Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS)
- 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.
- Acronym
- HIMALAYA
- Short title
- Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS)
- Official title
- A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of SAR443820 in Adult Participants With Amyotrophic Lateral Sclerosis, Followed by an Open-label Extension
- Control arm
- Placebo
- Registry reports results
- Listing at source
- Listed
- Recruitment status
- Terminated
- Phase
- Phase 2
- Study type
- Interventional
- Reason stopped
- The study was terminated as its Part A did not meet the primary endpoint.
- Completion date
- 2024-03-07
- First posted
- 2022-02-14
- Registry last updated
- 2025-03-21
- Primary completion date
- 2024-03-07
- Start date
- 2022-04-13
- Actual participants
- Participants
- Participant count basis
- Actual
- Protocol amendments
- Randomisation ratio
- Number of sites
- Data monitoring committee
- Registry sponsor category
- Industry
- Lead sponsor
- Sanofi
- Source registry
- ClinicalTrials.gov
- Registry ID
- NCT05237284
- ClinicalTrials.gov ID
- NCT05237284
- Registry record
- Open registry record
- Allocation
- Randomised
- Model
- Parallel groups
- Purpose
- Treatment
- Masking
- Triple masking
- Masked roles
- Participants, Investigators, Outcome assessors
Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
Timeframe: 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
Timeframe: 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.
Part A: Combined Assessment of the Function and Survival Score at Week 24
Timeframe: 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.
Combined Assessment of the Function and Survival Score at Weeks 76 and 104
Timeframe: 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.
Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
Timeframe: 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)
Timeframe: 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)
Timeframe: 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)
Timeframe: 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: Change From Baseline to Week 24 in Muscle Strength
Timeframe: 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.
Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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.
- Sex
- All
- Age groups
- Adults, Older adults
- Minimum age
- 18 Years
- Maximum age
- 80 Years
- Healthy volunteers
- No
- 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.
- 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.
- UC San Diego Health Site Number : 8400022La Jolla, United States
- USC Site Number : 8400008Los Angeles, United States
- University of California Irvine Site Number : 8400012Orange, United States
- California Pacific Medical Center Site Number : 8400015San Francisco, United States
- University of Colorado Site Number : 8400025Aurora, United States
- Georgetown University Medical Center Site Number : 8400020Washington D.C., United States
- Mayo Clinic Site Number : 8400029Jacksonville, United States
- AdventHealth Medical Group - Neurology at Winter Park Site Number : 8400006Winter Park, United States
- Northwestern Medical Group, Department of Neurology Site Number : 8400003Chicago, United States
- Johns Hopkins University Site Number : 8400028Baltimore, United States
- Massachusetts General Hospital Site Number : 8400001Boston, United States
- Mount Sinai - Union Square Site Number : 8400002New York, United States
- Penn State Milton S. Hershey Medical Center Site Number : 8400004Hershey, United States
- University of Pennsylvania Site Number : 8400021Philadelphia, United States
- Thomas Jefferson University Hospital Site Number : 8400014Philadelphia, United States
- University of Utah Site Number : 8400009Salt Lake City, United States
- Froedtert Hospital & Medical College of Wisconsin Site Number : 8400010Milwaukee, United States
- Investigational Site Number : 0560001Leuven, Belgium
- Investigational Site Number : 1240004Edmonton, Canada
- Investigational Site Number : 1240007Hamilton, Canada
- Investigational Site Number : 1240006London, Canada
- Investigational Site Number : 1240008Toronto, Canada
- Investigational Site Number : 1240002Montreal, Canada
- Investigational Site Number : 1240001Québec, Canada
- Investigational Site Number : 1560001Beijing, China
And 38 more, listed on the interactive page.
- PubMed 38010108Related publication
- Related resource (www.sanofistudies.com)
- 2023
- 2023-509442-36-00
- U1111-1263-5766
- 2021-004156-42
Related records
Drugs (1)
Lead sponsors (1)
Conditions (1)
- Amyotrophic lateral sclerosis Primary condition