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ATLAS: A Study of BIIB067 When Initiated in Clinically Presymptomatic Adults With a Confirmed Superoxide Dismutase 1 Mutation

Sponsor
Biogen (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04856982
Collaborator
(none)
150
Enrollment
29
Locations
4
Arms
74.7
Anticipated Duration (Months)
5.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy of BIIB067 when initiated 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 of BIIB067 and to evaluate the effect of BIIB067 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
  • Drug: BIIB067 (Tofersen)
  • Drug: Placebo
 Phase 3

Study Design

Study Type:
Interventional
Anticipated 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
Anticipated Primary Completion Date :
Aug 7, 2026
Anticipated Study Completion Date :
Aug 7, 2027

Arms and Interventions

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 BIIB067 100 milligram (mg) or placebo via intrathecal (IT) injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years.

Drug: BIIB067 (Tofersen)
Administered as specified in the treatment arm
Other Names:
  • Tofersen

    • 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 BIIB067 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years. Participants who received BIIB067 during Part B will receive BIIB067 100 mg on Days 1, 29, and every 28 days thereafter for up to 2 years, with a dose of placebo on Day 15 to maintain the study blind.

    Drug: BIIB067 (Tofersen)
    Administered as specified in the treatment arm
    Other Names:
  • Tofersen

    • 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 BIIB067 100 mg via IT injection on Days 1, 15, 29, and every 28 days thereafter for up to 2 years.

    Drug: BIIB067 (Tofersen)
    Administered as specified in the treatment arm
    Other Names:
  • Tofersen

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 12 Months of Part B Baseline [Up to 12 months]

    Secondary Outcome Measures

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

    2. Parts B and C: Time to Emergence of Clinically Manifest ALS [Up to 2 years]

    3. Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score [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.

    4. Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC) [Up to 2 years]

    5. 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 2 years]

      Permanent ventilation is defined as ≥22 hours of invasive or non-invasive mechanical ventilation per day for ≥21 consecutive days.

    6. Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis [Up to 2 years]

    7. Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period [Up to 2 years]

    8. Parts B, C and D: Change from Baseline in Plasma NfL Concentrations [Up to 2 years]

    9. Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations [Up to 2 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 and/or edaravone. If the participant has been on riluzole and/or edaravone, 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

    Locations

    Site City State Country Postal Code
    1 Research Site Scottsdale Arizona United States 85251
    2 UC San Diego La Jolla California United States 92037
    3 California Pacific Medical Center San Francisco California United States 94109
    4 Holy Cross Hospital Phil Smith Neuroscience Institute Fort Lauderdale Florida United States 33308
    5 University of Miami Miami Florida United States 33136
    6 Emory University Atlanta Georgia United States 30322
    7 Northwestern University Chicago Illinois United States 60611
    8 Johns Hopkins Hospital Baltimore Maryland United States 21287
    9 Massachusetts General Hospital Boston Massachusetts United States 02114
    10 Washington University School of Medicine Saint Louis Missouri United States 63110
    11 Columbia University Medical Center New York New York United States 10032
    12 Austin Neuromuscular Center Austin Texas United States 78756
    13 Macquarie University Sydney New South Wales Australia 2109
    14 UZ Leuven Leuven Belgium 3000
    15 Research Site São Paulo Brazil 04037-002
    16 University of Calgary Calgary Alberta Canada T2N 4Z6
    17 Research Site Toronto Ontario Canada M4N 3M5
    18 Genge Partners Inc. Montréal Quebec Canada H3A 2B4
    19 Hôpital Pitié-Salpêtrière Paris France 75013
    20 Hannover Medical School Hannover Germany 30625
    21 Research Site Ulm Germany 89081
    22 Cresla "Rita Levi Montalcini" Department of Neuroscience Torino Italy 10126
    23 Kagoshima University Hospital Kagoshima-shi Kagoshima-Ken Japan 890-8520
    24 University of Tokyo Hospital Bunkyo-ku Tokyo-To Japan 113-8655
    25 Hanyang University Seoul Hospital Seoul Korea, Republic of 4763
    26 Centrum Medyczne Neuro Protect Warszawa Poland 01-684
    27 Research Site Valencia Spain 46026
    28 University Hospital of Umea Umeå Sweden 90185
    29 Sheffield Sheffield Staffordshire United Kingdom S10 2HQ

    Sponsors and Collaborators

    • Biogen

    Investigators

    • Study Director: Medical Director, Biogen

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Biogen
    ClinicalTrials.gov Identifier:
    NCT04856982
    Other Study ID Numbers:
    • 233AS303
    • 2020-004590-51
    First Posted:
    Apr 23, 2021
    Last Update Posted:
    Aug 22, 2022
    Last Verified:
    Aug 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Motor Neuron Disease
    Amyotrophic Lateral Sclerosis

    Study Results

    No Results Posted as of Aug 22, 2022