ]
• 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 ]

Original Secondary Outcome Measures (submitted: April 20, 2021)

• Parts B and C: Percentage of Participants with Emergence of Clinically Manifested ALS Within 2 Years of Part B Baseline [ Time Frame: Up to 2 years ]
• Parts B and C: Time to Emergence of Clinically Manifested ALS [ Time Frame: Up to 2 years ]
• Parts B and C: Change in Revised ALS Functional Rating Scale (ALSFRS-R) Total Score [ Time Frame: Up to 2 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 and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) [ Time Frame: Up to 2 years ]
• Parts B and C: Percentage of Participants with Ventilation Assistance-free Survival (VAFS) [ Time Frame: Up to 2 years ]
  VAFS is defined as time to the earliest occurrence of 1 of the following events: Death or permanent ventilation. Permanent ventilation is defined as ≥ 22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥ 21 consecutive days.
• Parts B and C: Percentage of Participants with Overall Survival [ Time Frame: Up to 2 years ]
• Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period [ Time Frame: Up to 2 years ]
• Parts B, C and D: Change from Baseline in Plasma NfL Concentrations [ Time Frame: Up to 2 years ]
• Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations [ Time Frame: Up to 2 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of BIIB067 (Tofersen) Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation

Intervention

• Drug: Tofersen
  Administered as specified in the treatment arm
  Other Names:

  • BIIB067
  • QALSODY
• Drug: Placebo
  Administered as specified in the treatment arm

Study Arms

• 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.
  Interventions:

  • Drug: Tofersen
  • Drug: Placebo
• 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.
  Interventions:

  • Drug: Tofersen
  • Drug: Placebo
• 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.
  Intervention: Drug: Tofersen

• Publications *: 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. Erratum In: Neurotherapeutics. 2022 Sep 29;:

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 20, 2021): 150
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 7, 2027
• Estimated Primary Completion Date: August 7, 2027 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

Contact: Global Biogen Clinical Trial Center; clinicaltrials@biogen.com

• Listed Location Countries: Australia, Belgium, Brazil, Canada, France, Germany, Italy, Japan, Korea, Republic of, Poland, Spain, Sweden, United Kingdom, United States
• Removed Location Countries: Russian Federation

Administrative Information

• NCT Number: NCT04856982
• Other Study ID Numbers: 233AS303; 2020-004590-51 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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/

• Current Responsible Party: Biogen
• Original Responsible Party: Same as current
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: February 2024