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
Overview
- Phase
- Phase 2
- Intervention
- SAR443820
- Conditions
- Amyotrophic Lateral Sclerosis
- Sponsor
- Sanofi
- Enrollment
- 305
- Locations
- 63
- Primary Endpoint
- Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
- Status
- Terminated
- Last Updated
- last year
Overview
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.
Investigators
Eligibility Criteria
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 SAR
- •Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers within the specified washout period before the screening visit.
Arms & Interventions
SAR443820
twice daily (BID) oral SAR443820
Intervention: SAR443820
Placebo
twice daily (BID) oral placebo
Intervention: Placebo
Outcomes
Primary Outcomes
Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score
Time Frame: 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
Time Frame: 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 Outcomes
- 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))
- 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)
- Part A: Combined Assessment of the Function and Survival Score at Week 24(Week 24)
- Combined Assessment of the Function and Survival Score at Weeks 76 and 104(Weeks 76 and 104)
- 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)
- 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)
- 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)
- 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)
- Part A: Change From Baseline to Week 24 in Muscle Strength(Baseline (Day 1, pre-dose) and Week 24)
- 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)
- Part B: Time From Baseline to the Occurrence of Death(Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks)