Evaluate the Efficacy and Safety of Orelabrutinib in Adult Patients With Systemic Lupus Erythematosus

Study Overview
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Brief Summary
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This is a phase IIb, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of orelabrutinib in adult subjects with SLE who are receiving standard of care (SOC) therapy.

Official Title
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A Phase IIb, Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Orelabrutinib in Adult Patients With Systemic Lupus Erythematosus

Conditions
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Systemic Lupus Erythematosus, SLE

Intervention / Treatment
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* Drug: Orelabrutinib (Low Dose)
* Drug: Orelabrutinib (High Dose)
* Drug: Orelabrutinib Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: have had a detailed understanding of the nature, significance, potential benefits, potential risks, and procedures of the study, and voluntarily signed a written Informed Consent Form (ICF). Males or females aged≥18 and ≤75 years. Have a clinical diagnosis of SLE 6 months prior to signing the ICF, meeting at least 4 of the 11 American College of Rheumatology (ACR) classification criteria for SLE. SLEDAI-2K≥8 at screening. Are on a stable SLE SOC therapy consisting of any of the following medications for a period of at least 30 days prior to the first dose: glucocorticoid, and/or anti-malarials, and/or immunosuppressive agents. Have a positive test for anti-dsDNA antibody (> normal range) and/or anti-nuclear antibody (ANA) and/or anti-Smith antibody at screening. Women of childbearing potential must take a complementary barrier method of contraception in combination with a highly effective method of contraception at screening, throughout the trial, and within 90 days after the last dose of the investigational agent. In this trial. Exclusion Criteria: Medical conditions: Pregnant or lactating women, and men or women who have birth plans in the past 12 months. Have neuropsychiatric systemic lupus erythematosus (NPSLE) within 6 months prior to the first dose, including seizures, psychosis, organic brain syndrome, cerebrovascular accident, cranial neuropathy, cerebritis, cerebral vasculitis or lupus headache. Have severe lupus nephritis, or have required hemodialysis or high-dose glucocorticoid within 90 days prior to the first dose. Have autoimmune diseases other than SLE (excluding secondary Sjogren's syndrome). Have a history of any non-SLE disease that has required treatment with oral or intravenous or intramuscular or subcutaneous injection glucocorticoids for more than a total of 2 weeks within the last 24 weeks prior to signing the ICF. Have a history of or current diagnosis of Central Nervous System (CNS) diseases. Have clinically documented cardiovascular diseases that are obviously unstable or not effectively treated. Have significant active lung diseases (e.g., interstitial lung disease, obstructive pulmonary disease). Have severe hepatobiliary diseases. Have a history of malignant neoplasm. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant. Have known allergies to any component of the investigational agent as described in the Protocol. Concomitant medication and surgery: Have received rituximab, epratuzumab, or any other B cell-depleting therapy within 12 months prior to randomization. Have received cyclophosphamide and chlorambucil within 6 months prior to randomization. Have received belimumab, tumor necrosis factor (TNF) blockers, interleukin receptor blockers or other biological agents within 3 months prior to randomization (or 5 half-lives, whichever is longer). Lab tests: Have a positive test for human immunodeficiency virus (HIV) antibody. Have a positive test for Hepatitis B Surface Antigen (HBsAg) or hepatitis C antibody, or have a positive test for hepatitis B virus (HBV) DNA by Polymerase Chain Reaction (PCR) if positive for Hepatitis B Core Antibody (HBcAb). Have abnormal tissue or organ function, meeting any of the following at screening: Absolute neutrophil count (ANC) < 1.5 × 10^9/L; hemoglobin < 90 g/L; lymphocyte count < 0.8 × 10^9 /L. Calculated estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation < 45 mL/min/1.73 m2. Others: Have other conditions that are not appropriate for participation in the trial as considered by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Orelabrutinib Lower Dose<br> | Drug: Orelabrutinib (Low Dose)<br>* Subjects will be administered with lower dose of Orelabrutinib orally once daily in combination with SOC therapy<br>|
| Experimental: Orelabrutinib Higher Dose<br> | Drug: Orelabrutinib (High Dose)<br>* Subjects will be administered with higher dose of Orelabrutinib orally once daily in combination with SOC therapy<br>|
| Placebo Comparator: Placebo<br> | Drug: Orelabrutinib Placebo<br>* Subjects will be administered with Orelabrutinib Placebo orally once daily in combination with SOC therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SLE Responder Index (SRI) - 4 response rate | SRI-4 response is defined as: 1)≥4 point reduction from baseline in SLE disease activity index-2000 (SLEDAI-2K) score; 2) no worsening (increase of <0.3 points from baseline) in Physician's Global Assessment (PGA); 3) no new A organ domain score or no more than 1 new B organ domain scores compared with baseline in British Isles Lupus Assessment Group (BILAG)-2004. | Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SLE Responder Index (SRI) - 6 response rate | SRI-6 response is defined as: 1)≥6 point reduction from baseline in SLE disease activity index-2000 (SLEDAI-2K) score; 2) no worsening (increase of <0.3 points from baseline) in Physician's Global Assessment (PGA); 3) no new A organ domain score or no more than 1 new B organ domain scores compared with baseline in British Isles Lupus Assessment Group (BILAG)-2004. | Week 48 | 
| British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate | BICLA response is defined as: 1) In BILAG-2004, reduction of all baseline A to B/C/D and baseline B to C/D, and no worsening in other organ systems (as defined by no new A organ domain score or no more than 1 new B organ domain scores); 2) No worsening from baseline in SLEDAI-2K, where worsening is defined as an increase from baseline of >0 points in SLEDAI-2K; 3) No worsening (increase of <0.3 points from baseline) in PGA. | Week 48 | 
| Time to 1st flare |  | Week 48 | 
| The proportion of subjects whose average prednisone dose has been reduced by≥25% from baseline to ≤7.5 mg/day |  | Week 48 | 
| Changes from baseline in the levels of complement C3, complement C4, and anti-dsDNA antibody | Adopt the unified unit standard of central laboratory testing | Week 48 | 
| Treatment Emergent Adverse Events, Treatment Related Adverse Events, Treatment Emergent Serious Adverse Events, Treatment Related Serious Adverse Events. |  | Up to Week 52 | 
| Mean change from baseline in the 36-Item Short Form Health Survey (SF-36) scores (The SF-36 consists of eight domains. Each domain score ranges from 0-100. The higher the score, the better the health. ) |  | Week 48 |