Back to resultsAn Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS) (VALOR (Part C))
Primary Purpose
Amyotrophic Lateral Sclerosis
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tofersen
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring IONIS-SOD1Rx, SOD1, ALS
Eligibility 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.
Sites / Locations
- Barrow Neurological Institute
- University of California San Diego Medical Center
- California Pacific Medical Center
- Mayo Clinic in Florida
- University of Miami School of Medicine
- Bioclinica Research
- Emory University Hospital
- Northwestern University Feinberg School of Medicine
- Johns Hopkins University
- Massachusetts General Hospital
- Henry Ford Hospital
- Mayo Clinic - Rochester
- Washington University School of Medicine
- Neurology Associates, P.C.
- Columbia University Medical Center
- The Cleveland Clinic Foundation
- Providence ALS Center
- University of Pennsylvania
- New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company
- Methodist Neurological Institute
- Westmead Hospital
- UZ Leuven
- University of Calgary - Health Sciences Centre
- Research Site
- Sunnybrook Health Sciences Centre
- Montreal Neurological Institute
- Bispebjerg Hospital
- Hopital Pitie Salpetriere
- University of Ulm
- ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
- The University of Tokyo Hospital
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
- Research Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Arm 12
Arm Type
Placebo Comparator
Experimental
Experimental
Experimental
Experimental
Placebo Comparator
Experimental
Experimental
Experimental
Experimental
Placebo Comparator
Experimental
Arm Label
Part A-SAD: Combined Placebo
Part A-SAD: Cohort 1: Tofersen 10 mg
Part A-SAD: Cohort 2: Tofersen 20 mg
Part A-SAD: Cohort 3: Tofersen 40 mg
Part A-SAD: Cohort 4: Tofersen 60 mg
Part B-MAD: Combined Placebo
Part B-MAD: Cohort 5: Tofersen 20 mg
Part B-MAD: Cohort 6: Tofersen 40 mg
Part B-MAD: Cohort 7: Tofersen 60 mg
Part B-MAD: Cohort 8: Tofersen 100 mg
Part C-Pivotal: Placebo
Part C-Pivotal: Tofersen 100 mg
Arm Description
Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.
Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.
Participants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.
Participants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.
Participants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.
Participants will be administered tofersen-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.
Participants will be administered tofersen 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.
Participants will be administered tofersen 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5.
Participants will be administered tofersen 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 6.
Participants will be administered tofersen 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7.
Participants will be administered tofersen-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.
Participants will be administered tofersen 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.
Outcomes
Primary Outcome Measures
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
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 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.
Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities
Clinical laboratory assessments included hematology, chemistry, and urinalysis.
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
The criteria for clinically significant vital sign abnormalities include: Temperature: >38 degree Celsius (°C) or an increase from baseline of ≥1°C; Pulse: >120 beats per minute (bpm) or an increase from baseline of >20 bpm, <50 bpm or a decrease from baseline of >20 bpm; Systolic blood pressure (BP): >180 mmHg or an increase from baseline of >40 mmHg, <90 mmHg or a decrease from baseline of >30 mmHg; Diastolic BP: >105 mmHg or an increase from baseline of >30 mmHg, <50 mmHg or a decrease from baseline of >20 mmHg.
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities
Clinically significant physical examination abnormalities included weight decreased.
Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities
Clinically significant neurological examination abnormalities included hyporeflexia.
Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities
Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)
Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast)
Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)
Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression.
Secondary Outcome Measures
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Total CSF SOD1 protein ratio to baseline was calculated.
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
Vital capacity was measured by means of an SVC test, administered in the upright position.
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength.
Part C: Time to Death or Permanent Ventilation
Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days).
Part C: Time to Death
Part C: Number of Participants Experiencing AEs and SAEs
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 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.
Full Information
NCT ID
NCT02623699
First Posted
November 24, 2015
Last Updated
July 7, 2023
Sponsor
Biogen
Collaborators
Ionis Pharmaceuticals, Inc.
1. Study Identification
Unique Protocol Identification Number
NCT02623699
Brief Title
An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
Acronym
VALOR (Part C)
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Completed
Study Start Date
January 20, 2016 (Actual)
Primary Completion Date
July 16, 2021 (Actual)
Study Completion Date
July 16, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen
Collaborators
Ionis Pharmaceuticals, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The primary objectives of Parts A and B of this study are to evaluate the safety, tolerability, and pharmacokinetics (PK) of ascending doses of tofersen in adults with ALS and a documented superoxide dismutase 1 (SOD1) mutation. The primary objective of Part C of this study is to evaluate the clinical efficacy of tofersen administered to adults with ALS and a confirmed SOD1 mutation.
The secondary objective of Parts A and B of this study is to evaluate the effects of tofersen on levels of total SOD1 protein in the cerebrospinal fluid (CSF). The secondary objectives of Part C are to evaluate the safety, tolerability, pharmacodynamic (PD), and biomarker effects of tofersen.
Detailed Description
This is a 3-part study to examine the efficacy, safety, tolerability, PK, and PD of tofersen. Part A is the single ascending dose (SAD) component of the study, Part B is the multiple ascending dose (MAD) component of 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.
The study completed on 16 Jul 2021. In total, the study enrolled 176 participants, of which 108 enrolled in Part C.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
Keywords
IONIS-SOD1Rx, SOD1, ALS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
176 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Part A-SAD: Combined Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.
Arm Title
Part A-SAD: Cohort 1: Tofersen 10 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.
Arm Title
Part A-SAD: Cohort 2: Tofersen 20 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 20 mg once by intrathecal bolus injection on Day 1 of Cohort 2 after the safety review of Cohort 1.
Arm Title
Part A-SAD: Cohort 3: Tofersen 40 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 40 mg once by intrathecal bolus injection on Day 1 of Cohort 3 after the safety review of Cohort 2.
Arm Title
Part A-SAD: Cohort 4: Tofersen 60 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 60 mg once by intrathecal bolus injection on Day 1 of Cohort 4 after the safety review of Cohort 3.
Arm Title
Part B-MAD: Combined Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be administered tofersen-matching placebo, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.
Arm Title
Part B-MAD: Cohort 5: Tofersen 20 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 20 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection.
Arm Title
Part B-MAD: Cohort 6: Tofersen 40 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 40 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety and PK review of Cohort 5.
Arm Title
Part B-MAD: Cohort 7: Tofersen 60 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 60 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 6.
Arm Title
Part B-MAD: Cohort 8: Tofersen 100 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 100 mg, 3 loading doses once every 2 weeks on Days 1, 15, 29 and 2 maintenance doses once every 4 weeks on Days 57 and 85 by intrathecal injection after the safety, PK review and SOD1 PD review of Cohort 7.
Arm Title
Part C-Pivotal: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be administered tofersen-matching placebo, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.
Arm Title
Part C-Pivotal: Tofersen 100 mg
Arm Type
Experimental
Arm Description
Participants will be administered tofersen 100 mg, 3 loading doses administered once every 2 weeks on Days 1, 15, 29 followed by 5 maintenance doses administered once every 4 weeks on Days 57, 85, 113, 141, 169 up to 24 weeks by intrathecal bolus injection.
Intervention Type
Drug
Intervention Name(s)
Tofersen
Other Intervention Name(s)
BIIB067, QALSODY
Intervention Description
Administered as specified in the treatment arm.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Administered as specified in the treatment arm.
Primary Outcome Measure Information:
Title
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
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 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.
Time Frame
Part A: First dose up to Day 63; Part B: First dose up to Day 289
Title
Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities
Description
Clinical laboratory assessments included hematology, chemistry, and urinalysis.
Time Frame
Part A: Up to Day 57; Part B: Up to Day 169
Title
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
Description
The criteria for clinically significant vital sign abnormalities include: Temperature: >38 degree Celsius (°C) or an increase from baseline of ≥1°C; Pulse: >120 beats per minute (bpm) or an increase from baseline of >20 bpm, <50 bpm or a decrease from baseline of >20 bpm; Systolic blood pressure (BP): >180 mmHg or an increase from baseline of >40 mmHg, <90 mmHg or a decrease from baseline of >30 mmHg; Diastolic BP: >105 mmHg or an increase from baseline of >30 mmHg, <50 mmHg or a decrease from baseline of >20 mmHg.
Time Frame
Part A: Up to Day 57; Part B: Up to Day 169
Title
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities
Description
Clinically significant physical examination abnormalities included weight decreased.
Time Frame
Part A: Up to Day 57; Part B: Up to Day 169
Title
Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities
Description
Clinically significant neurological examination abnormalities included hyporeflexia.
Time Frame
Part A: Up to Day 57; Part B: Up to Day 169
Title
Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities
Time Frame
Part A: Up to Day 57; Part B: Up to Day 169
Title
Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)
Time Frame
Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Title
Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)
Time Frame
Part A: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1; Part B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1 and 1, 2, 4, 6 hrs post-dose on Day 85
Title
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
Time Frame
Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1
Title
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)
Time Frame
Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Title
Parts A and B: 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: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Title
Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)
Time Frame
Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Title
Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)
Time Frame
Part A: Pre-dose Day 1, Days 29 and 57; Part B: Pre-dose Days 1, 15, 29, 57 and 85; Day 106 and 169
Title
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
Description
The ALSFRS-R measures 4 functional domains, including respiratory, bulbar function, gross motor skills, and fine motor skills. There are 12 questions, each scored from 0 (no function) to 4 (full function), for a total possible score of 48. Scores decline with disease progression. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Higher scores represent better function, negative change from baseline indicates disease progression.
Time Frame
Baseline, Week 28 (Day 197)
Secondary Outcome Measure Information:
Title
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Description
Total CSF SOD1 protein ratio to baseline was calculated.
Time Frame
Day 85
Title
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Description
Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
Time Frame
Week 28 (Day 197)
Title
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
Description
NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
Time Frame
Baseline, Day 197 (Week 28)
Title
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
Description
Vital capacity was measured by means of an SVC test, administered in the upright position.
Time Frame
Baseline, Week 28 (Day 197)
Title
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
Description
Quantitative muscle strength was evaluated using HHD, which tests isometric strength of multiple muscles using standard participant positioning. Sixteen muscle groups were evaluated in both upper and lower extremities. The muscle strength values were normalized to Z scores as (post-baseline measurements - mean)/SD and averaged to provide HHD overall megascore. The overall megascore was created by averaging all eight bilateral measurement Z scores, if no more than 10 (≤ 10) measures are missing. A negative change from baseline indicated decreased muscle strength.
Time Frame
Baseline, Week 28 (Day 197)
Title
Part C: Time to Death or Permanent Ventilation
Description
Time to Death or Permanent Ventilation is defined as the time to the earliest occurrence of one of the following events that were adjudicated by an independent committee: Death; Permanent ventilation (≥22 hours of mechanical ventilation [invasive or noninvasive] per day for ≥21 consecutive days).
Time Frame
Baseline up to Week 28 (Day 197)
Title
Part C: Time to Death
Time Frame
Baseline up to Week 28 (Day 197)
Title
Part C: Number of Participants Experiencing AEs and SAEs
Description
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 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.
Time Frame
First dose up to Day 236
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
Barrow Neurological Institute
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
University of California San Diego Medical Center
City
La Jolla
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Mayo Clinic in Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
University of Miami School of Medicine
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Bioclinica Research
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Northwestern University Feinberg School of Medicine
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Mayo Clinic - Rochester
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Neurology Associates, P.C.
City
Lincoln
State/Province
Nebraska
ZIP/Postal Code
68506
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
The Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Providence ALS Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97213
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
New Orleans Center for Clinical Research/Volunteer Research Group, an AMR Company
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37920
Country
United States
Facility Name
Methodist Neurological Institute
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Westmead Hospital
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
UZ Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
University of Calgary - Health Sciences Centre
City
Calgary
State/Province
Alberta
ZIP/Postal Code
T2N 1N4
Country
Canada
Facility Name
Research Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2G3
Country
Canada
Facility Name
Sunnybrook Health Sciences Centre
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M4N 3M5
Country
Canada
Facility Name
Montreal Neurological Institute
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 2B4
Country
Canada
Facility Name
Bispebjerg Hospital
City
Copenhagen
ZIP/Postal Code
2400
Country
Denmark
Facility Name
Hopital Pitie Salpetriere
City
Paris
ZIP/Postal Code
75651
Country
France
Facility Name
University of Ulm
City
Ulm
State/Province
Baden Wuerttemberg
ZIP/Postal Code
89081
Country
Germany
Facility Name
ALS Center - Dept. of Neuroscience "Rita Levi Montalcini", University of Turin
City
Torino
ZIP/Postal Code
10126
Country
Italy
Facility Name
The University of Tokyo Hospital
City
Bunkyo-Ku
Country
Japan
Facility Name
Research Site
City
Fukuoka-shi
Country
Japan
Facility Name
Research Site
City
Kagoshima City
Country
Japan
Facility Name
Research Site
City
Shinjuku-ku
Country
Japan
Facility Name
Research Site
City
Suita-Shi
Country
Japan
Facility Name
Research Site
City
Yangsan-si
State/Province
Gyeongsangnam-do
ZIP/Postal Code
50612
Country
Korea, Republic of
Facility Name
Research Site
City
Seoul
ZIP/Postal Code
04763
Country
Korea, Republic of
Facility Name
Research Site
City
Warszawa
ZIP/Postal Code
01684
Country
Poland
Facility Name
Research Site
City
London
State/Province
Greater London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
Facility Name
Research Site
City
Sheffield
State/Province
South Yorkshire
ZIP/Postal Code
S10 2HQ
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
In accordance with Biogen's Clinical Trial Transparency and Data Sharing Policy on http://clinicalresearch.biogen.com/
IPD Sharing URL
https://vivli.org/
Citations:
PubMed Identifier
36129998
Citation
Miller TM, Cudkowicz ME, Genge A, Shaw PJ, Sobue G, Bucelli RC, Chio A, Van Damme P, Ludolph AC, Glass JD, Andrews JA, Babu S, Benatar M, McDermott CJ, Cochrane T, Chary S, Chew S, Zhu H, Wu F, Nestorov I, Graham D, Sun P, McNeill M, Fanning L, Ferguson TA, Fradette S; VALOR and OLE Working Group. Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2022 Sep 22;387(12):1099-1110. doi: 10.1056/NEJMoa2204705.
Results Reference
derived
PubMed Identifier
32640130
Citation
Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL, Maragakis NJ, McDermott CJ, Pestronk A, Ravits J, Salachas F, Trudell R, Van Damme P, Zinman L, Bennett CF, Lane R, Sandrock A, Runz H, Graham D, Houshyar H, McCampbell A, Nestorov I, Chang I, McNeill M, Fanning L, Fradette S, Ferguson TA. Phase 1-2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. N Engl J Med. 2020 Jul 9;383(2):109-119. doi: 10.1056/NEJMoa2003715.
Results Reference
derived
Learn more about this trial
An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
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