Amyotrophic Lateral Sclerosis (ALS) motor neurone disease
Conditions
Interventions
SAR443060 (RIPK1 kinase inhibitor)
Sponsors
Sanofi-aventis
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Double-blinded part: 6) Diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria (Ludolph et al. 2015;) 7) Less than 3 years since symptom onset 8) Forced vital capacity (FVC) >50% predicted measured within 30 days of screening 9) If subject is taking approved ALS treatments (riluzole and/or edaravone), doses must be stable for >=2 months prior to screening and subject is expected to stay on a stable regimen throughout the study. 11) Subjects must be able to swallow the study capsules. Open Label Extension: 1) Successful completion of both periods of the double-blind, crossover part of this study within 12 months of anticipated first dose of OLE 2) Body weight of at least 45 kg 6) Stable prescription medications including riluzole and/or edaravone for >= 1 month. New prescription medications or changes to existing medications during this trial period are allowed with investigator discretion. 7) Subjects must either be able to swallow the study capsules (thickening agents to assist in swallowing are permitted) or have a G-tube in place and are able to administer study drug through G-tube either independently or with help via a caregiver.
Exclusion criteria
Exclusion criteria: Double-blinded part: 1) Unstable or poorly controlled comorbid disease process of any organ system currently requiring active treatment or likely to require treatment adjustment during the study, as assessed by the investigator or Sponsor 2) History of a clinically significant non-ALS neurologic disorder (other than frontal temporal lobe dementia), including, but not limited to, muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson*s disease, Lewy body dementia, vascular dementia, Huntington*s disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection or abscess 3) History of head trauma resulting in loss of consciousness or clinically significant concussion within 1 year before screening, or any head trauma that resulted in permanent neurologic deficit 4) Clinical laboratory test values outside the normal range at screening, unless assessed by the investigator and CRO medical monitor as clinically acceptable or as specified in other exclusion criteria below 21) Use of or intention to use any prohibited prescription or over-the-counter (OTC) medication (including vitamin/mineral supplements and herbal medicines such as St. John*s Wort) that is a moderate to strong CYP3A inducer or inhibitor within 7 days or 5 half-lives (whichever is longer) of the first dose administration or anticipated use through the follow-up visit. Note: other medications are permitted if subject is on a stable regimen for at least 30 days before first dose administration. Nonsystemic medications (e.g., topical medications unlikely to achieve meaningful plasma exposure), subcutaneous lidocaine, paracetamol, and caffeine for treatment of post-LP headache, and medications needed to treat AEs and medical emergencies are permitted. Other medication may also be permitted if jointly agreed to by both investigator and Sponsor. 22) Use of anticoagulation, daily aspirin >100 mg, or anti-platelet medications within 5 half-lives before the first administration of study drug or anticipated need for these medications through the final follow-up visit. Note: the use of OTC nonsteroidal anti-inflammatory drugs (NSAIDs) at doses specified in the OTC drug label for less than 3 consecutive days is permitted. 23) History of bleeding disorders included but not limited to thrombocytopenia (defined as platelets 14 days prior to start of OLE, presence of clinical laboratory test values outside the normal range at OLE screening, significant physical examination abnormalities, or persistent AEs from the double-blind part of the study, unless assessed by the investigator as clinically acceptable 3) New diagnosis of a clinically significant non-ALS neurologic disorder (other than frontal temporal lobe dementia), including, but not limited to: muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson*s disease, Lewy body demen
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and tolerability: AEs, clinical laboratory evaluations (hematology, clinical chemistry, urinalysis), 12 lead ECGs, vital sign measurements, and physical examinations. Responses obtained from the Columbia-Suicide Severity Rating Scale (C-SSRS) will also be used to derive a category for suicidality according to the Columbia Classification of Suicide Assessment (C-CASA). | — |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetics: Blood and CSF will be collected for the analysis of plasma and CSF concentrations of SAR443060. The following endpoints may be determined for SAR443060 in plasma following each treatment. They will be derived by noncompartmental analysis of the plasma concentration-time data: • Cmax • AUC from time zero to 12 hours (AUC0-12h), AUC from time zero to the last measured concentration above the limit of quantification (AUC0-last), and/or AUC from time zero extrapolated to infinity (AUC0-*), as appropriate • Tmax • Terminal disposition rate constant (*z) with the respective t1/2 • Other parameters, including oral volume of distribution and oral clearance, may be determined as appropriate. • CSF-to-plasma ratios on Days 29 and 71 These parameters may also be determined for metabolites if appropriate. Pharmacodynamics: PD of SAR443060 is measured by RIPK1 pS166 in PBMCs from blood. Exploratory biomarker assays for cytokines, lipids, and metabolomics may be explored in PBMCs, plasma, urine, and CSF. Exploratory Clinical: • Clinical changes in the ALSFRS-R | — |
Countries
Netherlands
Outcome results
None listed