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

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ClinicalTrials.gov Identifier: NCT02623699
Recruitment Status : Recruiting
First Posted : December 8, 2015
Last Update Posted : November 11, 2019
Sponsor:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE November 24, 2015
First Posted Date  ICMJE December 8, 2015
Last Update Posted Date November 11, 2019
Actual Study Start Date  ICMJE January 20, 2016
Estimated Primary Completion Date July 6, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 7, 2019)
  • 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.
  • Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  • Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  • Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  • Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  • Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: Part A and B: Up to Day 169 ]
  • PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax) [ Time Frame: Part A and B: Up to Day 169 ]
  • PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax) [ Time Frame: Part A and B: Up to Day 169 ]
  • 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 ]
  • 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 ]
  • PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
  • PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2) [ Time Frame: Part A and B: Up to Day 169 ]
  • Change from Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28 [ 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 3, 2015)
  • Number of participants experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • Number of Participants With Clinically Significant Laboratory Assessment Abnormalities [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • Number of Participants With Clinically Significant Vital Sign Abnormalities [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • Number of Participants With Clinically Significant Physical Examination Abnormalities [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • Number of Participants With Clinically Significant Neurological Examination Abnormalities [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameter of BIIB067 (Isis-SOD1Rx) in plasma: Maximum observed concentration (Cmax) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameter of BIIB067 (Isis-SOD1Rx) in plasma: Time to reach maximum observed concentration (Tmax) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameter of BIIB067 (Isis-SOD1Rx) in plasma: Area under the concentration-time curve from time zero to infinity (AUCinf) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameter of BIIB067 (Isis-SOD1Rx) in plasma: Area under the concentration-time curve from time zero to the time of the last measurable concentration (AUClast) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameter of BIIB067 (Isis-SOD1Rx) in plasma: Apparent terminal elimination half-life (t1/2) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
  • PK parameters of BIIB067 (Isis-SOD1Rx) in CSF levels: Terminal elimination half-life (t1/2) [ Time Frame: up to day 169 ]
    Part A: up to day 57; Part B: up to day 169
Change History Complete list of historical versions of study NCT02623699 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2019)
  • Change From Baseline in CSF Levels of SOD1 Protein. [ Time Frame: Part A, B and C: Up to Day 169 ]
  • 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.
  • 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
  • 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.
  • 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.
  • Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part C: Baseline to Day 225 ]
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 3, 2015)
Change From Baseline in CSF Levels of SOD1 Protein. [ Time Frame: up to day 169 ]
Part A: up to day 57; Part B: up to day 169
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
Official Title  ICMJE 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
Brief Summary

The primary objective of Parts A and B of this study is to evaluate the safety, tolerability, and pharmacokinetics (PK) of BIIB067 (Tofersen) 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.

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 is the fixed dose component of the study. Hence, the overall phase of development of the study is 1/2/3.

Parts A and B were completed on 15-Jan-2019. In total, the study is estimated to enroll 183 participants, with 99 in Part C.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • Drug: BIIB067
    Part A, B and C
    Other Name: Tofersen
  • Other: Placebo
    Part A, B and C
Study Arms  ICMJE
  • Experimental: Single Ascending Dose
    Part A: Randomized single ascending dose
    Interventions:
    • Drug: BIIB067
    • Other: Placebo
  • Experimental: Multiple Ascending Dose
    Part B: Randomized multiple ascending dose
    Interventions:
    • Drug: BIIB067
    • Other: Placebo
  • Experimental: Fixed Dose
    Part C: Fixed Dose
    Interventions:
    • Drug: BIIB067
    • Other: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 7, 2019)
183
Original Estimated Enrollment  ICMJE
 (submitted: December 3, 2015)
72
Estimated Study Completion Date  ICMJE July 6, 2021
Estimated Primary Completion Date July 6, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  • Current hepatitis C infection (defined as positive hepatitis C virus [HCV] antibody and detectable HCV ribonucleic acid [RNA]). Participants with positive HCV antibody and undetectable HCV RNA are eligible to participate in the study (United States Centers for Disease Control and Prevention).
  • 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 anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: US Biogen Clinical Trial Center 866-633-4636 clinicaltrials@biogen.com
Contact: Global Biogen Clinical Trial Center clinicaltrials@biogen.com
Listed Location Countries  ICMJE Australia,   Belgium,   Canada,   France,   Germany,   Japan,   United Kingdom,   United States
Removed Location Countries Italy,   Sweden
 
Administrative Information
NCT Number  ICMJE NCT02623699
Other Study ID Numbers  ICMJE 233AS101
2015-004098-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Ionis Pharmaceuticals, Inc.
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP