ALS Caused by Superoxide Dismutase 1 (SOD1) Mutation
Conditions
Brief summary
The primary objective of the study is to evaluate the long-term safety and tolerability of BIIB067 (tofersen) in participants with amyotrophic lateral sclerosis (ALS) and confirmed superoxide dismutase 1 (SOD1) mutation. The secondary objectives are to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), biomarker effects, and efficacy of BIIB067 administered to participants with ALS and a confirmed SOD1 mutation.
Interventions
DRUGTofersen
Participants will receive a loading dose regimen followed by maintenance dosing.
Sponsors
Ionis Pharmaceuticals, Inc.
Biogen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Must have diagnosis of superoxide dismutase 1-amyotrophic lateral sclerosis (SOD1-ALS), and must have completed the End of Study Visit for either Parts A, B, or C of Study 233AS101 (NCT02623699) (i.e., were not withdrawn). * If taking riluzole, participant must be receiving a stable dose for ≥30 days prior to Day 1. * If taking edaravone, participant must have initiated edaravone ≥60 days (2 treatment cycles) prior to Day 1. Edaravone may not be administered on dosing days during 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. * For female participants of childbearing potential must agree to practice effective contraception during the study and be willing and able to continue contraception for 5 months after their last dose of study treatment. * Participants from Study 233AS101 Parts A and B must have a washout ≥16 weeks between the last dose of study treatment received in Study 233AS101 and the first dose of BIIB067 received in the current Study 233AS102. Key
Exclusion criteria
* History of allergies to a broad range of anesthetics. * Presence of risk for increased or uncontrolled bleeding and/or risk of bleeding that is not managed optimally and could place a participant at an increased risk for bleeding during or after a Lumbar Puncture (LP) procedure. These risks could include, but are not limited to, anatomical factors at or near the LP site (e.g., vascular abnormalities, neoplasms, or other abnormalities) and underlying disorders of the coagulation cascade, platelet function, or platelet count (e.g., hemophilia, Von Willebrand's disease, liver disease). * Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system (CNS) catheter. * Prior or current treatment with small interfering ribonucleic acid (RNA), stem cell therapy, or gene therapy. * Treatment with another investigational drug, biological agent (excluding BIIB067), or device within 1 month or 5 half-lives of study agent, whichever is longer. * Current or anticipated need, in the opinion of the Investigator, of a diaphragm pacing system (DPS) during the study period. * 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. * Female participants who are pregnant or currently breastfeeding. * Current enrollment in any other interventional study. NOTE: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | From first dose of the study drug in the current study up to end of follow-up period (up to Week 364) | 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. An 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. TEAEs were defined as any AEs or SAE with an onset date and time that was on or after the first dose of study drug, or any pre-existing condition that worsened in severity after the first dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of BIIB067 in Cerebrospinal Fluid (CSF) | Week 4 | — |
| 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Baseline, Weeks 52, 104 and 148 | This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. |
| 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Baseline, Weeks 52, 104 and 148 | This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. |
| 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Baseline, Weeks 52, 104 and 148 | 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). The ALSFRS-R total score was calculated as the sum of the 4 functional domain scores, ranging from 0 to 48, where higher scores representing better function. Negative change from baseline indicates disease progression. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. |
| Plasma Concentration of BIIB067 | Week 4 | — |
| 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Baseline, Weeks 52, 104 and 148 | Quantitative muscle strength was evaluated using the HHD Megascore, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) 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. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. |
| 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Baseline, Weeks 52, 104 and 148 | Individual muscle strength was evaluated using handheld dynamometer which tests the isometric strength of multiple muscles using standard participant positioning. Eight muscle groups were examined (per each side) in both upper and lower extremities. Negative change from baseline=decreased muscle strength. The analyses was based on observed data. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. |
| 233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation | From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364) | Permanent ventilation was defined as ≥ 22 hours of mechanical ventilation \[invasive or noninvasive\] per day for ≥ 21 consecutive days. An event of permanent ventilation was based on an adjudicated event (i.e., adjudicated by the Endpoint Adjudication Committee (EAC) as having met the permanent ventilation criteria defined in the protocol). Time to death or permanent ventilation was defined as the time to the earliest occurrence of death or permanent ventilation. The start date for calculating time to death or permanent ventilation in days was date of first dose. Participants without an event were censored at the last known alive dates. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to permanent ventilation or death was summarized using the Kaplan-Meier product limit method. |
| 233AS101 and 233AS102 ISE: Time to Death | From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364) | Time to death was defined as the time from first dose received in 233AS101 to death. Participants who do not meet the endpoint definition were censored at the participant's last known alive date. Only events that were adjudicated by the EAC are included. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to death was summarized using the Kaplan-Meier product limit method. |
| 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Baseline, Weeks 52, 104 and 148 | Vital capacity was measured by means of an SVC test, administered in the upright position. Upright SVC was determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society. The percent predicted SVC was calculated as \[observed SVC divided by predicted SVC\]\*100%. The predicted SVC was adjusted by sex, age, height, which was programmed into and performed by the equipment used. Negative change from baseline indicated worsening of respiratory capacity. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline. |
Countries
Belgium, Canada, Denmark, France, Germany, Italy, Japan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled and took part at the investigative sites in Belgium, Canada, France, Germany, Italy, Japan, Denmark, the United Kingdom, and the United States from 08 Mar 2017 to 12 Aug 2024.
Pre-assignment details
A total of 139 participants were randomized in the study, of which 95 participants rolled over from Part C and 44 participants rolled over from Parts A and B of the parent study 233AS101 (NCT02623699).
Participants by arm
| Arm | Count |
|---|---|
| 233AS101: Part C (Prior Placebo) Participants who were randomized to placebo in Part C of the parent study 233AS101 received 3 loading doses of BIIB067, 100mg, Q2W, on Days 1, 15, and 29 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067, Q4W, until the last enrolled participant had their Week 152 maintenance dose visit. | 32 |
| 233AS101: Part C (Prior BIIB067 100 mg) Participants who were randomized to BIIB067 100 mg in Part C of the parent study 233AS101 received 2 loading doses of BIIB067, 100 mg, on Days 1 and 29, and one dose of BIIB067-matched placebo on Day 15 by IT bolus injection in this study followed by up to 90 maintenance doses of BIIB067,Q4W, until the last enrolled participant had their Week 152 maintenance dose visit. | 63 |
| 233AS101: Part A and B (All Doses) Participants who were randomized to BIIB067 or placebo in Part A (at doses 10 mg, 20 mg, 40 mg and 60 mg) or Part B (at doses 20 mg, 40 mg, 60 mg and 100 mg) of the parent study 233AS101 received 3 loading doses of BIIB067, 20 mg, 40 mg, 60 mg, or 100 mg, eventually escalated to 100 mg, 2 weeks apart, and up to 90 maintenance doses, Q4W, by IT bolus injection until the last enrolled participant had their Week 152 maintenance dose visit in this study. | 44 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Consent Withdrawn | 6 | 5 | 3 |
| Overall Study | Death | 7 | 14 | 5 |
| Overall Study | Disease Progression | 5 | 7 | 7 |
| Overall Study | Investigator Decision | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Reason not Specified | 2 | 2 | 1 |
Baseline characteristics
| Characteristic | 233AS101: Part C (Prior Placebo) | 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101: Part A and B (All Doses) | Total |
|---|---|---|---|---|
| Age, Continuous | 52.8 years STANDARD_DEVIATION 11 | 48.1 years STANDARD_DEVIATION 11.8 | 49.8 years STANDARD_DEVIATION 11.04 | 49.7 years STANDARD_DEVIATION 11.45 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 40 Participants | 26 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 20 Participants | 18 Participants | 44 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 4 Participants | 4 Participants | 1 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Black or African American | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Not Reported | 6 Participants | 20 Participants | 18 Participants | 44 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Race White | 22 Participants | 37 Participants | 23 Participants | 82 Participants |
| Sex: Female, Male Female | 15 Participants | 24 Participants | 19 Participants | 58 Participants |
| Sex: Female, Male Male | 17 Participants | 39 Participants | 25 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 32 | 14 / 63 | 5 / 44 |
| other Total, other adverse events | 31 / 32 | 63 / 63 | 43 / 44 |
| serious Total, serious adverse events | 16 / 32 | 33 / 63 | 22 / 44 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs)
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. An 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. TEAEs were defined as any AEs or SAE with an onset date and time that was on or after the first dose of study drug, or any pre-existing condition that worsened in severity after the first dose of study drug.
Time frame: From first dose of the study drug in the current study up to end of follow-up period (up to Week 364)
Population: The safety population included all participants who were enrolled and received at least one dose of study treatment in 233AS102.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TEAEs | 31 Participants |
| 233AS101: Part C (Prior Placebo) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TESAEs | 16 Participants |
| 233AS101: Part C (Prior BIIB067 100 mg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TEAEs | 63 Participants |
| 233AS101: Part C (Prior BIIB067 100 mg) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TESAEs | 33 Participants |
| 233AS101: Part A and B (All Doses) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TESAEs | 22 Participants |
| 233AS101: Part A and B (All Doses) | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious AEs (TESAEs) | TEAEs | 43 Participants |
Secondary
233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline
This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 52 | 0.78 ratio |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 104 | 0.81 ratio |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 148 | 0.75 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 52 | 0.67 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 104 | 0.74 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 Integrated Summary of Efficacy (ISE): Total CSF Superoxide Dismutase 1 (SOD1) Protein Ratio to Baseline | Week 148 | 0.79 ratio |
Comparison: Week 52 - The analysis was based on an analysis of covariance (ANCOVA) model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation (MI) including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.95% CI: [0.69, 1.08]
Comparison: Week 104 - The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.371195% CI: [0.75, 1.11]ANCOVA
Comparison: Week 148 - The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.634495% CI: [0.84, 1.34]ANCOVA
Secondary
233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore
Quantitative muscle strength was evaluated using the HHD Megascore, which tests isometric strength of multiple muscles using standard participant positioning. Approximately 8 muscle groups were examined (per each side) 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. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 52 | -0.41 score on a scale | Standard Error 0.101 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 104 | -0.56 score on a scale | Standard Error 0.154 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 148 | -0.43 score on a scale | Standard Error 0.089 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 52 | -0.15 score on a scale | Standard Error 0.079 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 104 | -0.42 score on a scale | Standard Error 0.112 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Handheld Dynamometry (HHD) Overall Megascore | Week 148 | -0.38 score on a scale | Standard Error 0.062 |
Comparison: Week 52 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.95% CI: [0.051, 0.477]
Comparison: Week 104 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.320795% CI: [-0.141, 0.43]ANCOVA
Comparison: Week 148 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline HHD overall megascore and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.545295% CI: [-0.124, 0.234]ANCOVA
Secondary
233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD
Individual muscle strength was evaluated using handheld dynamometer which tests the isometric strength of multiple muscles using standard participant positioning. Eight muscle groups were examined (per each side) in both upper and lower extremities. Negative change from baseline=decreased muscle strength. The analyses was based on observed data. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 52 | -4.94 kilogram (kg) | Standard Deviation 8.015 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 148 | -3.02 kilogram (kg) | Standard Deviation 5.066 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 148 | 0.95 kilogram (kg) | Standard Deviation 5.242 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 52 | -4.03 kilogram (kg) | Standard Deviation 5.663 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 148 | -2.48 kilogram (kg) | Standard Deviation 5.075 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 104 | -1.32 kilogram (kg) | Standard Deviation 6.289 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 52 | -0.96 kilogram (kg) | Standard Deviation 1.45 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 148 | 0.49 kilogram (kg) | Standard Deviation 3.407 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 148 | -2.48 kilogram (kg) | Standard Deviation 7.339 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 52 | -3.82 kilogram (kg) | Standard Deviation 5.892 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 104 | -0.63 kilogram (kg) | Standard Deviation 1.266 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 104 | -0.76 kilogram (kg) | Standard Deviation 4.086 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 52 | -3.89 kilogram (kg) | Standard Deviation 6.747 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 148 | 0.09 kilogram (kg) | Standard Deviation 5.096 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 148 | -0.41 kilogram (kg) | Standard Deviation 1.604 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 52 | -0.86 kilogram (kg) | Standard Deviation 1.381 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 148 | -0.43 kilogram (kg) | Standard Deviation 1.496 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 104 | -0.38 kilogram (kg) | Standard Deviation 1.057 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 52 | -1.15 kilogram (kg) | Standard Deviation 1.486 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 148 | -0.23 kilogram (kg) | Standard Deviation 1.545 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 104 | -1.26 kilogram (kg) | Standard Deviation 7.361 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 52 | -0.98 kilogram (kg) | Standard Deviation 1.425 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 104 | -0.69 kilogram (kg) | Standard Deviation 1.089 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 104 | -0.31 kilogram (kg) | Standard Deviation 0.947 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 52 | -3.42 kilogram (kg) | Standard Deviation 6.671 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 148 | -0.86 kilogram (kg) | Standard Deviation 1.861 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 148 | -1.10 kilogram (kg) | Standard Deviation 2.324 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 52 | -0.78 kilogram (kg) | Standard Deviation 1.21 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 148 | 0.65 kilogram (kg) | Standard Deviation 4.56 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 104 | -0.54 kilogram (kg) | Standard Deviation 1.059 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 52 | -2.82 kilogram (kg) | Standard Deviation 7.56 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 148 | -0.69 kilogram (kg) | Standard Deviation 1.009 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 104 | -2.41 kilogram (kg) | Standard Deviation 6.545 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 52 | -4.90 kilogram (kg) | Standard Deviation 5.964 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 104 | -5.47 kilogram (kg) | Standard Deviation 3.59 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 104 | -2.16 kilogram (kg) | Standard Deviation 9.453 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 52 | -3.66 kilogram (kg) | Standard Deviation 4.775 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 148 | -0.19 kilogram (kg) | Standard Deviation 7.407 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 148 | -5.43 kilogram (kg) | Standard Deviation 5.303 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 52 | -5.68 kilogram (kg) | Standard Deviation 8.907 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 104 | 0.17 kilogram (kg) | Standard Deviation 5.714 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 104 | -5.86 kilogram (kg) | Standard Deviation 3.501 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 52 | -4.74 kilogram (kg) | Standard Deviation 5.494 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 148 | -6.74 kilogram (kg) | Standard Deviation 7.308 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 52 | -0.66 kilogram (kg) | Standard Deviation 1.208 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 104 | -0.86 kilogram (kg) | Standard Deviation 5.279 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 104 | -0.47 kilogram (kg) | Standard Deviation 1.226 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 104 | -2.72 kilogram (kg) | Standard Deviation 4.638 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 104 | -1.65 kilogram (kg) | Standard Deviation 6.267 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 148 | -0.66 kilogram (kg) | Standard Deviation 2.394 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 52 | 1.80 kilogram (kg) | Standard Deviation 10.744 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 104 | -1.54 kilogram (kg) | Standard Deviation 13.222 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Knee Extension: Week 148 | -2.01 kilogram (kg) | Standard Deviation 9.711 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 52 | -0.51 kilogram (kg) | Standard Deviation 8.484 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 104 | -4.16 kilogram (kg) | Standard Deviation 14.329 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Shoulder Flexion: Week 148 | -4.12 kilogram (kg) | Standard Deviation 8.543 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 52 | -0.24 kilogram (kg) | Standard Deviation 8.031 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 104 | -3.12 kilogram (kg) | Standard Deviation 13.334 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Elbow Flexion: Week 148 | -3.33 kilogram (kg) | Standard Deviation 8.753 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 52 | -0.41 kilogram (kg) | Standard Deviation 7.17 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 104 | -1.74 kilogram (kg) | Standard Deviation 8.517 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Wrist Extension: Week 148 | -2.49 kilogram (kg) | Standard Deviation 6.086 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 52 | -0.93 kilogram (kg) | Standard Deviation 4.448 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 104 | -0.62 kilogram (kg) | Standard Deviation 2.279 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Index Finger (First Dorsal Interosseous): Week 148 | -1.28 kilogram (kg) | Standard Deviation 4.913 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 52 | -0.70 kilogram (kg) | Standard Deviation 2.497 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 104 | -0.19 kilogram (kg) | Standard Deviation 2.382 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction Thumb (Abductor Pollicus Brevis): Week 148 | -0.78 kilogram (kg) | Standard Deviation 3.049 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 52 | 0.72 kilogram (kg) | Standard Deviation 7.701 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 104 | -4.20 kilogram (kg) | Standard Deviation 11.516 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Ankle Dorsiflexion: Week 148 | -2.33 kilogram (kg) | Standard Deviation 9.533 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 52 | -0.96 kilogram (kg) | Standard Deviation 5.728 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 104 | -2.81 kilogram (kg) | Standard Deviation 9.304 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Shoulder Flexion: Week 148 | -3.18 kilogram (kg) | Standard Deviation 8.139 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 52 | -1.20 kilogram (kg) | Standard Deviation 7.015 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 104 | -3.04 kilogram (kg) | Standard Deviation 9.717 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Elbow Flexion: Week 148 | -3.28 kilogram (kg) | Standard Deviation 8.704 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 52 | -0.63 kilogram (kg) | Standard Deviation 4.87 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 104 | -0.50 kilogram (kg) | Standard Deviation 1.999 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Wrist Extension: Week 148 | -1.89 kilogram (kg) | Standard Deviation 5.033 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 52 | -0.36 kilogram (kg) | Standard Deviation 1.405 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 104 | -0.45 kilogram (kg) | Standard Deviation 1.569 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Index Finger (First Dorsal Interosseous): Week 148 | -0.46 kilogram (kg) | Standard Deviation 1.193 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 52 | -1.24 kilogram (kg) | Standard Deviation 4.595 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 104 | -0.24 kilogram (kg) | Standard Deviation 2.016 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction Thumb (Abductor Pollicus Brevis): Week 148 | -1.10 kilogram (kg) | Standard Deviation 5.247 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 52 | -1.12 kilogram (kg) | Standard Deviation 5.112 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 104 | -0.21 kilogram (kg) | Standard Deviation 1.639 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Abduction 5th Digit (Abductor Digiti Minimi): Week 148 | -1.36 kilogram (kg) | Standard Deviation 5.634 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 52 | 1.05 kilogram (kg) | Standard Deviation 8.973 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 104 | -3.09 kilogram (kg) | Standard Deviation 13.046 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Knee Extension: Week 148 | -1.60 kilogram (kg) | Standard Deviation 7.685 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 52 | -1.05 kilogram (kg) | Standard Deviation 5.923 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 104 | -3.78 kilogram (kg) | Standard Deviation 13.008 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Left Abduction 5th Digit (Abductor Digiti Minimi): Week 52 | -0.49 kilogram (kg) | Standard Deviation 2.296 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Individual Muscle Strength Assessed by HHD | Right Ankle Dorsiflexion: Week 148 | -3.40 kilogram (kg) | Standard Deviation 8.172 |
Secondary
233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC)
Vital capacity was measured by means of an SVC test, administered in the upright position. Upright SVC was determined by performing 3 to 5 measures, in accordance with criteria established by the American Thoracic Society and the European Respiratory Society. The percent predicted SVC was calculated as \[observed SVC divided by predicted SVC\]\*100%. The predicted SVC was adjusted by sex, age, height, which was programmed into and performed by the equipment used. Negative change from baseline indicated worsening of respiratory capacity. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 52 | -18.7 percentage of predicted volume | Standard Error 3.7 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 104 | -23.7 percentage of predicted volume | Standard Error 5.9 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 148 | -18.1 percentage of predicted volume | Standard Error 5.74 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 52 | -10.6 percentage of predicted volume | Standard Error 2.99 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 104 | -14.4 percentage of predicted volume | Standard Error 4.46 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) | Week 148 | -13.8 percentage of predicted volume | Standard Error 4.07 |
Comparison: Week 52 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.95% CI: [0.3, 15.9]
Comparison: Week 104 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.096395% CI: [-1.7, 20.4]ANCOVA
Comparison: Week 148 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline percent predicted SVC and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.438895% CI: [-6.6, 15.2]ANCOVA
Secondary
233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score
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). The ALSFRS-R total score was calculated as the sum of the 4 functional domain scores, ranging from 0 to 48, where higher scores representing better function. Negative change from baseline indicates disease progression. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 52 | -9.5 score on a scale | Standard Error 1.46 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 104 | -13.1 score on a scale | Standard Error 2.12 |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 148 | -13.5 score on a scale | Standard Error 2.28 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 52 | -5.9 score on a scale | Standard Error 1.16 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 104 | -9.4 score on a scale | Standard Error 1.69 |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Change From Baseline in Total Amyotropic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) Score | Week 148 | -9.9 score on a scale | Standard Error 1.77 |
Comparison: Week 52 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.95% CI: [0.5, 6.7]
Comparison: Week 104 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.105495% CI: [-0.8, 8.2]ANCOVA
Comparison: Week 148 - The analysis was based on an ANCOVA model that included treatment as a fixed effect and adjusted for the following covariates: baseline plasma NfL, baseline ALSFRS-R total score, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, baseline NfL, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.143295% CI: [-1.2, 8.4]ANCOVA
Secondary
233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline
This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on the data collected from both 233AS101 and 233AS102 studies. This is reported as a part of the final integrated analyses. Baseline is defined as the Day 1 of 233AS101 Part C. Data has been reported for Weeks 52, 104 and 148 from the 233AS101 Part C baseline.
Time frame: Baseline, Weeks 52, 104 and 148
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study. Number analyzed 'n' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Group | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 52 | 0.62 ratio |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 104 | 0.41 ratio |
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 148 | 0.36 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 52 | 0.50 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 104 | 0.33 ratio |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Neurofilament Light Chain (NfL) Plasma Concentration Ratio to Baseline | Week 148 | 0.33 ratio |
Comparison: Week 52 - The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.95% CI: [0.63, 1.03]
Comparison: Week 104 - The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.230695% CI: [0.6, 1.13]ANCOVA
Comparison: Week 148 - The analysis was based on an ANCOVA model with natural log transformed data. The model included covariates for the corresponding baseline value i.e. log value, and use of riluzole or edaravone. Multiple imputation including treatment group, use of riluzole or edaravone, and the relevant baseline and postbaseline values for the endpoint was used for missing data.p-value: =0.67395% CI: [0.61, 1.38]ANCOVA
Secondary
233AS101 and 233AS102 ISE: Time to Death
Time to death was defined as the time from first dose received in 233AS101 to death. Participants who do not meet the endpoint definition were censored at the participant's last known alive date. Only events that were adjudicated by the EAC are included. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to death was summarized using the Kaplan-Meier product limit method.
Time frame: From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Time to Death | NA weeks |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Time to Death | NA weeks |
p-value: =0.310895% CI: [0.199, 1.357]Log Rank
Secondary
233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation
Permanent ventilation was defined as ≥ 22 hours of mechanical ventilation \[invasive or noninvasive\] per day for ≥ 21 consecutive days. An event of permanent ventilation was based on an adjudicated event (i.e., adjudicated by the Endpoint Adjudication Committee (EAC) as having met the permanent ventilation criteria defined in the protocol). Time to death or permanent ventilation was defined as the time to the earliest occurrence of death or permanent ventilation. The start date for calculating time to death or permanent ventilation in days was date of first dose. Participants without an event were censored at the last known alive dates. This outcome measure was not a standalone analysis for 233AS102. Analysis was performed on data collected from both 233AS101 & 233AS102 studies. This is reported as a part of final integrated analyses. Time to permanent ventilation or death was summarized using the Kaplan-Meier product limit method.
Time frame: From the baseline of the study 233AS101 up to the end of the follow-up period of the current study (up to Week 364)
Population: Integrated analysis was performed on overall ITT population which included all Part C participants of 233AS101 and participants who rolled over from 233AS101 Part C into 233AS102. 'Overall number of participants analyzed' exceeds the total number of participants who started study 233AS102 as it indicates participants who were randomized in the Part C 233AS101 study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 233AS101: Part C (Prior Placebo) | 233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation | NA weeks |
| 233AS101: Part C (Prior BIIB067 100 mg) | 233AS101 and 233AS102 ISE: Time to Death or Permanent Ventilation | NA weeks |
p-value: =0.420295% CI: [0.282, 1.461]Log Rank
Secondary
Concentration of BIIB067 in Cerebrospinal Fluid (CSF)
Time frame: Week 4
Population: As planned, concentration of BIIB067 in CSF was summarized for 233AS101 Part C participants only. PK population included all participants who received at least 1 dose of study treatment \& had at least 1 post-dosing PK concentration measurement in current study. 'Overall number of participants analyzed' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | Concentration of BIIB067 in Cerebrospinal Fluid (CSF) | 19.35 ng/mL | Standard Error 2.829 |
| 233AS101: Part C (Prior BIIB067 100 mg) | Concentration of BIIB067 in Cerebrospinal Fluid (CSF) | 9.18 ng/mL | Standard Error 0.711 |
Secondary
Plasma Concentration of BIIB067
Time frame: Week 4
Population: As planned, plasma concentration of BIIB067 was summarized for 233AS101 Part C participants only. Pharmacokinetic (PK) population included all participants who received at least 1 dose of study treatment \& had at least 1 post-dosing PK concentration measurement in current study. 'Overall number of participants analyzed' indicates the number of participants evaluable for this outcome measure at specified time point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 233AS101: Part C (Prior Placebo) | Plasma Concentration of BIIB067 | 1.22 nanograms per milliliter (ng/mL) | Standard Error 0.118 |
| 233AS101: Part C (Prior BIIB067 100 mg) | Plasma Concentration of BIIB067 | 2.05 nanograms per milliliter (ng/mL) | Standard Error 0.516 |