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A Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 in Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03626012
Recruitment Status : Active, not recruiting
First Posted : August 10, 2018
Last Update Posted : May 5, 2020
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:
The primary objective of this study is to evaluate the safety and tolerability of BIIB078 in adults with C9ORF72-Amyotrophic Lateral Sclerosis (ALS). The secondary objectives of this study are to evaluate the pharmacokinetic profile of BIIB078 and to evaluate the effects of BIIB078 on clinical function. As the first-in-human study, the study enrolls a small number of participants in each cohort. Every participant in a cohort is treated with the same dose or placebo. The study is designed to evaluate and confirm the safety of each dose before enrolling and exposing new participants to a higher dose in the next cohort. Therefore, proceeding from cohort to cohort, the recruitment status of "Active, not recruiting" may change. Please contact clinicaltrials@biogen.com for further information.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: BIIB078 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 1 Multiple-Ascending-Dose Study to Assess the Safety, Tolerability, and Pharmacokinetics of BIIB078 Administered Intrathecally to Adults With C9ORF72-Associated Amyotrophic Lateral Sclerosis
Actual Study Start Date : September 10, 2018
Estimated Primary Completion Date : September 28, 2021
Estimated Study Completion Date : September 28, 2021


Arm Intervention/treatment
Experimental: Cohort 1: BIIB078 First Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB078
Administered as specified in the treatment arm.

Experimental: Cohort 2: BIIB078 Second Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB078
Administered as specified in the treatment arm.

Experimental: Cohort 3: BIIB078 Third Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days.
Drug: BIIB078
Administered as specified in the treatment arm.

Experimental: Cohort 4: BIIB078 Fourth Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.
Drug: BIIB078
Administered as specified in the treatment arm.

Experimental: Cohort 5: BIIB078 Fifth Dosage
BIIB078 will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by five maintenance doses on five later days.
Drug: BIIB078
Administered as specified in the treatment arm.

Placebo Comparator: Cohorts 1-5: Placebo
Matching placebo will be administered as a loading regimen of 3 doses, on Day 1 and two later days, followed by two maintenance doses on two later days (Cohorts 1 through 3) and five maintenance doses on five later days (Cohorts 4 and 5).
Drug: Placebo
Administered as specified in the treatment arm.




Primary Outcome Measures :
  1. Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline through End of Study (Approximately Day 323) ]
    An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death, places participant at immediate risk of death, requires initial or prolonged inpatient hospitalization, results in persistent or significant disability/incapacity, results in congenital anomaly, is a medically important event.


Secondary Outcome Measures :
  1. Serum BIIB078 Concentration [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  2. Area Under the Concentration-Time Curve (AUC) from Time 0 to Infinity (AUCinf) [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  3. AUC from Time 0 to Time of the Last Measurable Concentration (AUClast) [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  4. Maximum Observed Concentration (Cmax) [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  5. Time to Reach Cmax (Tmax) [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  6. Terminal Elimination Half-Life (t 1/2) [ Time Frame: Baseline and at multiple time points up to Day 260 ]
  7. Change from Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Scores [ Time Frame: Baseline up to Day 323 ]
    The ALSFRS-R has been demonstrated to predict survival. The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48 [Cedarbaum 1999], with higher scores representing better function.

  8. Change from Baseline in Percent of Predicted Slow Vital Capacity (SVC) [ Time Frame: Baseline up to Day 260 ]
  9. Change from Baseline in Muscle Strength [ Time Frame: Baseline up to Day 260 ]
    Quantitative muscle strength will be evaluated using hand-held dynamometry (HHD), which tests isometric strength of multiple muscles using standard subject positioning. Approximately 8 muscle groups will be examined (per each side) in both upper and lower extremities.

