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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02623699




Registration number
NCT02623699
Ethics application status
Date submitted
24/11/2015
Date registered
8/12/2015
Date last updated
28/07/2023

Titles & IDs
Public title
An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
Scientific 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
Secondary ID [1] 0 0
2015-004098-33
Secondary ID [2] 0 0
233AS101
Universal Trial Number (UTN)
Trial acronym
VALOR (Part C)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amyotrophic Lateral Sclerosis 0 0
Condition category
Condition code
Neurological 0 0 0 0
Neurodegenerative diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Tofersen
Treatment: Drugs - Placebo

Placebo comparator: Part A-SAD: Combined Placebo - Participants will be administered tofersen-matching placebo once by intrathecal bolus injection on Day 1 of Cohorts 1, 2, 3, and 4 respectively.

Experimental: Part A-SAD: Cohort 1: Tofersen 10 mg - Participants will be administered tofersen 10 mg once by intrathecal bolus injection on Day 1.

Experimental: Part A-SAD: Cohort 2: Tofersen 20 mg - 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.

Experimental: Part A-SAD: Cohort 3: Tofersen 40 mg - 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.

Experimental: Part A-SAD: Cohort 4: Tofersen 60 mg - 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.

Placebo comparator: Part B-MAD: Combined Placebo - 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.

Experimental: Part B-MAD: Cohort 5: Tofersen 20 mg - 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.

Experimental: Part B-MAD: Cohort 6: Tofersen 40 mg - 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.

Experimental: Part B-MAD: Cohort 7: Tofersen 60 mg - 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.

Experimental: Part B-MAD: Cohort 8: Tofersen 100 mg - 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.

Placebo comparator: Part C-Pivotal: Placebo - 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.

Experimental: Part C-Pivotal: Tofersen 100 mg - 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.


Treatment: Drugs: Tofersen
Administered as specified in the treatment arm.

Treatment: Drugs: Placebo
Administered as specified in the treatment arm.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Parts A and B: Number of Participants Experiencing Adverse Events (AEs) and Serious Adverse Events (SAEs)
Assessment method [1] 0 0
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.
Timepoint [1] 0 0
Part A: First dose up to Day 63; Part B: First dose up to Day 289
Primary outcome [2] 0 0
Parts A and B: Number of Participants With Clinically Significant Laboratory Abnormalities
Assessment method [2] 0 0
Clinical laboratory assessments included hematology, chemistry, and urinalysis.
Timepoint [2] 0 0
Part A: Up to Day 57; Part B: Up to Day 169
Primary outcome [3] 0 0
Parts A and B: Number of Participants With Clinically Significant Vital Sign Abnormalities
Assessment method [3] 0 0
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.
Timepoint [3] 0 0
Part A: Up to Day 57; Part B: Up to Day 169
Primary outcome [4] 0 0
Parts A and B: Number of Participants With Clinically Significant Physical Examination Abnormalities
Assessment method [4] 0 0
Clinically significant physical examination abnormalities included weight decreased.
Timepoint [4] 0 0
Part A: Up to Day 57; Part B: Up to Day 169
Primary outcome [5] 0 0
Parts A and B: Number of Participants With Clinically Significant Neurological Examination Abnormalities
Assessment method [5] 0 0
Clinically significant neurological examination abnormalities included hyporeflexia.
Timepoint [5] 0 0
Part A: Up to Day 57; Part B: Up to Day 169
Primary outcome [6] 0 0
Parts A and B: Number of Participants With Clinically Significant 12-lead Electrocardiograms (ECGs) Abnormalities
Assessment method [6] 0 0
Timepoint [6] 0 0
Part A: Up to Day 57; Part B: Up to Day 169
Primary outcome [7] 0 0
Parts A and B: PK Parameter of BIIB067 in Plasma: Maximum Observed Concentration (Cmax)
Assessment method [7] 0 0
Timepoint [7] 0 0
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
Primary outcome [8] 0 0
Parts A and B: PK Parameter of BIIB067 in Plasma: Time to Reach Maximum Observed Concentration (Tmax)
Assessment method [8] 0 0
Timepoint [8] 0 0
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
Primary outcome [9] 0 0
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24h)
Assessment method [9] 0 0
Timepoint [9] 0 0
Parts A and B: Pre-dose, 1, 2, 4, 6 hrs post-dose on Day 1
Primary outcome [10] 0 0
Parts A and B: PK Parameter of BIIB067 in Plasma: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf)
Assessment method [10] 0 0
Timepoint [10] 0 0
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
Primary outcome [11] 0 0
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)
Assessment method [11] 0 0
Timepoint [11] 0 0
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
Primary outcome [12] 0 0
Parts A and B: PK Parameter of BIIB067 in Plasma: Apparent Terminal Elimination Half-life (t1/2)
Assessment method [12] 0 0
Timepoint [12] 0 0
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
Primary outcome [13] 0 0
Parts A and B: PK Parameters of BIIB067 in CSF Levels: Terminal Elimination Half-life (t1/2)
Assessment method [13] 0 0
Timepoint [13] 0 0
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
Primary outcome [14] 0 0
Part C: Change From Baseline in Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score at Week 28
Assessment method [14] 0 0
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.
Timepoint [14] 0 0
Baseline, Week 28 (Day 197)
Secondary outcome [1] 0 0
Part B: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Assessment method [1] 0 0
Total CSF SOD1 protein ratio to baseline was calculated.
Timepoint [1] 0 0
Day 85
Secondary outcome [2] 0 0
Part C: CSF Levels of Total SOD1 Protein Concentration Ratio to Baseline
Assessment method [2] 0 0
Total CSF SOD1 protein ratio to baseline was calculated and LS Geometric Mean ratio to baseline was reported.
Timepoint [2] 0 0
Week 28 (Day 197)
Secondary outcome [3] 0 0
Part C: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
Assessment method [3] 0 0
NfL is a biomarker whose concentration was assessed in plasma. Plasma NfL ratio to baseline was calculated.
Timepoint [3] 0 0
Baseline, Day 197 (Week 28)
Secondary outcome [4] 0 0
Part C: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 28
Assessment method [4] 0 0
Vital capacity was measured by means of an SVC test, administered in the upright position.
Timepoint [4] 0 0
Baseline, Week 28 (Day 197)
Secondary outcome [5] 0 0
Part C: Change From Baseline in Handheld Dynamometry (HHD) Megascore as Measured by the HHD Device at Week 28
Assessment method [5] 0 0
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.
Timepoint [5] 0 0
Baseline, Week 28 (Day 197)
Secondary outcome [6] 0 0
Part C: Time to Death or Permanent Ventilation
Assessment method [6] 0 0
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).
Timepoint [6] 0 0
Baseline up to Week 28 (Day 197)
Secondary outcome [7] 0 0
Part C: Time to Death
Assessment method [7] 0 0
Timepoint [7] 0 0
Baseline up to Week 28 (Day 197)
Secondary outcome [8] 0 0
Part C: Number of Participants Experiencing AEs and SAEs
Assessment method [8] 0 0
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.
Timepoint [8] 0 0
First dose up to Day 236

