Safety, Tolerability, and Pharmacodynamic Exploration of Orelabrutinib in Patients With Amyotrophic Lateral Sclerosis (ALS)

Korábbi kezelés

• Inability to swallow or tolerate oral medication at screening.
• Major surgery within 6 weeks before screening or an anticipated requirement for major surgery during the study.
• A bleeding disorder, an active bleeding episode within the previous 3 months, or current use of anticoagulant or antiplatelet medication.
• Conditions that substantially affect gastrointestinal function, such as chronic diarrhea, intestinal obstruction, or previous gastrectomy.
• Previous exposure to inhibitors of the Bruton's tyrosine kinase (BTK) pathway.
• Use of strong or moderate CYP3A inhibitors or strong or moderate CYP3A inducers that cannot be safely discontinued or replaced before screening.
• Receipt of a live vaccine within the previous 2 weeks or planned receipt of a live vaccine during the study. Inactivated vaccines may be administered according to local recommendations, but vaccination dates and adverse events must be recorded.
• Drug abuse or alcohol abuse.
• Pregnancy or breastfeeding, or being a female of childbearing potential who is unwilling to use contraception during the study and for 180 days after the last dose of study medication.
• Current participation or planned participation in another investigational drug trial.

Más betegség

• Current or previous malignancy.
• Known hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection, or any uncontrolled systemic infection.
• Any history of pulmonary fibrosis, interstitial pneumonitis, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, or severe pulmonary impairment.
• Any other clinically significant medical condition that could pose a risk to the participant, interfere with safety assessments, or increase the risk of death during the study.

Laborértékek

• Any of the following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3 times the upper limit of normal (ULN); estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m²; absolute neutrophil count (ANC) ≤1.5 × 10⁹/L; platelet count ≤100 × 10⁹/L; hemoglobin ≤100 g/L; international normalized ratio (INR) ≥1.5 times ULN; or activated partial thromboplastin time (aPTT) ≥1.5 times ULN.
• Current clinically significant cardiovascular disease, including New York Heart Association (NYHA) class III or IV cardiac disease, such as arrhythmia, congestive heart failure, or myocardial infarction; left ventricular ejection fraction (LVEF) <50%; primary cardiomyopathy; a history of clinically significant QTc prolongation or QTc >470 ms in females or >450 ms in males; or uncontrolled hypertension.

Egyéb

• Tracheostomy or use of noninvasive ventilation (NIV) for ≥22 hours per day.
• Inability to understand the informed consent form (ICF).

• Age 18 to 75 years, inclusive, regardless of sex.
• Diagnosis of amyotrophic lateral sclerosis (ALS), confirmed by a neurologist, meeting either the Gold Coast diagnostic criteria or the revised El Escorial criteria for clinically probable laboratory-supported, clinically probable, or clinically definite ALS.
• No more than 36 months from symptom onset to enrollment.
• Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score ≥35 at screening.
• Forced vital capacity (FVC) ≥70% of predicted and slow vital capacity (SVC) ≥70% of predicted, without dyspnea at rest, orthopnea, or a requirement for long-term noninvasive ventilation or supplemental oxygen.
• Ability to safely swallow the study medication as whole tablets with water at screening and before the first dose. The study medication must not be split, crushed, chewed, or dissolved for administration.
• Concomitant riluzole and/or edaravone is permitted, provided that riluzole has been administered at a stable dose for at least 30 days and/or edaravone treatment has been stable for at least one treatment cycle.
• Assessed as having full capacity to provide informed consent.