Phase 3 Randomized Double-Blind Study of Orelabrutinib for Primary Progressive Multiple Sclerosis in Patients With PPMS

The primary objective is to evaluate the efficacy of orelabrutinib compared with placebo in delaying disability progression in primary progressive multiple sclerosis, which is clinically relevant for assessing whether treatment can slow long-term neurological deterioration. The secondary objectives are to evaluate additional efficacy outcomes, including disability progression, clinical endpoints, magnetic resonance imaging lesions, cognitive performance, and quality of life, as well as to assess the safety and tolerability of orelabrutinib and its pharmacokinetics.

The trial enrolled 307 participants with Primary Progressive Multiple Sclerosis of both sexes, including vulnerable individuals, as a patient population. Eligible participants were 18 to 60 years of age and had a diagnosis of PPMS according to McDonald criteria. The population was selected on the basis of documented disability progression independent of clinical relapse during the 24 months before screening, with an Expanded Disability Status Scale score of 3.0 to 6.5 at screening. No additional information on general health status or lifestyle considerations was provided.

This randomized, double-blind, placebo-controlled Phase 3 study evaluates oral orelabrutinib 80 mg tablets versus matching placebo in participants with primary progressive multiple sclerosis. The main objective is to assess efficacy in delaying disability progression. The trial is planned to run from 29 May 2026 to 2 July 2030. Study participation begins with a screening visit to determine eligibility, including age, diagnosis, documented disability progression, and Expanded Disability Status Scale score criteria. Eligible participants then enter the treatment phase and undergo scheduled follow-up visits for assessment of efficacy and safety outcomes, including confirmation of composite confirmed disability progression over at least 12 weeks. The end-of-study visit is performed at completion of the trial period or after early discontinuation. The expected duration of participant involvement is not specified. Early termination may occur if eligibility criteria are no longer met or if the participant discontinues from the study for any reason.

The investigational treatment was orelabrutinib, administered as an oral tablet at a dose of 80 mg. The study compared orelabrutinib with matching placebo tablets. The placebo tablets were designed to match orelabrutinib tablets in appearance, shape, size, and weight. The trial was randomized and double-blind, and treatment assignment was maintained under blinded conditions throughout the study. Compliance with study medication administration was monitored as part of the trial conduct.

Efficacy will be assessed by composite confirmed disability progression in Primary Progressive Multiple Sclerosis. The primary endpoint is time to onset of 12-week cCDP events, confirmed over at least 12 weeks. cCDP is defined as an increase in Expanded Disability Status Scale score of at least 1.0 point from baseline when the baseline score is 5.0 or less, or at least 0.5 points from baseline when the baseline score is greater than 5.0, or as at least a 20% increase in the Timed 25-Foot Walk Test, or as at least a 20% increase in the 9-Hole Peg Test.