Eligibility
Key inclusion criteria
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/01/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
16/07/2021
Sample size
Target
Accrual to date
Final
176
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 0 0
2145 - Westmead
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Florida
Country [4] 0 0
United States of America
State/province [4] 0 0
Georgia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Maryland
Country [7] 0 0
United States of America
State/province [7] 0 0
Massachusetts
Country [8] 0 0
United States of America
State/province [8] 0 0
Michigan
Country [9] 0 0
United States of America
State/province [9] 0 0
Minnesota
Country [10] 0 0
United States of America
State/province [10] 0 0
Missouri
Country [11] 0 0
United States of America
State/province [11] 0 0
Nebraska
Country [12] 0 0
United States of America
State/province [12] 0 0
New York
Country [13] 0 0
United States of America
State/province [13] 0 0
Ohio
Country [14] 0 0
United States of America
State/province [14] 0 0
Oregon
Country [15] 0 0
United States of America
State/province [15] 0 0
Pennsylvania
Country [16] 0 0
United States of America
State/province [16] 0 0
Tennessee
Country [17] 0 0
United States of America
State/province [17] 0 0
Texas
Country [18] 0 0
Belgium
State/province [18] 0 0
Leuven
Country [19] 0 0
Canada
State/province [19] 0 0
Alberta
Country [20] 0 0
Canada
State/province [20] 0 0
Ontario
Country [21] 0 0
Canada
State/province [21] 0 0
Quebec
Country [22] 0 0
Denmark
State/province [22] 0 0
Copenhagen
Country [23] 0 0
France
State/province [23] 0 0
Paris
Country [24] 0 0
Germany
State/province [24] 0 0
Baden Wuerttemberg
Country [25] 0 0
Italy
State/province [25] 0 0
Torino
Country [26] 0 0
Japan
State/province [26] 0 0
Bunkyo-Ku
Country [27] 0 0
Japan
State/province [27] 0 0
Fukuoka-shi
Country [28] 0 0
Japan
State/province [28] 0 0
Kagoshima City
Country [29] 0 0
Japan
State/province [29] 0 0
Shinjuku-ku
Country [30] 0 0
Japan
State/province [30] 0 0
Suita-Shi
Country [31] 0 0
Korea, Republic of
State/province [31] 0 0
Gyeongsangnam-do
Country [32] 0 0
Korea, Republic of
State/province [32] 0 0
Seoul
Country [33] 0 0
Poland
State/province [33] 0 0
Warszawa
Country [34] 0 0
United Kingdom
State/province [34] 0 0
Greater London
Country [35] 0 0
United Kingdom
State/province [35] 0 0
South Yorkshire

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Biogen
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Ionis Pharmaceuticals, Inc.
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Biogen
Country 0 0
Phone 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement


What supporting documents are/will be available?



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02623699