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A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB105 in Participants With Amyotrophic Lateral Sclerosis With or Without Poly-cytosine-adenine-guanine (CAG) Expansion in the Ataxin-2 Gene

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ClinicalTrials.gov Identifier: NCT04494256
Recruitment Status : Recruiting
First Posted : July 31, 2020
Last Update Posted : April 12, 2022
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:
The primary objective is to evaluate the safety and tolerability of BIIB105 in participants with amyotrophic lateral sclerosis (ALS) or poly-CAG expansion (polyQ)-ALS. The secondary objective is to assess the pharmacokinetic (PK) profile of BIIB105 in serum of participants with ALS or poly-CAG expansion (polyQ)-ALS.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: BIIB105 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB105 Administered Intrathecally to Adults With Amyotrophic Lateral Sclerosis With or Without Poly-CAG Expansion in the Ataxin-2 Gene
Actual Study Start Date : September 28, 2020
Estimated Primary Completion Date : July 15, 2026
Estimated Study Completion Date : July 15, 2026


Arm Intervention/treatment
Experimental: Part 1: Cohort A
Participants with ALS will receive BIIB105 Dose 1, intrathecally (IT), as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 1: Cohort B
Participants with ALS will receive BIIB105 Dose 2, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 1: Cohort C1
Participants with ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 1: Cohort D1
Participants with ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 1: Cohort C2
Participants with polyQ-ALS will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 1: Cohort D2
Participants with polyQ-ALS will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Placebo Comparator: Part 1: Cohorts A-D2: Placebo
Participants with ALS and polyQ-ALS for Cohorts A, B, C1 and C2 will receive matching placebo to BIIB105 as 3 loading doses on Day 1 and two later days, followed by two maintenance doses on two later days and for Cohorts D1 and D2 will receive matching placebo to BIIB105 as 3 loading doses on Day 1 and two later days, followed by five maintenance doses on five later days.
Drug: Placebo
Administered as specified in the treatment arm.

Experimental: Part 2: Cohorts A-C2: Open-Label (pending sponsor approval)
Participants that complete Cohorts A, B, C1, and C2 will receive BIIB105 Dose 3, IT, as 3 loading doses on Day 1 and two later days, followed by twenty-five maintenance doses on twenty-five later days.
Drug: BIIB105
Administered as specified in the treatment arm.

Experimental: Part 2: Cohorts D1, D2: Open-Label
Participants that complete Cohorts D1 and D2 in the blinded Loading Dose Period, who received placebo in Part 1 will receive BIIB105 Dose 4, IT, as 3 loading doses on Day 1, and two later days, while participants who received BIIB105 in Part 1 will receive 2 loading doses of BIIB105 Dose 4, IT, on Days 1 and one later day, and placebo on Day 15. After the blinded Loading Dose Period, participants will receive BIIB105 Dose 4 as twenty-five maintenance doses on twenty-five later days.
Drug: BIIB105
Administered as specified in the treatment arm.




Primary Outcome Measures :
  1. Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part 1: Up to Day 260; Part 2: Up to Day 820 ]
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event.


Secondary Outcome Measures :
  1. Serum Concentration of BIIB105 [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]
  2. Area Under the Concentration-Time Curve from Time Zero to Infinity (AUCinf) [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]
  3. Area Under the Concentration-Time Curve From Time Zero to Time of the Last Measurable Concentration (AUClast) [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]
  4. Maximum Observed Concentration (Cmax) [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]
  5. Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]
  6. Elimination Half-Life (t1/2) [ Time Frame: Part 1-Cohorts A, B, C1, C2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 92, Cohorts D1, D2- Predose and at multiple time points up to 6 hours postdose from Day 1 to Day 176; Part 2- Prior dosing on Day 1 up to Day 673 ]


Information from the National Library of Medicine

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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 Inclusion Criteria:

Part 1:

  • Ability of the participant to understand the purpose and risks of the study and indicate informed consent, and the ability of the participant or the participant's legally authorized representative, to provide signed and dated informed consent and authorization to use protected health information in accordance with national and local privacy regulations.
  • All women of childbearing potential and all men must ensure that highly effective contraception is used during the study and for at least 6 months for female participants and 8 months for male participants after their last dose of study treatment.
  • No known presence or family history of mutations in the superoxide dismutase 1 (SOD1) or fused in sarcoma (FUS) genes.
  • Participants in Cohorts A, B, C1 and D1, must meet the laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria (revised according to the Airlie House Conference 1998 [Brooks 2000]). Participants in Cohort C2 and D2, must meet any of the prior conditions, but may also only meet clinically possible criteria for diagnosing ALS, or exhibit weakness attributable to ALS in the presence of ataxin-2 protein (ATXN2) intermediate repeats.
  • In participants in Cohorts C2 and D2, confirmed intermediate cytosine-adenine-guanine/cytosine-adenine-adenine (CAG/CAA) repeat expansion in the ataxin-2 gene or RNA (ATXN2) gene as defined by at least 1 allele carrying 30 to 33 CAG/CAA repeats.
  • Slow vital capacity (SVC) criteria:
  • In participants in Cohorts A, B, C1, and D1, SVC ≥60% of predicted value as adjusted for sex, age, and height (from the sitting position).
  • In participants in Cohort C2 and D2, SVC ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position).
  • If taking riluzole, participant must be on a stable dose for≥30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study.
  • Participants taking concomitant edaravone at study entry must be on a stable dose for ≥60 days prior to the first dose of study treatment (Day 1).
  • Screening values of coagulation parameters including platelet count, international normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) should be within normal ranges.
  • Has an informant/caregiver who, in the Investigator's judgment, has frequent and sufficient contact with the participant as to be able to provide accurate information about the participant's cognitive and functional abilities at screening.

Part 2:

  • Ability of the participant to review the initial informed consent completed in Part 1, understand the purpose and risks of the study, and indicate continued consent.
  • Participants must have completed Study 275AS101 Part 1 through Week 25 (Day 175 Visit for Cohorts A, B, C1, C2; Day 176 Visit for Cohorts D1, D2).
  • Participants from Cohorts A, B, C1, and C2 must have a washout of ≥16 weeks between the last dose of study treatment received in Study 275AS101 Part 1 and the first dose of BIIB105 received in Study 275AS101 Part 2. Participants from Cohorts D1 and D2 do not require a washout period.
  • If taking riluzole, participant must be on a stable dose for ≥ 30 days prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that it should be discontinued for medical reasons, in which case it may not be restarted during the study.
  • Participants taking concomitant edaravone at study entry must be on a stable dose for ≥ 60 days prior to the first dose of study treatment (Day 1).
  • Screening values of coagulation parameters including platelet count, INR, PT, and aPTT should be within normal ranges.

Key Exclusion Criteria

Part 1:

  • History or positive test result at Screening for human immunodeficiency virus (HIV).
  • Current hepatitis C infection.
  • Current hepatitis B infection.
  • History of alcohol or substance abuse ≤6 months of Screening that would limit participation in the study, as determined by the Investigator.
  • Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
  • Presence of tracheostomy.
  • In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator.
  • In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as hemoglobin A1c (HbA1c) ≥8% during Screening.
  • Prescreening Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) slope > -0.4 points/month, where prescreening ALSFRS-R slope is defined as: (ALSFRS-R score at Screening - 48) / (months from date of symptom onset to date of Screening) in participants from Cohorts A, B, C1, and D1.
  • Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening.
  • Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for lumbar puncture (LP) according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
  • Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.

Part 2:

  • History or positive test result at Screening for HIV.
  • Current hepatitis C infection.
  • Current hepatitis B infection.
  • History of alcohol or substance abuse ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator.
  • Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
  • In participants from Cohorts A, B, C1, and D1, history of myocardial infarction, as determined by the Investigator.
  • In participants from Cohorts A, B, C1, and D1, poorly controlled type 1 or 2 diabetes mellitus defined as HbA1c ≥ 8% during Screening.
  • Treatment with another investigational drug (including investigational drugs for ALS through compassionate use programs; excluding BIIB105) or biological agent within 1 month or 5 half-lives of study agent, whichever is longer, before Screening.
  • Treatment with an antiplatelet or anticoagulant therapy that cannot safely be interrupted for LP according to local standard of care and/or institutional guidelines, in the opinion of the Investigator or Prescriber.
  • Female participants who are pregnant or currently breastfeeding and those intending to become pregnant during the study.

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


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): NCT04494256


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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United States, California
Research Site Recruiting
La Jolla, California, United States, 92093
Research Site Recruiting
Stanford, California, United States, 94305
United States, Florida
Research Site Not yet recruiting
Jacksonville, Florida, United States, 32224
United States, Georgia
Research Site Recruiting
Atlanta, Georgia, United States, 30322
United States, Maryland
Research Site Recruiting
Baltimore, Maryland, United States, 21218
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States, 02114
United States, Missouri
Research Site Recruiting
Saint Louis, Missouri, United States, 63110
United States, Pennsylvania
Research Site Recruiting
Philadelphia, Pennsylvania, United States, 19104
United States, Utah
Research Site Recruiting
Salt Lake City, Utah, United States, 84132
Canada, Quebec
Research Site Recruiting
Montreal, Quebec, Canada, H3A 2B4
Italy
Research Site Not yet recruiting
Torino, Italy
Contact: Adriano Chio         
Principal Investigator: Adriano Chio         
Netherlands
Research Site Recruiting
Utrecht, Netherlands, 3584 CX
Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen
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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT04494256    
Other Study ID Numbers: 275AS101
2020-000207-36 ( EudraCT Number )
First Posted: July 31, 2020    Key Record Dates
Last Update Posted: April 12, 2022
Last Verified: April 2022
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 http://clinicalresearch.biogen.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
Sclerosis
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases