Amyotrophic Lateral Sclerosis
Conditions
Brief summary
This study will assess the efficacy and safety of PTC857 treatment in participants diagnosed with ALS.
Detailed description
Participants will be randomized to 1 of the 2 treatment groups: PTC857 or matching placebo. Following successful completion of the Treatment Period, participants who enter the LTE Period, will receive open-label PTC857 for 28 weeks. Following completion of the LTE period, participants who enter the Continued LTE Period will receive open-label PTC857 for an additional 108 weeks.
Interventions
DRUGPTC857
PTC8657 will be administered as an oral solution twice a day.
DRUGPlacebo
Matching placebo will be administered as an oral solution twice a day.
Sponsors
PTC Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * ALS with preserved function, defined as: 1. Onset of the first symptom leading to the diagnosis of ALS ≤24 months at the time of the initial Screening Visit 2. Revised EL Escorial criteria of either: (i) Clinically definite ALS (ii) Clinically probable ALS * A total ALSFRS-R score of at least 34 at the start of the Screening Period * No significant respiratory compromise as evidenced by slow vital capacity ≥60% at the start of the Screening Period * All chronic concomitant medications (both prescription and over the counter), and non-pharmacologic therapy regimens, excluding standard-of-care therapy riluzole, edaravone, or sodium phenylbutyrate/taurursodiol, should be stable and unchanged from 14 days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study * Female participants must have a negative breast cancer imaging screening status (not considered clinically abnormal and/or requiring further evaluation/treatment) within 6 months prior to the Screening Visit, or during the Screening Period. * Standard-of-care therapy for the treatment of ALS (riluzole, edaravone, or sodium phenylbutyrate/taurursodiol) should be stable and unchanged from 30 (-3) days prior to the start of the Screening Period and intend to remain stable and unchanged throughout the course of the study. Key
Exclusion criteria
* Females who are pregnant or nursing or plan to become pregnant during the study * Participants with clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular/ischemic disease or any other condition that, in the opinion of the investigator would jeopardize the safety of the participant or impact the validity of the study results * Any clinically significant medical or psychiatric condition or medical history that, in the opinion of the investigator or the medical monitor, would interfere with the participant's ability to participate in the study or increase the risk of participation for that participant * Current participation in any other investigational study with an investigational product or participation within 30 days prior to the start of the Screening Period or 5 half-lives of the previously taken investigational drug, whichever is longer * Participant has previously received PTC857 * Participant is receiving a combination of edaravone and sodium phenylbutyrate/taurursodiol treatment, where applicable, within 30 days prior to the start of the Screening Period * For female participants, any past medical history of breast cancer, regardless of remission status, or any first degree relative with history of breast cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population) | Week 24 | The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 306 (ITT1 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. Multiple imputation was used to impute participants with missing ALSFRS-R score at Week 24. A higher rank was considered a better outcome. Least square (LS) means and standard error (SE) were calculated using analysis of covariance (ANCOVA) model. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population) | Baseline, Week 24 | The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using mixed model repeated measures (MMRM). |
| Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population) | Baseline, Week 24 | The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using MMRM. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 through Week 24 | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that began after the first administration of study drug or any existing AEs that worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. |
| Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24 | Baseline, Week 24 | The SVC is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent of predicted SVC is reported. LS mean and SE were calculated using MMRM. |
| Change From Baseline in Modified Norris Scale Total Score at Week 24 | Baseline, Week 24 | Modified Norris scale is used to assess the motor/limb and bulbar function. The Modified Norris Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris Scale and the Norris Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity function, and the Norris Bulbar Scale has 13 items to evaluate bulbar function. Each item was rated in 4 ordinal categories, corresponding to the following values and ratings or functional scores: normal (3 points), somewhat impaired (2 points), inadequate (1 point), and cannot do at all (0 points). The total score was calculated by summing all the scales, ranging from 0 (worst) to 102 (best) where higher scores indicated better functional abilities. LS mean and SE were calculated using MMRM. |
| Overall Survival Rate | Baseline to Week 24 | Overall survival rate was defined as percentage of participants who were alive at given timepoint. Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die. |
| Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population) | Week 24 | The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 334 (ITT2 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. A higher rank was considered a better outcome. LS mean and SE were calculated using ANCOVA model. |
| Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24 | Baseline, Week 24 | The ALSAQ-40 is a disease-specific measure of health-related quality of life (QOL) for ALS. The ALSAQ-40 is comprised of 40 questions measuring 5 discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of 5 options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score ranging from 0 (no impairment) to 160 (severe impairment) was calculated by adding the 5 domain scores. A lower score indicates a better health state. LS mean and SE were calculated using MMRM. |
| Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24 | Baseline, Week 24 | The NfL is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions. |
| Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma | Day 1 and Day 29 | — |
| Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma | Day 1 and Day 29 | — |
| Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF) | Day 1 and Day 29 | — |
| Overall Survival | Baseline to Week 24 | Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die. |
Countries
Argentina, Australia, Belgium, Czechia, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, United States
Participant flow
Pre-assignment details
The study included Treatment (Part A), long-term extension (LTE) (Part B), and Continued LTE (Part C) periods.
Participants by arm
| Arm | Count |
|---|---|
| Utreloxastat Participants received utreloxastat during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who entered the LTE Period received open-label utreloxastat for 28 weeks. Following completion of the LTE period, participants who entered the Continued LTE Period received open-label utreloxastat for an additional 108 weeks. | 220 |
| Placebo Participants received matching placebo during the 24-Week Treatment Period. Following successful completion of the Treatment Period, participants who entered the LTE Period received open-label utreloxastat for 28 weeks. Following completion of the LTE period, participants who entered the Continued LTE Period received open-label utreloxastat for an additional 108 weeks. | 114 |
| Total | 334 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part A (24 Weeks) | Adverse Event | 9 | 2 |
| Part A (24 Weeks) | Death | 8 | 3 |
| Part A (24 Weeks) | Disease Progression | 1 | 1 |
| Part A (24 Weeks) | Other Than Specified | 5 | 1 |
| Part A (24 Weeks) | Screen Failure | 2 | 0 |
| Part A (24 Weeks) | Withdrawal by Subject | 18 | 7 |
| Part B (28 Weeks) | Adverse Event | 3 | 0 |
| Part B (28 Weeks) | Death | 21 | 11 |
| Part B (28 Weeks) | Disease Progression | 2 | 1 |
| Part B (28 Weeks) | Lost to Follow-up | 2 | 1 |
| Part B (28 Weeks) | Other Than Specified | 4 | 2 |
| Part B (28 Weeks) | Physician Decision | 1 | 0 |
| Part B (28 Weeks) | Study terminated by sponsor | 85 | 53 |
| Part B (28 Weeks) | Withdrawal by Subject | 17 | 5 |
| Part C (108 Weeks) | Death | 0 | 1 |
| Part C (108 Weeks) | Lost to Follow-up | 0 | 1 |
| Part C (108 Weeks) | Study terminated by sponsor | 34 | 23 |
| Part C (108 Weeks) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Utreloxastat | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 10.97 | 57.1 years STANDARD_DEVIATION 9.88 | 57.7 years STANDARD_DEVIATION 10.61 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 19 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 189 Participants | 93 Participants | 282 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Race Asian Descent | 10 Participants | 5 Participants | 15 Participants |
| Race/Ethnicity, Customized Race Black or African Descent | 5 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Other | 22 Participants | 13 Participants | 35 Participants |
| Race/Ethnicity, Customized Race White | 183 Participants | 96 Participants | 279 Participants |
| Sex: Female, Male Female | 77 Participants | 28 Participants | 105 Participants |
| Sex: Female, Male Male | 143 Participants | 86 Participants | 229 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 220 | 3 / 114 | 23 / 173 | 15 / 100 |
| other Total, other adverse events | 167 / 220 | 88 / 114 | 115 / 173 | 53 / 100 |
| serious Total, serious adverse events | 36 / 220 | 11 / 114 | 48 / 173 | 25 / 100 |
Outcome results
Primary
Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population)
The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 306 (ITT1 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. Multiple imputation was used to impute participants with missing ALSFRS-R score at Week 24. A higher rank was considered a better outcome. Least square (LS) means and standard error (SE) were calculated using analysis of covariance (ANCOVA) model.
Time frame: Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population) | 172.22 units on a scale | Standard Error 13.25 |
| Placebo | Combined Assessment of Function (ALS Functional Rating Scale-Revised [ALSFRS-R]) and Survival (CAFS) Rank After 24 Weeks of Treatment (Intention-to-Treat [ITT] 1 Analysis Population) | 165.36 units on a scale | Standard Error 14.65 |
p-value: 0.51695% CI: [-13.86, 27.59]ANCOVA
Secondary
Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma
Time frame: Day 1 and Day 29
Population: Pharmacokinetic (PK) analysis set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and had at least 1 measurable post-baseline plasma or CSF utreloxastat concentration. 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Utreloxastat | Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma | Day 1 | 2670 hours*nanograms (ng)/mL | Standard Deviation 1330 |
| Utreloxastat | Area Under the Concentration-time Curve From 0 to Measurable Timepoint (AUC0-t) of Utreloxastat in Plasma | Day 29 | 4220 hours*nanograms (ng)/mL | Standard Deviation 1110 |
Secondary
Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24
The ALSAQ-40 is a disease-specific measure of health-related quality of life (QOL) for ALS. The ALSAQ-40 is comprised of 40 questions measuring 5 discrete dimensions of health status that are affected by the disease: physical mobility (10 items); activities of daily living and independence (10 items); eating and drinking (3 items); communication (7 items); emotional reactions (10 items). Participants were asked to indicate the frequency of each event by selecting one of 5 options (Likert scale: 0-4): never/rarely/sometimes/often/ always or cannot do at all. The total score ranging from 0 (no impairment) to 160 (severe impairment) was calculated by adding the 5 domain scores. A lower score indicates a better health state. LS mean and SE were calculated using MMRM.
Time frame: Baseline, Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24 | 27.9 units on a scale | Standard Error 3.05 |
| Placebo | Change From Baseline in ALS Assessment Questionnaire (ALSAQ-40) Total Score at Week 24 | 23.9 units on a scale | Standard Error 3.48 |
Secondary
Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population)
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using mixed model repeated measures (MMRM).
Time frame: Baseline, Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population) | 29.4 units on a scale | Standard Error 0.73 |
| Placebo | Change From Baseline in ALSFRS-R Score at Week 24 (ITT1 Analysis Population) | 31.4 units on a scale | Standard Error 0.93 |
Secondary
Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population)
The ALSFRS-R is a quickly administered (5-minute) ordinal rating scale that assesses the participant's capability and independence in 12 functional activities across 4 subdomains of bodily function (bulbar, gross motor, fine motor, and respiratory) relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0 (total loss of function) to 4 (no loss of function), with the total score ranging from 0 to 48 and higher scores indicating less functional impairment. LS mean and SE were calculated using MMRM.
Time frame: Baseline, Week 24
Population: ITT2 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population) | 27.7 units on a scale | Standard Error 0.71 |
| Placebo | Change From Baseline in ALSFRS-R Score at Week 24 (ITT2 Analysis Population) | 29.1 units on a scale | Standard Error 0.88 |
Secondary
Change From Baseline in Modified Norris Scale Total Score at Week 24
Modified Norris scale is used to assess the motor/limb and bulbar function. The Modified Norris Scale is a rating scale for ALS that consists of 2 parts: the Limb Norris Scale and the Norris Bulbar Scale. The Limb Norris Scale has 21 items to evaluate extremity function, and the Norris Bulbar Scale has 13 items to evaluate bulbar function. Each item was rated in 4 ordinal categories, corresponding to the following values and ratings or functional scores: normal (3 points), somewhat impaired (2 points), inadequate (1 point), and cannot do at all (0 points). The total score was calculated by summing all the scales, ranging from 0 (worst) to 102 (best) where higher scores indicated better functional abilities. LS mean and SE were calculated using MMRM.
Time frame: Baseline, Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in Modified Norris Scale Total Score at Week 24 | -18.2 units on a scale | Standard Error 1.57 |
| Placebo | Change From Baseline in Modified Norris Scale Total Score at Week 24 | -18.0 units on a scale | Standard Error 1.82 |
Secondary
Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24
The NfL is a marker of axonal degeneration and is robustly elevated in the blood of many neurological and neurodegenerative conditions.
Time frame: Baseline, Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24 | 69.98 picograms (pg)/milliliter (mL) | Standard Error 6.69 |
| Placebo | Change From Baseline in Neurofilament Light Chain (NfL) Activity at Week 24 | 64.75 picograms (pg)/milliliter (mL) | Standard Error 7.08 |
Secondary
Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24
The SVC is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent of predicted SVC is reported. LS mean and SE were calculated using MMRM.
Time frame: Baseline, Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24 | -14.62 percent predicted SVC | Standard Error 2.106 |
| Placebo | Change From Baseline in Percent Predicted Slow Vital Capacity (SVC) at Week 24 | -15.92 percent predicted SVC | Standard Error 2.518 |
Secondary
Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population)
The CAFS is a composite endpoint based on time to earlier occurrence of death and change from baseline in ALSFRS-R score. ALSFRS-R is a rating scale where 12 functions were rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome in a pairwise fashion by time to death and change on ALSFRS-R, assigned a score which was sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 334 (ITT2 Analysis Set) lowest rank corresponds to participant who died first and highest rank to the participant with best ALSFRS-R outcome among those who survived. A higher rank was considered a better outcome. LS mean and SE were calculated using ANCOVA model.
Time frame: Week 24
Population: ITT2 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Utreloxastat | Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population) | 188.58 units on a scale | Standard Error 14.81 |
| Placebo | Combined Assessment of Function (ALSFRS-R) and Survival (CAFS) Rank After 24 Weeks of Treatment (ITT2 Analysis Population) | 181.89 units on a scale | Standard Error 15.96 |
Secondary
Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma
Time frame: Day 1 and Day 29
Population: PK analysis set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and had at least 1 measurable post-baseline plasma or CSF utreloxastat concentration. 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Utreloxastat | Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma | Day 1 | 796 ng/mL | Standard Deviation 492 |
| Utreloxastat | Maximum Observed Concentration (Cmax) of Utreloxastat in Plasma | Day 29 | 881 ng/mL | Standard Deviation 397 |
Secondary
Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF)
Time frame: Day 1 and Day 29
Population: PK analysis set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and had at least 1 measurable post-baseline plasma or CSF utreloxastat concentration. 'Overall number of participants analyzed' = participants evaluable for this outcome measure. 'Number analyzed' = participants evaluable at specified timepoint.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Utreloxastat | Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF) | Day 1 | NA ng/mL |
| Utreloxastat | Mean Concentration of Utreloxastat in Cerebrospinal Fluid (CSF) | Day 29 | NA ng/mL |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A TEAE was defined as an AE that began after the first administration of study drug or any existing AEs that worsened after the first dose of study drug. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'.
Time frame: Day 1 through Week 24
Population: Safety set included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Utreloxastat | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 174 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 90 Participants |
Secondary
Overall Survival
Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die.
Time frame: Baseline to Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Utreloxastat | Overall Survival | NA months |
| Placebo | Overall Survival | NA months |
Secondary
Overall Survival Rate
Overall survival rate was defined as percentage of participants who were alive at given timepoint. Overall survival was defined as the time in months from the date of first dose to the date of death from any cause or date last known alive for those who did not die.
Time frame: Baseline to Week 24
Population: ITT1 Analysis Set included all randomized participants who received at least 1 dose of double-blind study drug in the Treatment Period and who had a decrease in the ALSFRS-R score of ≤4 points during the Screening Period.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Utreloxastat | Overall Survival Rate | 95.8 percentage of participants |
| Placebo | Overall Survival Rate | 97.9 percentage of participants |