A Study of Rocbrutinib in PRL-Positive Relapsing-Remitting Multiple Sclerosis

Inclusion criteria

• Age 18 to 65 years (inclusive), male or female.
• Diagnosis of relapsing-remitting multiple sclerosis (RRMS) according to the 2017 revised McDonald criteria.
• Disease activity, meeting at least one of the following: (a) at least 2 documented relapses within 2 years, or at least 1 relapse within 1 year prior to signing the ICF; OR (b) at least 1 T1 gadolinium-enhancing (Gd+) lesion confirmed by brain MRI within 180 days prior to signing the ICF.
• Measurable lesions: at least 4 paramagnetic rim lesions (PRL) in the CNS observed by 7T MRI within 4 weeks prior to randomization.
• Concomitant medication: subjects with RRMS may receive stable-dose dimethyl fumarate (DMF); other treatments require discontinuation and washout (see Exclusion Criterion #13).
• EDSS score ≥0 and ≤5.5 at screening and baseline assessments prior to randomization.
• Neurological status stable for at least 30 days prior to randomization.
• Adequate hepatic and renal function: AST and ALT ≤2.0 × ULN; serum total bilirubin ≤1.2 × ULN (≤3.0 × ULN if documented Gilbert's syndrome); serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min (Cockcroft-Gault formula).
• All male subjects and female subjects of childbearing potential must use medically acceptable contraception throughout the treatment period and for 1 week after the last dose; female subjects of childbearing potential must have a negative serum pregnancy test within 7 days before start of treatment and must not be lactating; male subjects must not donate sperm during the study and for 1 week after the last dose.
• Willing and able to provide written informed consent and to comply with the study treatment schedule and visit plan.

Exclusion criteria

• Subjects with a disease duration of RRMS \>10 years and an EDSS score ≤2.
• Neurological or autoimmune diseases other than RRMS that, in the investigator's judgment, may affect efficacy evaluation due to clinical symptoms or concomitant medication.
• Contraindications to MRI or allergy to gadolinium-based contrast agents.
• Currently diagnosed with or suspected of progressive multifocal leukoencephalopathy (PML), or a history of PML.
• History of malignancy within 2 years prior to randomization, except adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, localized squamous cell carcinoma, and malignancies confirmed by the investigator to have been cured by surgery or other treatments.
• History of serious infection or potential risk of serious infection, including: HIV infection; syphilis or tuberculosis infection (except previously infected subjects judged cured by the investigator or specialist); HBsAg- or HBcAb-positive with HBV-DNA above the upper limit of normal of the study site (subjects with HBsAg- or HBcAb-positive but HBV-DNA negative may be enrolled and require anti-HBV therapy during the study); HCV antibody-positive with HCV-RNA above the ULN or qualitatively positive (HCV-RNA-negative subjects may be enrolled).
• Prior organ, allogeneic stem cell or bone marrow transplantation and/or anti-rejection therapy.
• Systemic chronic, recurrent or serious infection within 90 days prior to randomization (e.g., pneumonia, sepsis).
• Uncontrolled active systemic bacterial, fungal or viral infection within 4 weeks prior to randomization.
• Receipt of live attenuated vaccines within 4 weeks prior to randomization, or planned during the study or within 4 weeks after the end of study treatment.
• Prior treatment with BTK inhibitors for malignant or autoimmune indications.
• Any other medical condition or complication that adversely affects participation in the study, including but not limited to: short expected survival due to pre-existing health conditions; inability to undergo primary efficacy endpoint evaluation; severe and/or uncontrolled systemic diseases judged unsuitable for the study by the investigator (including uncontrolled hypertension or diabetes ≥CTCAE Grade 2, unstable angina, congestive heart failure, respiratory diseases requiring continuous oxygen, severe thromboembolism, uncontrolled major bleeding or bleeding from vital organs, known platelet dysfunction, severe hepatic/renal or metabolic diseases such as cirrhosis or renal failure).
• Poor cardiac function: NYHA class ≥2, or LVEF \<50% by echocardiography, or significant abnormalities on screening ECG (atrial fibrillation/flutter, second-degree type II or third-degree atrioventricular block, CTCAE ≥Grade 2 bradycardia, or mean QTcF ≥450 ms on ≥3 independent ECGs).
• History of cerebral infarction or intracranial hemorrhage (except lacunar infarction judged by the investigator as not affecting enrollment).
• History of myocardial infarction within 180 days.
• Receipt of any investigational drug within 3 months or 5 half-lives (whichever is longer) prior to randomization.
• Receipt of the following MS treatments within the specified periods prior to randomization: systemic corticosteroids within 4 weeks; intravenous immunoglobulin or S1P receptor modulators (e.g., fingolimod) within 2 months; azathioprine, mycophenolate mofetil or methotrexate within 3 months; anti-CD20 monoclonal antibodies (e.g., ofatumumab, ocrelizumab, rituximab) within 6 months, or if the last dose was \>6 months before screening but peripheral blood B cells have not recovered to normal levels; teriflunomide within 6 months (washout may be shortened to 1 month if plasma teriflunomide concentration \<0.02 mg/L after rapid clearance); anti-α4-integrin antibody (natalizumab) within 6 months; anti-CD52 antibody (alemtuzumab) within 4 years; prior total lymphoid irradiation, mitoxantrone (with cardiotoxicity or cumulative dose ≥120 mg/m²), or other potent immunosuppressive therapy with long-lasting effects.
• Major surgery (usually defined as Grade III or above per institutional regulations) or serious trauma within 4 weeks prior to randomization.
• Planned long-term use during the study of: strong or moderate CYP3A inhibitors or inducers, OATP1B3 sensitive substrates, or proton pump inhibitors (see Appendices 2 and 3).
• Receipt of anticoagulants or antiplatelet agents within 7 days or 5 half-lives (whichever is longer) prior to randomization.
• Conditions affecting the ability to swallow the drug, or conditions seriously affecting drug absorption or pharmacokinetics (e.g., refractory nausea/vomiting, short bowel syndrome).
• Disease symptoms unfavorable for oral administration of the study drug; unresolved toxicity from prior treatment affecting AE assessment; underlying disease leading to poor compliance; or alcohol/drug abuse or dependence.
• Hypersensitivity to rocbrutinib tablets/dimethyl fumarate capsules or any of their excipients.
• Any other condition judged by the investigator as unsuitable for participation in this study.