Amyotrophic Lateral Sclerosis
Conditions
Brief summary
This was a parallel treatment, Phase 2, randomized, double-blind study to assess the efficacy, safety, tolerability, PK, and PD of twice daily (BID) oral SAR443820 compared with placebo in male and female participants, 18 to 80 years of age with ALS followed by an open-label, long-term extension period. Study ACT16970 consisted of 2 parts (A and B) as follows: Part A was a 24-week, double blind, placebo-controlled part, preceded by a screening period of up to 4 weeks before Day 1. On Day 1 of Part A, participants were randomized in a 2:1 ratio to the SAR443820 treatment arm or matching placebo arm as listed below: * Treatment arm: SAR443820, BID * Placebo arm: Placebo, BID Randomization was stratified by the geographic region of the study site, region of ALS onset (bulbar vs other areas), use of riluzole (yes vs no), use of edaravone (yes vs no) and use of the combination of sodium phenylbutyrate and taurursodiol (named Relyvrio in the United States of America \[USA\] and Albrioza in Canada) (yes vs no). Participants attended in-clinic study assessments at baseline (Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 21, Week 22, Week 23, and Week 24. All ongoing participants at Week 24 rolled to open-label extension Part B. The Week 24 Visit was the end of Part A and the beginning of Part B. Part B was an open-label, long-term extension period that starts from Week 24 and continues up to Week 106. The objectives of Part B were to provide extended access to SAR443820 participants in Part A and to further evaluate the safety and efficacy of long-term SAR443820 treatment. The treatment assignment of participants at randomization in Part A remained blinded to Investigators, participants, and site personnel until the end of Part B. Every participant, except those who discontinued Investigational Medicinal Product (IMP) treatment permanently in Part A, received BID oral tablets of SAR443820 in Part B.
Detailed description
The study duration included an up to 4-week screening period, 24-week double-blind treatment period in Part A, 80-week open-label treatment period in Part B and 2-week post-treatment follow-up period, with a maximum total study duration of 110 weeks.
Interventions
DRUGSAR443820
Tablet oral
DRUGPlacebo
Tablet
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of possible, clinically probable ALS, clinically probable laboratory supported ALS, or clinically definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria * Time since onset of first symptom of ALS ≤2 years. * Slow Vital Capacity (SVC) ≥60% of the predicted value. * Had to be able to swallow the study tablets at the screening visit. * Either not currently receiving riluzole or on a stable dose of riluzole for at least 4 weeks before the screening visit. Participants receiving riluzole were expected to remain on the same dose throughout the duration of the study. * Either not currently receiving edaravone or on the approved standard schedule of edaravone treatment. Participants receiving edaravone had to have completed at least 1 cycle of treatment before the screening visit and were expected to continue edaravone treatment throughout the duration of the study. * Either not currently receiving the combination of sodium phenylbutyrate and taurursodiol or on the approved standard schedule of the combination of sodium phenylbutyrate and taurursodiol treatment for at least 4 weeks before the screening visit. Participants receiving the combination of sodium phenylbutyrate and taurursodiol were expected to remain on the approved standard schedule throughout the duration of the study. * Participants with a body weight no less than 45 kg and body mass index no less than 18 kg/m2 at the screening visit * Female participants with childbearing potential were eligible to participate if they were not pregnant or breastfeeding and agreed to use adequate contraceptive method during study intervention period and for at least 32 days after the last dose of study drug. * Male participants had to agree to use highly effective contraceptive method during the study period and for at least 92 days following their last dose of the study drug. Male participants were not donate sperms for the duration of study and 92 days after last dose of study drug.
Exclusion criteria
* A history of seizure (History of febrile seizure during childhood was allowed). * Having central IV lines, such as a peripherally inserted central catheter (PICC XE ' PICC ' \\f Abbreviation \\t 'peripherally inserted central catheter' ) or midline or portacath lines. * With significant cognitive impairment, psychiatric disease, other neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse other causes of neuromuscular weakness, or any other condition that would make the participants unsuitable for participating in the study or could interfere with assessment or completing the study in the opinion of the Investigator. * History of recent serious infection (eg, pneumonia, septicemia) within 4 weeks of the screening visit; infection requiring hospitalization or treatment with IV antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infection (such as tuberculosis) deemed unacceptable as per the Investigator's judgment. * With active herpes zoster infection within 2 months prior to the screening visit. * A documented history of attempted suicide within 6 months prior to the screening visit, present with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) , or in the Investigator's judgment are at risk for a suicide attempt. * History of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than ALS precluding their safe participation in this study. * Participants who were pregnant or were currently breastfeeding. * A known history of allergy to any ingredients of SAR443820. * Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers within the specified washout period before the screening visit. * Received a live vaccine within 14 days before the screening visit. * Participants with concurrent participation in any other interventional clinical study or who had received treatment with another investigational drug (eg sodium phenylbutyrate or taurursodiol ) within 4 weeks or 5 halflives of the investigational agent before the screening visit, whichever is longer. * Participants who had received stem cell or gene therapy for ALS at any time in the past. * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3.0 × upper limit of normal (ULN) * Bilirubin \>1.5 × ULN unless the participant had documented Gilbert syndrome (isolated bilirubin \>1.5 × ULN was acceptable if bilirubin was fractionated and direct bilirubin is \<35%) * Serum albumin \<3.5 g/dL * Estimated glomerular filtration rate \<60 mL/min/1.73 m2 (Modification of Diet in Renal Disease \[MDRD\]) The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Baseline (Day 1, pre-dose) and Week 24 | The ALSFRS-R is an instrument to evaluate the functional status of participants with ALS. It consists of 12 items across 4 sub-domains of bodily function: bulbar, fine motor, gross motor, and breathing. Each item was scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function). The total scores was the sum of the individual items score and it ranges from 0 to 48, with a higher score indicating better function. The analysis was performed using mixed-effect model with repeated measures (MMRM). Baseline was defined as the Day 1 pre-dose value. |
| Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52 | Week 52 | The CAFS at Week 52 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Week 52. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (modified ITT\[mITT\] population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Baseline (Day 1, pre-dose) and Weeks 52, 76 and 104 | The ALSFRS-R is an instrument to evaluate the functional status of participants with ALS. It consists of 12 items across 4 sub-domains of bodily function: bulbar, fine motor, gross motor, and breathing. Each item was scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function). The total scores was the sum of the individual items score and it ranges from 0 to 48, with a higher score indicating better function. Baseline was defined as the Day 1 pre-dose value. |
| Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104 | The ALSAQ-5 is a patient-reported outcome that consists of 5 items derived from the ALSAQ-40. The 5 items closely resemble those of the 5-dimension scores of the ALSAQ-40: eating and drinking; communication; activities of daily living/independence; physical mobility; and emotional functioning. Each item was scored on a 5-point Likert scale ranging from 0 (never) to 4 (always or cannot do at all) according to the frequency of a particular problem. The total scores was the sum of the individual items score and it ranges from 0 to 20, with higher scores indicative of greater physical and emotional limitations. Baseline was defined as the Day 1 pre-dose value. |
| Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104 | SVC is the maximum volume of air that can be slowly exhaled after slow, maximal inhalation. SVC is measured in participants while they are in an upright position at least 3 trials per assessment or up to 5 trials when the highest and second highest of the first 3 measurements differ by 10% or more. Baseline was defined as the Day 1 pre-dose value. |
| Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) | Baseline (Day 1, pre-dose) and Part A: Week 24 and Part B: Week 52 | Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal injury. Baseline was defined as the Day 1 pre-dose value. |
| Part A: Combined Assessment of the Function and Survival Score at Week 24 | Week 24 | The CAFS at Week 24 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Week 24. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (mITT population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome. |
| Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation | Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks | The survival endpoint was defined as the time to death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days), whichever comes first. Baseline was defined as the Day 1 pre-dose value. |
| Part B: Time From Baseline to the Occurrence of Death | Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks | Time to the occurrence of death from baseline due to any reason has been reported. Baseline was defined as the Day 1 pre-dose value. |
| Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | From first dose of SAR443820 up to 14 days after last dose of SAR443820 administration in Part B, approximately 82 weeks for Parts A+B combined Arm (SAR443820/SAR443820), approximately 58 weeks for Part B Arm (Placebo/SAR443820) | An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as the AEs that developed, worsened or became serious during the treatment-emergent period (defined as time from first administration of study treatment (Day 1) to last administration of study treatment + 14 days). Serious adverse events (SAE): Any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. All TEAE occurring after SAR443820 initiation are provided for both randomized treatment arms in this endpoint. |
| Parts A and B: Plasma Concentration of SAR443820 | Part A: Day 1: 0.25- 1 hour and 1-3 hours post-dose; Weeks 2 and 8: pre-dose; Week 8: 0.25-3 hours post-dose; Part B: Week 28: pre-dose | Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820. |
| Part A: Change From Baseline to Week 24 in Muscle Strength | Baseline (Day 1, pre-dose) and Week 24 | The muscles measured in the study included upper limb and lower-limb muscle groups. Bilateral hand grip were measured using a grip dynamometer and all other muscles were measured using a handheld dynamometer (HHD). Nine upper and lower extremity muscles or muscle groups were examined: shoulder flexion, elbow flexion, wrist extension, first dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each group was measured at least twice bilaterally and the average of the 2 highest measurements were analyzed. Individual muscles are standardized into the corresponding Z-scores using data from standard sample of healthy participants. A Z-score of 0 in a muscle measurement is equal to the mean of that measurement from the standard sample. Negative numbers indicate decreased muscle strength. For analysis, individual Z-scores were averaged to produce a total megascore including all available muscle groups. Baseline was defined as the Day 1 pre-dose value. |
| Combined Assessment of the Function and Survival Score at Weeks 76 and 104 | Weeks 76 and 104 | The CAFS at Weeks 76 and 106 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Weeks 76 and 104. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (mITT population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome. |
Countries
Belgium, Canada, China, France, Germany, Italy, Japan, Netherlands, Poland, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This study is double-blind followed by an open-label extension, 2 parts: Part (A and B) conducted at 63 investigational sites in 13 countries. A total of 397 participants were screened between 13 Apr 2022 and 17 July 2023, of which 92 were screen failures. Screen failures were due to not meeting the eligibility criteria.
Pre-assignment details
The study consisted of a screening period (up to 4 weeks prior to randomization), treatment period (a 24-week double-blinded in Part A, an 80-week open-label in Part B), and a 2-week post-treatment follow up period, with a maximum total study duration of 110 weeks. The study was terminated as Part A did not meet the primary endpoint.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A. | 102 |
| Part A: SAR443820 Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A. | 203 |
| Total | 305 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A (Double-blind Period: 24 Weeks) | Adverse Event | 6 | 20 | 0 | 0 |
| Part A (Double-blind Period: 24 Weeks) | Other | 0 | 2 | 0 | 0 |
| Part A (Double-blind Period: 24 Weeks) | Poor compliance to protocol | 0 | 1 | 0 | 0 |
| Part A (Double-blind Period: 24 Weeks) | Withdrawal by Subject | 8 | 13 | 0 | 0 |
| Part B (Open-label Period: 80 Weeks) | Adverse Event | 0 | 0 | 13 | 16 |
| Part B (Open-label Period: 80 Weeks) | Other | 0 | 0 | 0 | 3 |
| Part B (Open-label Period: 80 Weeks) | Poor compliance to protocol | 0 | 0 | 0 | 1 |
| Part B (Open-label Period: 80 Weeks) | Study terminated by sponsor | 0 | 0 | 64 | 126 |
| Part B (Open-label Period: 80 Weeks) | Withdrawal by Subject | 0 | 0 | 11 | 21 |
Baseline characteristics
| Characteristic | Part A: Placebo | Part A: SAR443820 | Total |
|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 11.5 | 57.0 years STANDARD_DEVIATION 11.6 | 56.9 years STANDARD_DEVIATION 11.5 |
| Baseline Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | 36.23 score on a scale STANDARD_DEVIATION 5 | 35.97 score on a scale STANDARD_DEVIATION 4.41 | 36.06 score on a scale STANDARD_DEVIATION 4.61 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 26 Participants | 52 Participants | 78 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 21 Participants | 26 Participants |
| Race (NIH/OMB) White | 69 Participants | 126 Participants | 195 Participants |
| Sex: Female, Male Female | 38 Participants | 84 Participants | 122 Participants |
| Sex: Female, Male Male | 64 Participants | 119 Participants | 183 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 | 5 / 102 | 11 / 202 | 9 / 79 | 12 / 136 |
| other Total, other adverse events | 56 / 102 | 116 / 202 | 29 / 79 | 43 / 136 |
| serious Total, serious adverse events | 17 / 102 | 34 / 202 | 17 / 79 | 26 / 136 |
Outcome results
Primary
Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
The ALSFRS-R is an instrument to evaluate the functional status of participants with ALS. It consists of 12 items across 4 sub-domains of bodily function: bulbar, fine motor, gross motor, and breathing. Each item was scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function). The total scores was the sum of the individual items score and it ranges from 0 to 48, with a higher score indicating better function. The analysis was performed using mixed-effect model with repeated measures (MMRM). Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Week 24
Population: The Intent-to-treat (ITT) population consisted of all randomized participants. Only participants with data collected at Baseline and Week 24 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | -5.9 score on a scale | Standard Deviation 5.9 |
| Part A: SAR443820 | Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | -6.1 score on a scale | Standard Deviation 5.4 |
Comparison: Analysis was performed using MMRM including treatment group, visit, randomization strata of the geographic region, ALS onset region, use of riluzole, use of edaravone, use of the combination of sodium phenylbutyrate and taurursodiol, treatment-by-visit interaction, disease duration, baseline ALSFRS-R score, baseline serum neurofilament light chain (NfL), disease duration-by-visit interaction, baseline NfL-by-visit interaction and baseline ALSFRS-R score-by-visit interaction.p-value: 0.528995% CI: [-1.706, 0.878]MMRM
Primary
Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52
The CAFS at Week 52 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Week 52. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (modified ITT\[mITT\] population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome.
Time frame: Week 52
Population: The mITT population consisted of all randomized participants who either died or had available baseline and at least 1 post-baseline ALSFRS-R assessment. All participants who had either early termination or who did not enter Part B, were also included in Week 52 analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52 | 154.89 score on a scale | Standard Deviation 92.16 |
| Part A: SAR443820 | Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52 | 145.24 score on a scale | Standard Deviation 82.09 |
Comparison: Analysis was performed using rank analysis of covariance (ANCOVA) model including treatment group, randomization strata of the geographic region of the study site, ALS onset region (bulbar or other areas), use of riluzole (yes or no), use of edaravone (yes or no), use of the combination of sodium phenylbutyrate and taurursodiol (yes or no), disease duration (from first symptom onset to the screening visit), baseline ALSFRS-R score and baseline NfL.p-value: 0.183ANCOVA
Secondary
Combined Assessment of the Function and Survival Score at Weeks 76 and 104
The CAFS at Weeks 76 and 106 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Weeks 76 and 104. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (mITT population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome.
Time frame: Weeks 76 and 104
Population: The mITT population consisted of all randomized participants who either died or had available baseline and at least 1 post-baseline ALSFRS-R assessment. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected. All participants who had either early termination or who did not enter Part B, were also included in Week 76 analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Combined Assessment of the Function and Survival Score at Weeks 76 and 104 | Week 76 | 155.54 score on a scale | Standard Deviation 92.17 |
| Part A: SAR443820 | Combined Assessment of the Function and Survival Score at Weeks 76 and 104 | Week 76 | 144.91 score on a scale | Standard Deviation 82.04 |
Secondary
Part A: Change From Baseline to Week 24 in Muscle Strength
The muscles measured in the study included upper limb and lower-limb muscle groups. Bilateral hand grip were measured using a grip dynamometer and all other muscles were measured using a handheld dynamometer (HHD). Nine upper and lower extremity muscles or muscle groups were examined: shoulder flexion, elbow flexion, wrist extension, first dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each group was measured at least twice bilaterally and the average of the 2 highest measurements were analyzed. Individual muscles are standardized into the corresponding Z-scores using data from standard sample of healthy participants. A Z-score of 0 in a muscle measurement is equal to the mean of that measurement from the standard sample. Negative numbers indicate decreased muscle strength. For analysis, individual Z-scores were averaged to produce a total megascore including all available muscle groups. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Week 24
Population: The ITT population consisted of all randomized participants. Only participants with data collected at Baseline and Week 24 are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Change From Baseline to Week 24 in Muscle Strength | -0.498 score on a scale | Standard Deviation 0.96 |
| Part A: SAR443820 | Part A: Change From Baseline to Week 24 in Muscle Strength | -0.495 score on a scale | Standard Deviation 0.704 |
Comparison: Analysis was performed using MMRM including treatment group, visit, randomization strata of the geographic region, ALS onset region, use of riluzole, use of edaravone, use of the combination of sodium phenylbutyrate and taurursodiol, treatment-by-visit interaction, disease duration, baseline megascore, baseline NfL, disease duration-by-visit interaction, baseline NfL-by-visit interaction and baseline megascore-by-visit interaction.p-value: 0.956595% CI: [-0.193, 0.183]MMRM
Secondary
Part A: Combined Assessment of the Function and Survival Score at Week 24
The CAFS at Week 24 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Week 24. ALSFRS-R is a rating scale where 12 functions are 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 by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (mITT population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome.
Time frame: Week 24
Population: The mITT population consisted of all randomized participants who either died or had available baseline and at least 1 post-baseline ALSFRS-R assessment. Only participants with data collected at Week 24 is reported. The study was terminated prematurely since the Part A did not meet the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part A: Combined Assessment of the Function and Survival Score at Week 24 | 151.19 score on a scale | Standard Deviation 90.71 |
| Part A: SAR443820 | Part A: Combined Assessment of the Function and Survival Score at Week 24 | 147.13 score on a scale | Standard Deviation 83.06 |
Comparison: CAFS at Week 24 was analyzed using the Wilcoxon-Mann-Whitney test to compare mean scores between the treatment groups at Week 24.p-value: 0.6999Wilcoxon (Mann-Whitney)
Secondary
Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
The ALSFRS-R is an instrument to evaluate the functional status of participants with ALS. It consists of 12 items across 4 sub-domains of bodily function: bulbar, fine motor, gross motor, and breathing. Each item was scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function). The total scores was the sum of the individual items score and it ranges from 0 to 48, with a higher score indicating better function. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Weeks 52, 76 and 104
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Week 52 | -11.9 score on a scale | Standard Deviation 7.8 |
| Part A: Placebo | Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Week 76 | -12.0 score on a scale | Standard Deviation 10.1 |
| Part A: SAR443820 | Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Week 52 | -12.1 score on a scale | Standard Deviation 8 |
| Part A: SAR443820 | Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score | Week 76 | -13.3 score on a scale | Standard Deviation 9 |
Secondary
Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation
The survival endpoint was defined as the time to death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days), whichever comes first. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation | 31.90 weeks | Standard Deviation 16.71 |
| Part A: SAR443820 | Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation | 31.54 weeks | Standard Deviation 18.82 |
Secondary
Part B: Time From Baseline to the Occurrence of Death
Time to the occurrence of death from baseline due to any reason has been reported. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Time From Baseline to the Occurrence of Death | 38.30 weeks | Standard Deviation 16.45 |
| Part A: SAR443820 | Part B: Time From Baseline to the Occurrence of Death | 29.93 weeks | Standard Deviation 17.13 |
Secondary
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5)
The ALSAQ-5 is a patient-reported outcome that consists of 5 items derived from the ALSAQ-40. The 5 items closely resemble those of the 5-dimension scores of the ALSAQ-40: eating and drinking; communication; activities of daily living/independence; physical mobility; and emotional functioning. Each item was scored on a 5-point Likert scale ranging from 0 (never) to 4 (always or cannot do at all) according to the frequency of a particular problem. The total scores was the sum of the individual items score and it ranges from 0 to 20, with higher scores indicative of greater physical and emotional limitations. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 24 | 2.1 score on a scale | Standard Deviation 3.1 |
| Part A: SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 24 | 2.4 score on a scale | Standard Deviation 3.1 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 52 | 4.1 score on a scale | Standard Deviation 4.2 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 76 | 5.0 score on a scale | Standard Deviation 3.5 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 52 | 4.4 score on a scale | Standard Deviation 3.5 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) | Week 76 | 5.8 score on a scale | Standard Deviation 5.3 |
Comparison: Analysis was performed using MMRM including treatment group, visit, randomization strata of the geographic region, ALS onset region, use of riluzole, use of edaravone, use of the combination of sodium phenylbutyrate and taurursodiol, treatment-by-visit interaction, disease duration, baseline ALSFRS-R score, baseline NfL, disease duration-by-visit interaction, and baseline ALSFRS-R score-by-visit interaction.p-value: 0.218295% CI: [-0.31, 1.35]MMRM
Secondary
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC)
SVC is the maximum volume of air that can be slowly exhaled after slow, maximal inhalation. SVC is measured in participants while they are in an upright position at least 3 trials per assessment or up to 5 trials when the highest and second highest of the first 3 measurements differ by 10% or more. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 24 | -13.43 percentage of predicted volume | Standard Deviation 14.66 |
| Part A: SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 24 | -11.24 percentage of predicted volume | Standard Deviation 13.35 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 76 | -31.30 percentage of predicted volume | Standard Deviation 30.72 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 52 | -22.44 percentage of predicted volume | Standard Deviation 16.35 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 52 | -18.29 percentage of predicted volume | Standard Deviation 15.75 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) | Week 76 | -22.68 percentage of predicted volume | Standard Deviation 15.93 |
Comparison: Analysis was performed using MMRM including treatment group, visit, randomization strata of the geographic region, ALS onset region, use of riluzole, use of edaravone, use of the combination of sodium phenylbutyrate and taurursodiol, treatment-by-visit interaction, disease duration, baseline SVC, baseline NfL, disease duration-by-visit interaction, baseline NfL-by-visit interaction, and baseline SVC-by-visit interaction.p-value: 0.813495% CI: [-3.075, 3.914]MMRM
Secondary
Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL)
Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal injury. Baseline was defined as the Day 1 pre-dose value.
