Clinical trial NCT05237284: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2022-02-14
Enrollment: 305
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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 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.

Primary outcomes:
measure: 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
measure: Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52
timeFrame: Week 52
Secondary outcomes:
measure: Part A: Combined Assessment of the Function and Survival Score at Week 24
timeFrame: Week 24
measure: Combined Assessment of the Function and Survival Score at Weeks 76 and 104
timeFrame: Weeks 76 and 104
measure: 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
measure: 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
measure: 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
measure: 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
measure: Part A: Change From Baseline to Week 24 in Muscle Strength
timeFrame: Baseline (Day 1, pre-dose) and Week 24
measure: 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
measure: 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
measure: 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)
measure: 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
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: UC San Diego Health Site Number : 8400022
state: California
city: Los Angeles
country: United States
facility: USC Site Number : 8400008
state: California
city: Orange
country: United States
facility: University of California Irvine Site Number : 8400012
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center Site Number : 8400015
state: California
city: Aurora
country: United States
facility: University of Colorado Site Number : 8400025
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center Site Number : 8400020
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Site Number : 8400029
state: Florida
city: Winter Park
country: United States
facility: AdventHealth Medical Group - Neurology at Winter Park Site Number : 8400006
state: Florida
city: Chicago
country: United States
facility: Northwestern Medical Group, Department of Neurology Site Number : 8400003
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University Site Number : 8400028
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Site Number : 8400001
state: Massachusetts
city: New York
country: United States
facility: Mount Sinai - Union Square Site Number : 8400002
state: New York
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center Site Number : 8400004
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Site Number : 8400021
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University Hospital Site Number : 8400014
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah Site Number : 8400009
state: Utah
city: Milwaukee
country: United States
facility: Froedtert Hospital & Medical College of Wisconsin Site Number : 8400010
state: Wisconsin
city: Leuven
country: Belgium
facility: Investigational Site Number : 0560001
city: Edmonton
country: Canada
facility: Investigational Site Number : 1240004
state: Alberta
city: Hamilton
country: Canada
facility: Investigational Site Number : 1240007
state: Ontario
city: London
country: Canada
facility: Investigational Site Number : 1240006
state: Ontario
city: Toronto
country: Canada
facility: Investigational Site Number : 1240008
state: Ontario
city: Montreal
country: Canada
facility: Investigational Site Number : 1240002
state: Quebec
city: Quebec
country: Canada
facility: Investigational Site Number : 1240001
city: Beijing
country: China
facility: Investigational Site Number : 1560001
city: Chengdu
country: China
facility: Investigational Site Number : 1560003
city: Guangzhou
country: China
facility: Investigational Site Number : 1560005
city: Hangzhou
country: China
facility: Investigational Site Number : 1560002
city: Wuhan
country: China
facility: Investigational Site Number : 1560004
city: Xi'An
country: China
facility: Investigational Site Number : 1560006
city: Caen
country: France
facility: Investigational Site Number : 2500007
city: Lille
country: France
facility: Investigational Site Number : 2500006
city: Marseille
country: France
facility: Investigational Site Number : 2500002
city: Montpellier
country: France
facility: Investigational Site Number : 2500003
city: Tours
country: France
facility: Investigational Site Number : 2500004
city: Vandoeuvre-les-nancy
country: France
facility: Investigational Site Number : 2500005
city: Berlin
country: Germany
facility: Investigational Site Number : 2760004
city: Dresden
country: Germany
facility: Investigational Site Number : 2760003
city: Haag In OB
country: Germany
facility: Investigational Site Number : 2760008
city: Hannover
country: Germany
facility: Investigational Site Number : 2760005
city: Lübeck
country: Germany
facility: Investigational Site Number : 2760002
city: Ulm
country: Germany
facility: Investigational Site Number : 2760001
city: Würzburg
country: Germany
facility: Investigational Site Number : 2760009
city: Milano
country: Italy
facility: Investigational Site Number : 3800001
city: Milano
country: Italy
facility: Investigational Site Number : 3800004
city: Torino
country: Italy
facility: Investigational Site Number : 3800002
city: Nagoya-shi
country: Japan
facility: Investigational Site Number : 3920003
state: Aichi
city: Ichikawa-shi
country: Japan
facility: Investigational Site Number : 3920004
state: Chiba
city: Tokushima-shi
country: Japan
facility: Investigational Site Number : 3920006
state: Tokushima
city: Fuchu-shi
country: Japan
facility: Investigational Site Number : 3920005
state: Tokyo
city: Ota-ku
country: Japan
facility: Investigational Site Number : 3920001
state: Tokyo
city: Koshi-shi
country: Japan
facility: Investigational Site Number : 3920002
city: Utrecht
country: Netherlands
facility: Investigational Site Number : 5280001
city: Krakow
country: Poland
facility: Investigational Site Number : 6160001
city: Ksawerow
country: Poland
facility: Investigational Site Number : 6160002
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240005
state: Barcelona [Barcelona]
city: Hospitalet de Llobregat
country: Spain
facility: Investigational Site Number : 7240002
state: Barcelona [Barcelona]
city: Madrid
country: Spain
facility: Investigational Site Number : 7240003
city: Valencia
country: Spain
facility: Investigational Site Number : 7240001
city: Stockholm
country: Sweden
facility: Investigational Site Number : 7520002
city: Umea
country: Sweden
facility: Investigational Site Number : 7520001
city: Plymouth
country: United Kingdom
facility: Investigational Site Number : 8260002
state: Devon
city: Stoke-on-Trent
country: United Kingdom
facility: Investigational Site Number : 8260003
state: Staffordshire
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References: