Phase 3 Randomized Double‑Blind Study of Orelabrutinib vs Placebo on Disability Progression in Non‑Active Secondary Progressive Multiple Sclerosis

The primary objective is to determine whether oral orelabrutinib 80 mg daily reduces the rate of disability progression compared with placebo in patients with non‑active secondary progressive multiple sclerosis, addressing an unmet need to slow irreversible functional decline. Secondary objectives are to: • assess the effect of orelabrutinib versus placebo on additional efficacy measures including clinical endpoints, MRI lesions, cognitive performance and quality of life; • evaluate the safety profile and tolerability of the investigational product; and • characterize the pharmacokinetic properties of orelabrutinib.

The trial enrolled 604 participants diagnosed with Secondary Progressive Multiple Sclerosis who were in a non‑active disease phase. Eligible individuals were aged 18 to 60 years, inclusive, and comprised both female and male patients. All participants had a documented history of relapsing‑remitting multiple sclerosis meeting the 2024 McDonald criteria, followed by a current diagnosis of SPMS according to the 2013 clinical course criteria, and demonstrated disability progression independent of clinical relapse over the 24 months preceding screening. Additional selection requirements included an Expanded Disability Status Scale score between 3.0 and 6.5, absence of clinical relapses for at least 24 months, and no gadolinium‑enhancing T1 brain lesions on MRI at screening. The population represented patients with moderate disability and no recent inflammatory activity; no specific lifestyle restrictions such as diet or physical activity were stipulated in the inclusion parameters.

The trial is a randomized, double‑blind, placebo‑controlled Phase III study evaluating the efficacy and safety of Orelabrutinib 80 mg oral tablets versus matching placebo in patients with Non‑active Secondary Progressive Multiple Sclerosis. After obtaining informed consent, participants undergo a screening visit to confirm eligibility criteria, including age 18–60 years, prior RRMS diagnosis, current SPMS status, documented disability progression without relapse for ≥24 months, absence of gadolinium‑enhancing lesions, and an EDSS score of 3.0–6.5. Eligible subjects are then randomized and receive study medication at baseline (Day 1). Follow‑up visits are scheduled at regular intervals throughout the study period, during which clinical assessments, MRI scans, and safety evaluations are performed to monitor disease progression and adverse events. The primary endpoint is the time to onset of confirmed disability progression (24‑week CDP), with secondary endpoints including 12‑week CDP and the number of new or enlarging T2 lesions on brain MRI. Participant involvement extends from the screening visit through the end‑of‑study visit, approximately 3.5 years (June 2026 to February 2030). Early termination may occur if a participant withdraws consent, experiences a serious adverse event, fails to meet protocol compliance, becomes pregnant, or is otherwise deemed unsuitable by the investigator.

The investigational product is Orelabrutinib, supplied as a 80 mg oral tablet. Each tablet contains the active substance orelabrutinib and is administered by mouth once daily throughout the treatment period. The tablets are produced in a standard tablet form and are to be taken with water under fasting conditions unless otherwise specified in the protocol.

The comparator is a matching placebo tablet that replicates the appearance, shape, size, and weight of the Orelabrutinib tablet. The placebo tablets contain no active pharmaceutical ingredient and are administered orally once daily using the same dosing schedule as the active arm.

Both study medications are dispensed in blinded containers and participants are instructed to record each dose in a study diary. Compliance is monitored by tablet count at each clinic visit and by review of the completed diaries. Any missed doses are to be documented, and participants are reminded to adhere to the prescribed dosing schedule.

Efficacy will be evaluated using a primary time‑to‑event endpoint defined as time to onset of confirmed disability progression (CDP) events, confirmed over at least 24 weeks. The occurrence of CDP will be determined by the Expanded Disability Status Scale, with the interval from randomization to the first confirmed event recorded for each participant. Analyses will be based on the calculated time intervals for all randomized subjects.

Secondary efficacy assessments include: (1) time to onset of CDP events on EDSS, confirmed over at least 12 weeks, measured in the same manner as the primary endpoint; and (2) the total number of new or enlarging T2 lesions on MRI scans of the brain, quantified by central reading of serial magnetic resonance images. Data collection will follow the protocol‑specified schedule for clinical visits and imaging assessments, and results will be summarized using appropriate descriptive and inferential statistical methods.