Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus

Efficacy and Safety of Sirolimus in Patients With Active Systemic Lupus Erythematosus Despite Standard of Care: a Multi-center, Double Blinded, Randomized, Placebo-controlled, Phase 3 Trial

This is a multi-center, double-blinded, randomized, placebo-controlled, phase 3 study to evaluate the efficacy and safety of sirolimus administered in addition to standard therapy, in patients with active SLE disease.

This study is a multi-center, double-blinded, randomized, placebo-controlled, phase 3 clinical trial to assess the efficacy and safety of sirolimus in patients with active systemic lupus erythematosus despite receiving standard background therapy.

Six large rheumatological referring centers across from China will participate in the study.

The study is divided into two phases. The first phase is a 24-week randomized, double-blinded, placebo-controlled trial, from which the primary end point will be generated, and the second phase is a 24-week open-labeled extension trial.

The study enrolls SLE patients between 18~65 years old who have SLEDAI-2K score ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia), despite conventional treatment (e.g., immunosuppressants, antimalarial drugs, glucocorticoids, NSAIDs, anti-hypertensive drugs, and/or topical medications). In addition, subjects must be serologically active (positive anti-dsDNA antibody and/or hypocomplementemia).

Subjects will be randomly assigned by 1:1 ratio to receive sirolimus (1.5mg/day) or placebo for the first 24-week phase. In the second 24-week open-labeled phase, sirolimus patients receive the same dose of sirolimus, and placebo group are switched to receive sirolimus at 1.5mg/day

Inclusion Criteria:

• Age between 18~65 years;
• Fulfilling the 2012 SLICC criteria for SLE; time from SLE diagnosis ≥ 3 months;
• Active disease as defined by a SLEDAI-2K score of ≥4 (not including scores for anti-dsDNA antibody and hypocomplementemia) at screening;
• Serologically active defining as positive anti-dsDNA antibody (>10IU/ml) or hypocomplementemia (C3<0.90g/L)
• Before the first dose of sirolimus, a stable regimen of oral corticoids (0-20 mg/day, prednisone or equivalent) ≥4 weeks; doses of antimalarials, or immunosuppressive agents (mycophenolate mofetil [MMF]/mycophenolic acid [MPA] ≤1.5g/day, or MTX ≤15mg/week) are required to be stable for at least 12 weeks prior to first dose). In addition, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, NSAIDs or other analgesics should be stable for at least 2 weeks.

Exclusion Criteria:

• Concomitant connective tissue disease or inflammatory disease that might confound efficacy assessments, e.g., systemic sclerosis, rheumatoid arthritis, dermatomyositis/polymyositis, etc;
• Neuropsychiatric SLE;
• Severe active lupus nephritis (urinary protein ≥3.5g/24h or urine protein/creatine ration> 3500mg/g or eGFR < 60ml/1.73m2/min);
• Pregnant or breast-feeding women;
• Previous treatment with sirolimus or allergic to sirolimus;
• Intravenous CTX within 6 months of enrollment;
• Intravenous immunoglobulin or prednisone dose >100mg/day within 3 months;
• Calcineurin inhibitors (e.g., tacrolimus or cyclosporin A) within 1 month;
• Traditional Chinese Herb (such as Tripterygium wilfordii Hook F) within 1 month;
• Concurrent active or uncontrolled infection (such as tuberculosis and hepatitis) requiring antibiotics or antivirus;
• WBC count <3×10^9/L;
• Abnormal biochemical indices including: alanine transaminase (ALT) or aspartate aminotransferase (AST) >1.5 times upper limit of laboratory reference range; total bilirubin or blood lipid (including total cholesterol, triglycerides, and low-density lipoprotein) >2 times upper limit of laboratory reference range;
• Any condition that may require multiple courses of systemic corticosteroids (e.g., uncontrolled asthma, COPD);
• Major surgery within the past month;
• Suffering from malignant tumors or a history of malignant tumors within 5 years before screening, or a history of lymphoproliferative diseases: Patients with previously treated cutaneous squamous cell carcinoma and basal cell carcinoma without evidence of recurrence are allowed to enroll; and Patients with cervical cancer in situ who have documented formal surgical cure are allowed to enroll;
• Previous stem cell transplantation (including hematopoietic stem cell transplantation and mesenchymal stem cell transplantation);
• Have a history of splenectomy;
• Subjects has certain conditions that may lead to dropping out of the study in advance or that may bring risk to subjects themselves if they participate in the study. This is judged by experienced clinicians.