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An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)

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ClinicalTrials.gov Identifier: NCT02623699
Recruitment Status : Recruiting
First Posted : December 8, 2015
Last Update Posted : September 5, 2019
Sponsor:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Biogen

Brief Summary:

The primary objective of Parts A and B of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB067 in adult with ALS. The primary objective of Part C of this study is to evaluate the clinical efficacy of BIIB067 administered to adult participants with ALS and confirmed superoxide dismutase 1 (SOD1) mutation.

The secondary objective of Parts A and B of this study is to evaluate the effects of BIIB067 on levels of SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, and pharmacodynamic (PD) effects of BIIB067 administered to adult participants with ALS and confirmed SOD1 mutation.


Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Drug: BIIB067 Other: Placebo Phase 3

Detailed Description:
This is a 3-part study to examine the efficacy, safety, tolerability, PK and PD of BIIB067. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of the study and Part C will be the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 144 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BIIB067 Administered to Adult Subjects With Amyotrophic Lateral Sclerosis and Confirmed Superoxide Dismutase 1 Mutation
Actual Study Start Date : January 20, 2016
Estimated Primary Completion Date : May 29, 2020
Estimated Study Completion Date : May 29, 2020


Arm Intervention/treatment
Experimental: Single Ascending Dose
Part A: Randomized single ascending dose
Drug: BIIB067
Part A, B and C

Other: Placebo
Part A, B and C

Experimental: Multiple Ascending Dose
Part B: Randomized multiple ascending dose
Drug: BIIB067
Part A, B and C

Other: Placebo
Part A, B and C

Experimental: Fixed Dose
Part C: Fixed Dose
Drug: BIIB067
Part A, B and C

Other: Placebo
Part A, B and C




Primary Outcome Measures :
  1. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part A and B: Up to Day 169 ]
    An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A SAE is any untoward medical occurrence that at any dose results in death, life-threatening event, requires inpatient hospitalization, significant disability/incapacity or congenital anomaly.

  2. Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  3. Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  4. Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  5. Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  6. Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  7. PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) [ Time Frame: Part A and B: Up to Day 169 ]
  8. PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part A and B: Up to Day 169 ]
  9. PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) [ Time Frame: Part A and B: Up to Day 169 ]
  10. PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) [ Time Frame: Part A and B: Up to Day 169 ]
  11. PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
  12. PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
  13. Slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Score [ Time Frame: Part C: Baseline to Day 197 ]
    There are 12 questions, each scored from 0 (no function) to 4 (full function). Total possible score is 48. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression.


Secondary Outcome Measures :
  1. Change From Baseline in CSF Levels of SOD1 Protein. [ Time Frame: Part A, B and C: Up to Day 169 ]
  2. Combined Assessment of Function and Survival (CAFS) Score [ Time Frame: Part C: Up to Day 197 ]
    CAFS is clinical outcome based on survival time and change in ALSFRS-R score. A higher CAFS score indicates a better group outcome.

  3. Change From Baseline in ALSFRS-R Score [ Time Frame: Part C: Baseline to Day 197 ]
    There are 12 questions, each scored from 0 (no function) to 4 (full function). Total possible score is 48. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression.

  4. Change From Baseline in Slow Vital Capacity (SVC) [ Time Frame: Part C: Baseline to Day 197 ]
    Vital capacity will be measured by means of an SVC test, administered in the upright position.

  5. Ventilation Assistance-free Survival (VAFS) [ Time Frame: Part C: Baseline to Day 225 ]
    It is defined as the time to the earliest occurrence of one of the following events: death, first use of non-invasive ventilation (NIV) for ≥22 hours per day for ≥10 consecutive days, first use of permanent assisted ventilation (PAV) for ≥22 hours per day for ≥7 consecutive days.

  6. Overall Survival [ Time Frame: Part C: Baseline to Day 225 ]
    Overall survival is defined as the time from randomization until death due to any cause.

  7. Change From Baseline in Muscle Strength Measured by Handheld Dynamometry (HHD) [ Time Frame: Part C: Baseline to Day 197 ]
    Quantitative muscle strength will be evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning.

  8. Change From Baseline in ALS Assessment Questionnaire (ALSAQ-5) Score [ Time Frame: Part C: Baseline to Day 197 ]
    ALSAQ-5 is a disease-specific participant self-reported health status questionnaire used to assess ALS-related health quality. The ALSAQ-5 total score ranges from 0 to 100, with a lower score representing a better health-related status.

  9. Change From Baseline in Fatigue Severity Scale (FSS) Score [ Time Frame: Part C: Baseline to Day 197 ]
    FSS is a self-reported questionnaire designed to assess disabling fatigue. It will be used to assess ALS-related health quality.

  10. Change From Baseline in EuroQol Five Dimension Five Level Questionnaire (EQ-5D-5L) Score [ Time Frame: Part C: Baseline to Day 197 ]
    EuroQol Five Dimension (EQ-5D) will be used to assess ALS-related health quality and consists of 2 sections.

  11. Change From Baseline in Work Productivity and Activity Inventory (WPAI) Score [ Time Frame: Part C: Baseline to Day 197 ]
    WPAI questionnaire will measure participant's impairments in work and activities. It will be used to assess ALS-related health quality. WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.

  12. Change From Baseline in Zarit Burden Interview (ZBI) Score [ Time Frame: Part C: Baseline to Day 197 ]
    ZBI will be used to assess ALS-related health quality. It is a self-report that measures the response of caregivers to a series of 22 questions about the impact of the participant's disabilities on their lives.

  13. Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score [ Time Frame: Part C: Baseline to Day 197 ]
    SF-36 will be used to assess ALS-related health quality. It is a validated 36-item participant-completed questionnaire. Higher scores indicate better function.

  14. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part C: Baseline to Day 225 ]
  15. Change From Baseline in Phosphorylated Axonal Neurofilament heavy chain (p-NFH) Concentration in CSF [ Time Frame: Part C: Baseline to Day 169 ]
    p-NFH is a biomarker whose concentration will be assessed in CSF.



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 A and B

  • Weakness attributable to ALS and documented SOD1 mutation at Screening Visit 2.
  • A forced vital capacity (FVC) ≥50% of predicted value as adjusted for sex, age, and height (from the sitting position). Participants with stable FVC <50% but ≥45%, whose FVC has not declined by more than 5% in the last 6 months may be considered for inclusion, at the discretion of the Investigator.
  • 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.
  • 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.

Key Exclusion Criteria: Part A and B

  • History of or positive test result for human immunodeficiency virus.
  • History of, or positive test result at Screening, for hepatitis C virus antibody.
  • Current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive hepatitis B surface antibody immunoglobulin G, and positive HBcAb) or vaccination (defined as positive anti-HBs) are eligible to participate in the study.
  • Treatment with another investigational drug, biological agent, or device within 1 month or 5 half-lives of study agent, whichever is longer. Specifically, no prior treatment with small interfering ribonucleic acid, stem cell therapy, or gene therapy is allowed.
  • Current enrollment in any other interventional study.
  • Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis (N4-methylthiosemicarbazone)) or pyrimethamine.
  • Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period.

Key Inclusion Criteria: Part C

  • Weakness attributable to ALS and confirmed SOD1 mutation at Screening Visit.
  • 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.
  • If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1 and expected to remain at that dose until the final study visit, unless the Investigator determines that edaravone should be discontinued for medical reasons, in which case it may not be restarted during the study. Edaravone may not be administered on dosing days of this study.
  • 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.

Key Exclusion Criteria: Part C

  • History of or positive test result for human immunodeficiency virus.
  • History of, or positive test result at Screening, for hepatitis C virus antibody.
  • Current hepatitis B infection (defined as positive for HBsAg and/or anti-HBc). participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive IgM anti-HBc, and positive anti-HBc) or vaccination (defined as positive anti-HBs) are eligible to participate in the study.
  • 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.
  • Current enrollment in any other interventional study.
  • Current or recent (within 1 month) use, or anticipated need, in the opinion of the Investigator, of copper (II) (diacetyl-bis(N4-methylthiosemicarbazone)) or pyrimethamine.
  • Current or anticipated need, in the opinion of the Investigator, of a DPS during the study period.

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): NCT02623699


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

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Sponsors and Collaborators
Biogen
Ionis Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Director Biogen

Additional Information:
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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02623699     History of Changes
Other Study ID Numbers: 233AS101
2015-004098-33 ( EudraCT Number )
First Posted: December 8, 2015    Key Record Dates
Last Update Posted: September 5, 2019
Last Verified: September 2019
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: http://www.biogenclinicaldatarequest.com
Keywords provided by Biogen:
IONIS-SOD1Rx
SOD1
ALS
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