Time frame: Baseline (Day 1, pre-dose) and Part A: Week 24 and Part B: Week 52
Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) | Week 24 | 1.016 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 5853.645 |
| Part A: SAR443820 | Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) | Week 24 | 0.996 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation 6136.969 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) | Week 52 | 0.925 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation -709.957 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) | Week 52 | 0.887 picograms per milliliter (pg/mL) | Geometric Coefficient of Variation -1488.592 |
Comparison: Analysis was performed using MMRM including treatment group, visit, randomization strata of the geographic region, ALS onset region, use of riluzole, use of edaravone, use of the combination of sodium phenylbutyrate and taurursodiol, treatment-by-visit interaction, disease duration, log transformed baseline NfL, disease duration-by-visit interaction, and log transformed baseline NfL-by-visit interaction.p-value: 0.235695% CI: [0.899, 1.027]MMRM
Secondary
Parts A and B: Plasma Concentration of SAR443820
Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820.
Time frame: Part A: Day 1: 0.25- 1 hour and 1-3 hours post-dose; Weeks 2 and 8: pre-dose; Week 8: 0.25-3 hours post-dose; Part B: Week 28: pre-dose
Population: Pharmacokinetic (PK) population consisted of all randomized participants who received at least 1 dose of SAR443820 and had at least 1 PK assessment with adequate documentation of dosing and sampling. It was prespecified (statistical analysis plan) that participants will be analyzed according to actual intervention received. In Part B, all participants received SAR443820, so data were combined. Only participants who received SAR443820 with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Parts A and B: Plasma Concentration of SAR443820 | Day 1: 0.25- 1 hours post-dose | 181.500 nanogram (ng)/mL | Standard Deviation 169.94 |
| Part A: Placebo | Parts A and B: Plasma Concentration of SAR443820 | Day 1: 1-3 hours post-dose | 250.188 nanogram (ng)/mL | Standard Deviation 95.867 |
| Part A: Placebo | Parts A and B: Plasma Concentration of SAR443820 | Week 2: pre-dose | 165.833 nanogram (ng)/mL | Standard Deviation 91.355 |
| Part A: Placebo | Parts A and B: Plasma Concentration of SAR443820 | Week 8: pre-dose | 165.089 nanogram (ng)/mL | Standard Deviation 92.686 |
| Part A: Placebo | Parts A and B: Plasma Concentration of SAR443820 | Week 8: 0.25- 3 hours post-dose | 365.488 nanogram (ng)/mL | Standard Deviation 198.609 |
| Part A: SAR443820 | Parts A and B: Plasma Concentration of SAR443820 | Week 28: pre-dose | 171.865 nanogram (ng)/mL | Standard Deviation 104.304 |
Secondary
Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation
An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as the AEs that developed, worsened or became serious during the treatment-emergent period (defined as time from first administration of study treatment (Day 1) to last administration of study treatment + 14 days). Serious adverse events (SAE): Any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. All TEAE occurring after SAR443820 initiation are provided for both randomized treatment arms in this endpoint.
Time frame: From first dose of SAR443820 up to 14 days after last dose of SAR443820 administration in Part B, approximately 82 weeks for Parts A+B combined Arm (SAR443820/SAR443820), approximately 58 weeks for Part B Arm (Placebo/SAR443820)
Population: The safety population consisted of all randomized participants who received at least 1 dose (including partial dose) of SAR443820. All participants from safety population and treated with SAR443820 are included in Part B arm and participants from safety population are included in Parts A+B arm. The combined safety analysis for TEAE provided the accurate summary of all TEAE in both treatment groups after the initiation of SAR443820.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TEAEs | 51 Participants |
| Part A: Placebo | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TESAEs | 13 Participants |
| Part A: SAR443820 | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TEAEs | 183 Participants |
| Part A: SAR443820 | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TESAEs | 53 Participants |