Primary, Part A: - To assess the effect of SAR443820 compared to placebo in reducing ALS progression as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R)Primary, Part B: - To assess the long-term effects of…
ID
Source
Brief title
Condition
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part A: Change from baseline in the ALSFRS-R total score from screening to Week
24
Part B: Combined assessment of the function and survival (CAFS) score at Week
52
Secondary outcome
Part A:
- Combined assessment of the function and survival (CAFS) score at Week 24
- Change from baseline in slow vital capacity (SVC) to Week 24
- Muscle strength measured by handheld dynamometry (HHD) over 24 weeks
- Change from baseline in Amyotrophic Lateral Sclerosis Assessment
Questionnaire (ALSAQ-5) to Week 24
- Change from baseline in serum neurofilament light chain (NfL) to Week 24
- Incidence of adverse events (AE), serious adverse events (SAE),
treatment-emergent adverse events (TEAE), potentially clinically significant
abnormalities (PCSA) in laboratory tests, electrocardiogram (ECG), and vital
signs over 24 weeks
- Plasma concentration of SAR443820
Part B:
- Combined assessment of the function and survival (CAFS) score at Week 76 and
Week 104
- Change from baseline in the ALSFRS-R total score to Week 52, Week 76, and
Week 104
- Time from baseline to the occurrence of either death or permanent assisted
ventilation (>22 hours daily for >7 consecutive days), whichever comes first,
before Week 52, Week 76, and Week 104
- Time from baseline to the occurrence of death before Week 52, Week 76, and
Week 104
- Change from baseline in slow vital capacity (SVC) to Week 52, Week 76, and
Week 104
- Change from baseline in Amyotrophic Lateral Sclerosis Assessment
Questionnaire (ALSAQ-5) to Week 52, Week 76, and Week 104
- Change from baseline in serum neurofilament light chain (NfL) to Week 52
- Incidence of adverse events (AE), serious adverse events (SAE),
treatment-emergent adverse events (TEAE), potentially clinically significant
abnormalities (PCSA) in laboratory tests, electrocardiogram (ECG), and vital
signs during Part B
- Plasma concentration of SAR443820
Background summary
ALS is a fatal neurodegenerative disorder characterized by progressive loss of
motor neurons in the cortex, brain stem, and spinal cord. Relentless and
progressive muscle atrophy and weakness are hallmarks of ALS. Most patients
with ALS die from respiratory failure within 3 to 5 years after disease onset.
The 2 Food and Drug Administration (FDA)-approved ALS treatments demonstrate
only a moderate effect either on survival (riluzole) or functional decline
(edaravone). There is a significant unmet medical need for treating individuals
with ALS. SAR443820 has demonstrated strong RIPK1 inhibition with high potency
in vitro in various cell types.
Study objective
Primary, Part A:
- To assess the effect of SAR443820 compared to placebo in reducing ALS
progression as measured by the Amyotrophic Lateral Sclerosis Functional Rating
Scale Revised (ALSFRS-R)
Primary, Part B:
- To assess the long-term effects of SAR443820 on function and survival
Secondary, both Part A and Part B (long-term):
- To assess the effect of SAR443820 compared to placebo on a combined
assessment of function and survival, respiratory function, muscle strength, and
quality of life (QoL)
- To assess the pharmacodynamic (PD) effect of SAR443820 compared to placebo on
a key disease biomarker
- To assess the safety and tolerability of SAR443820 compared to placebo
- To assess the pharmacokinetics (PK) of SAR443820
Study design
Phase 2, randomized, double-blind, placebo-controlled study followed by an
open-label extension period.
Intervention
Participants will be randomized in a 2:1 ratio to the SAR443820 treatment arm
or matching placebo arm as listed below:
• Treatment arm: SAR443820, 20 mg, BID
• Placebo arm: Placebo, BID
Study burden and risks
Risks related to blood sampling and side effects of the study drug.
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Paasheuvelweg 25
Amsterdam 1105 BP
NL
Listed location countries
Age
Inclusion criteria
• Male or female, 18-80 years of age (inclusive)
• 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.
• 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
are 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 must have completed at
least 1 cycle of treatment before the screening visit and are expected to
continue edaravone treatment throughout the duration of the study.
• Weight : Participants with a body weight no less than 45 kg and body mass
index no less than 18 kg/m2.
• Female participants with childbearing potential are eligible to participate
if they are not pregnant or breastfeeding and agree to use adequate
contraceptive method during study intervention period and for at least 32 days
after the last dose of study drug.
• Male participants must 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 must 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 is allowed).
• Having central IV lines, such as a peripherally inserted central catheter
(PICC) or midline or port-a-cath lines.
• With significant cognitive impairment, psychiatric disease, other
neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse, 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 (C-SSRS), 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 are pregnant or are currently breastfeeding.
• A known history of allergy to any ingredients of SAR443820.
Prior/concomitant therapy :
• Currently or previously treated with any strong or moderate CYP3A4 inhibitors
or strong CYP3A4 inducers listed in Appendix 10 of the protocol 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 have received treatment with another investigational drug
within 4 weeks or 5 half-lives of the investigational agent before the
screening visit, whichever is longer.
• Participants who have 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 has documented Gilbert syndrome
(isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 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])
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-004156-4-NL |
| CCMO | NL79644.041.21 |
| Other | U1111-1263-5766 |