A Study of Orelabrutinib in Patients With Primary Progressive Multiple Sclerosis

• Orelabrutinib (Drug): Orally
• Placebo (Drug): Orally

Primary outcomes

• Time to onset of composite confirmed disability progression (cCDP) , confirmed over at least 12 weeks (12-week cCDP) [Up to approximately 120 weeks]: * Expanded disability status scale (EDSS) score increase ≥ 1.0 point from baseline when the baseline score is ≤ 5.0, or ≥ 0.5 points from baseline when the baseline score is > 5.0, OR * ≥ 20% increase in the Timed 25-Foot Walk Test (T25FWT), OR * ≥ 20% increase in the 9-hole Peg Test (9HPT)

Secondary outcomes

• Time to onset of composite confirmed disability progression (cCDP) , confirmed over at least 24 weeks (24-week cCDP) [Up to approximately 120 weeks]
• Time to onset of confirmed disability progression (CDP) , confirmed over at least 24 weeks (24-week CDP) [Up to approximately 120 weeks]: Expanded disability status scale (EDSS) score increase ≥ 1.0 point from baseline when the baseline score is ≤ 5.0, or ≥ 0.5 points from baseline when the baseline score is > 5.0.
• MRI T2 lesion [Up to approximately 120 weeks]: The total number of new/enlarging T2 lesions on MRI scans of the brain from baseline to Week 120
• 12-week CDP [Up to approximately 120 weeks]: Time to onset of CDP, confirmed over at least 12 weeks
• Time to onset of CDP defined as ≥ 20% increase on 9-hole Peg Test (9HPT) from baseline, confirmed over at least 12 weeks (12-week CDP-9HPT) [Up to approximately 120 weeks]
• Time to onset of CDP defined as ≥ 20% increase on Timed 25-Foot Walk Test (T25FWT) from baseline, confirmed over at least 12 weeks (12-week CDP-T25FWT) [Up to approximately 120 weeks]
• 24-week cCDI [Up to approximately 120 weeks]: Time to onset of composite confirmed disability improvement (cCDI) events, confirmed over at least 24 weeks
• 24-week CDI-9HPT [Up to approximately 120 weeks]: Time to onset of CDI on 9HPT defined as ≥ 20% decrease on the 9HPT score from baseline, confirmed over at least 24 weeks
• 24-week CDI [Up to approximately 120 weeks]: Time to onset of CDI on EDSS confirmed over at least 24 weeks
• 24-week CDI-T25FWT [Up to approximately 120 weeks]: Time to onset of CDI on T25FWT defined as ≥ 20% decrease on the T25FWT score from baseline, confirmed over at least 24 weeks
• SDMT [Up to approximately 120 weeks]: The change in cognitive function as assessed by Symbol Digit Modalities Test (SDMT)
• AEs [Up to approximately 120 weeks]: Safety as assessed by the nature, severity, and incidence of adverse events (AEs) (graded according to National Cancer Institute-Common Terminology Criteria for AEs, NCI-CTCAE version 5.0); vital signs; electrocardiograms (ECGs); and clinical laboratory safety parameter

Sex: All, ages: 18 Years to 60 Years

Inclusion Criteria:

* 18 to 60 years of age, inclusive
* Diagnosed with Primary Progressive MS (PPMS) according to 2017 McDonald criteria
* Participant must have documented evidence of disability progression observed during the 24 months before screening.
* Expanded disability status scale (EDSS) score between 3.0 to 6.5 points, inclusive, at Screening.

Exclusion Criteria:

* Diagnosed with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS)
* Immunologic disorder other than MS or any other conditions requiring oral, intravenous (IV), intramuscular, or intra-articular corticosteroid therapy.
* History or current diagnosis of other neurological disorders that may mimic MS
* History of any other significant active medical condition
* History of suicidal behavior within 6 months prior to Screening
* Any prior history of malignancy if no recurrence within 5 years
* Patients on anticoagulation, or antiplatelet therapy will be excluded
* Patients took strong/moderate CYP3A inhibitors or strong/moderate CYP3A inducerswithin 14 days
* Clinically significant laboratory abnormalities at Screening.
* Any allergy, contraindication, or inability to tolerate orelabrutinib or any of the excipients in the study intervention
* Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
* History of alcohol abuse or alcohol use disorder or other drug abuse within 12 months prior to screening.