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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 : December 6, 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 (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.


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 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 183 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 : July 6, 2021
Estimated Study Completion Date : July 6, 2021


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

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 Name: Tofersen

Other: Placebo
Part A, B and C

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

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. 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.


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. 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.

  3. 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

  4. 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.

  5. 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.

  6. Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Part C: Baseline to Day 225 ]
  7. 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.
  • 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.


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

  Hide Study Locations
Locations
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United States, Arizona
Barrow Neurological Institute Recruiting
Phoenix, Arizona, United States, 85013
Contact: Aide Raya    602-406-8144    aide.raya@dignityhealth.org   
United States, California
University of California San Diego Medical Center Recruiting
La Jolla, California, United States, 92093-0949
Contact: Rose Previte    858-246-1319    rprevite@ucsd.edu   
California Pacific Medical Center Recruiting
San Francisco, California, United States, 94115
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224
University of Miami School of Medicine Recruiting
Miami, Florida, United States, 33136
Contact: Anne-Laure Grignon    305-243-8928    axg1571@med.miami.edu   
Bioclinica Research Recruiting
Orlando, Florida, United States, 32806
Contact: Matthew Bubalo    407-734-7841    matthew.bubalo@globalaes.com   
United States, Georgia
Emory University Hospital Recruiting
Atlanta, Georgia, United States, 30322
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Kristen Riley       kriley15@jhmi.edu   
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
United States, Minnesota
Mayo Clinic - Rochester Recruiting
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Jesse Markway    844-257-2273 or 314-362-6159    als@wustl.edu   
United States, Nebraska
Neurology Associates, P.C. Recruiting
Lincoln, Nebraska, United States, 68506
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
United States, Tennessee
New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company Recruiting
Knoxville, Tennessee, United States, 37920
Australia, New South Wales
Westmead Hospital Recruiting
Westmead, New South Wales, Australia, 2145
Contact: Steve Vucic    +61 2 8890 8738    steve.vucic@sydney.edu.au   
Belgium
UZ Leuven Recruiting
Leuven, Belgium, 3000
Contact    +32 16344280    ann.dhondt@uzleuven.be   
Canada, Ontario
Sunnybrook Health Sciences Centre Recruiting
Toronto, Ontario, Canada, M4N 3M5
Canada, Quebec
Montreal Neurological Institute Recruiting
Montreal, Quebec, Canada, H3A 2B4
Contact: Yousra Khalfallah    514-398-6188    yousra.khalfallah@mcgill.ca   
France
Hopital Pitie Salpetriere Recruiting
Paris, France, 75651
Contact: Maryvonne Retail    01 42 16 19 70    maryvonne.retail@aphp.fr   
Contact    01 42 16 57 62      
Germany
University of Ulm Recruiting
Ulm, Baden Wuerttemberg, Germany, 89081
Contact: Sebastian Michels    +49 (0)731-177 5219    sebastian.michels@rku.de   
Italy
ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin Recruiting
Torino, Italy, 10126
Contact: Giuseppe Fuda    +39 011 6335439    gio.fuda@gmail.com   
Japan
Research Site Recruiting
Kagoshima City, Kagoshima-Ken, Japan, 890-8520
Research Site Recruiting
Suita-Shi, Osaka-Fu, Japan, 565-0871
Research Site Recruiting
Bunkyo-Ku, Tokyo-To, Japan, 113-8655
Research Site Recruiting
Shinjuku-ku, Tokyo-To, Japan, 160-8582
United Kingdom
Research Site Recruiting
Sheffield, South Yorkshire, United Kingdom, S10 2HQ
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: December 6, 2019
Last Verified: December 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