Clinical trial NCT04856982: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis Associated With a SOD1 Gene Mutation
Lead sponsor: Biogen
Sponsor class: INDUSTRY
First posted: 2021-04-23
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Parts B and C: Percentage of Participants with Emergence of Clinically Manifest ALS Within 24 Months of Part B Baseline
timeFrame: Up to 24 months
Secondary outcomes:
measure: Parts B and C: Time to Emergence of Clinically Manifest ALS
timeFrame: Up to 5.6 years
measure: Parts B and C: Change in ALS Functional Rating Scale (ALSFRS-R) Total Score
timeFrame: Up to 5.6 years
measure: Parts B and C: Change from Baseline in Percent Predicted Slow Vital Capacity (SVC)
timeFrame: Up to 5.6 years
measure: Parts B and C: Percentage of Participants with Outcome as Death or Permanent Ventilation Based on Time to Death or Permanent Ventilation Analysis
timeFrame: Up to 5.6 years
measure: Parts B and C: Percentage of Participants with Outcome as Deaths Based on Time to Death Analysis
timeFrame: Up to 5.6 years
measure: Parts B, C and D: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the Treatment Period
timeFrame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years
measure: Parts B, C and D: Change from Baseline in Plasma NfL Concentrations
timeFrame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years
measure: Parts B, C and D: Change in Total Cerebrospinal Fluid (CSF) SOD1 Concentrations
timeFrame: Parts B and C: Up to 5.6 years and Part D: Up to 2 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Neurology
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center Research Institute
state: California
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital Phil Smith Neuroscience Institute
state: Florida
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Atlanta
country: United States
facility: The Emory Clinic
state: Georgia
city: Chicago
country: United States
facility: Northwestern Medicine
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Charlestown
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Austin
country: United States
facility: Austin Neuromuscular Center
state: Texas
city: Sydney
country: Australia
facility: Macquarie University
state: New South Wales
city: Leuven
country: Belgium
facility: UZ Leuven
state: Flemish Brabant
city: São Paulo
country: Brazil
facility: Hospital Sao Paulo
state: Sao Paulo
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montréal
country: Canada
facility: Genge Partners Inc.
state: Quebec
city: Paris cedex 13
country: France
facility: Groupe Hospitalier Pitie-Salpetriere
state: Paris
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
state: Baden Wuerttemberg
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Torino
country: Italy
facility: Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino
city: Kagoshima-shi
country: Japan
facility: Kagoshima University Hospital
state: Kagoshima-Ken
city: Bunkyo-ku
country: Japan
facility: University of Tokyo Hospital
state: Tokyo-To
city: Seoul
country: Korea, Republic of
facility: Hanyang University Seoul Hospital
city: Warszawa
country: Poland
facility: NeuroProtect Sp. z o.o.
state: Mazowieckie
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Umeå
country: Sweden
facility: University Hospital of Umea
state: Västerbotten County
city: Sheffield
country: United Kingdom
facility: University of Sheffield
state: South Yorkshire
Study officials:
affiliation: Biogen
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.