  10. Change from Baseline in Bulbar Strength [ Time Frame: Baseline up to Day 260 ]
    Bulbar strength will be measured by the Iowa Oral Pressure Instrument (IOPI). The IOPI is a commercially available tongue pressure measurement system composed of an airfilled bulb connected to a pressure transducer. The bulb can be placed in different positions in the mouth in order to assess different aspects of tongue weakness.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Ability of the participant to understand the purpose and risks of the study, to provide signed and dated informed consent, and to authorize the use of confidential health information in accordance with national and local participant privacy regulations; or, in the event of the participant's physical incapacity to sign, to confirm that understanding and consent orally to a legally authorized representative (LAR) for the express purpose of having said informed consent and authorization signed on his/her behalf.
  • All participants of childbearing potential must agree to practice highly effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment.
  • Must meet the possible, laboratory-supported probable, probable, or definite criteria for diagnosing ALS according to the World Federation of Neurology El Escorial criteria and have documentation of a clinical genetic test demonstrating the presence of a pathogenic mutation in C9ORF72.
  • Slow vital capacity (SVC) ≥ 50% of predicted value as adjusted for sex, age, and height (from the sitting position).
  • Participants taking concomitant riluzole at study entry must be on a stable dose for ≥ 30 days prior to the first dose of study treatment (Day 1).
  • 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).
  • ALS Cognitive Behavioral Screen (ALS-CBS) score ≥ 11 for the cognitive portion; ≥ 33 for the behavioral portion.
  • Medically able to undergo the study procedures, and to adhere to the visit schedule at the time of study entry, as determined by the Investigator.
  • 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.

Key Exclusion Criteria:

  • History of drug abuse or alcoholism ≤ 6 months of Screening that would limit participation in the study, as determined by the Investigator.
  • Tracheostomy.
  • Prescreening ALSFRS-R slope less than 0.4 points/month, where prescreening ALSFRS-R slope is defined as follows: (48 - ALSFRS-R score at Screening) / (months from date of symptom onset to date of Screening).
  • History of or positive test result at Screening for human immunodeficiency virus. .
  • History of, or positive test result at Screening for, hepatitis C virus antibody.
  • Treatment with another investigational drug or biological agent within 1 month of Screening or 5 half-lives of study agent, whichever is longer.
  • 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.
  • Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system during the study period.
  • Female participants who are pregnant or currently breastfeeding.

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): NCT03626012


Locations
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United States, California
Research Site
La Jolla, California, United States, 92037-0886
Research Site
Los Angeles, California, United States, 90048
Research Site
Palo Alto, California, United States, 94303
United States, Florida
Research Site
Jacksonville, Florida, United States, 32224
Research Site
Miami, Florida, United States, 33136
United States, Georgia
Research Site
Atlanta, Georgia, United States, 30322
United States, Maryland
Research Site
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02114
United States, Missouri
Research Site
Saint Louis, Missouri, United States, 63110
United States, Nebraska
Research Site
Lincoln, Nebraska, United States, 68506-2960
United States, New York
Research Site
New York, New York, United States, 10032
United States, Tennessee
Research Site
Knoxville, Tennessee, United States, 37920
Canada, Alberta
Research Site
Calgary, Alberta, Canada, T2N 1N4
Canada, Ontario
Research Site
Toronto, Ontario, Canada, M4N 3M5
Canada, Quebec
Research Site
Montreal, Quebec, Canada, H3A 2B4
Netherlands
Research Site
Utrecht, Netherlands, 3508 GA
Switzerland
Research Site
St. Gallen, Switzerland, 9007
United Kingdom
Research Site
London, Greater London, United Kingdom, SE5 9RS
Research Site
Sheffield, South Yorkshire, United Kingdom, S10 2HQ
Research Site
London, United Kingdom, NW1 2PG
Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen

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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT03626012    
Other Study ID Numbers: 245AS101
2017-000294-36 ( EudraCT Number )
First Posted: August 10, 2018    Key Record Dates
Last Update Posted: May 5, 2020
Last Verified: May 2020

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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