Sirolimus Monotherapy in the Treatment of Antiphospholipid Antibody Related Thrombocytopenia

Sirolimus Monotherapy in the Treatment of Antiphospholipid Antibody Related Thrombocytopenia: a Multicenter Randomized, Double Blind, Placebo Controlled, Clinical Trial

The goal of this clinical trial is to evaluate the efficacy and safety of sirolimus in patients with anti-phospholipid antibody-associated thrombocytopenia.

In the 6-month randomized, double-blind, placebo-controlled phase, participants will receive either sirolimus 1 mg once daily or matching placebo. Participants will be followed at 2 weeks, 1 month, 3 months, and 6 months after enrollment.

Participants who do not achieve the primary endpoint at 6 months may enter a 3-month open-label extension and receive sirolimus 1.5 mg once daily, with follow-up through month 9.

The main question is whether sirolimus improves the overall response rate at 6 months compared with placebo.

Primary outcome:

- Overall response rate at 6 months

Secondary outcomes:

• Overall response rate at 1 month and 3 months
• Complete response rate at 6 months
• Partial response rate at 6 months
• Change in anti-phospholipid antibody titers at 6 months
• Change in oral glucocorticoid dosage at 6 months

Exploratory outcomes:

• Proportion and reasons for early discontinuation during the double-blind phase
• Among participants who do not achieve the primary endpoint at 6 months and enter the open-label extension, overall response rate, complete response rate, partial response rate, and safety outcomes after 3 months of open-label treatment

Complete response: the platelet count is more than or equal to 100×10^9/L Partial response: If the platelet count is less than 100×10^9/L, it should be more than 2 times of the baseline count Overall response: both complete and partial response

Inclusion Criteria:

• persistent positive of antiphospholipid antibody (either lupus anticoagulant, anti-cardiolipin antibody, or anti-b2GP1 antibody, at least two times with 12 weeks apart)
• persistent thrombocytopenia (30-100×10^9/L, at least for 2 weeks)

Eligible concomitant treatment:

• prednisone or equivalent dose less than 10mg per day is allowed, and dose should be stable for more than 2 weeks
• hydroxychloroquine less than 400mg per day is allowed, and dose should be stable for more than 1 month
• anti-platelet and/or anti-coagulant therapy is allowed, and strength should be the stable for 1 week
• these following therapies should be discontinued for more than 5 half-lives before the enrollment, including thrombopoietin or thrombopoietin receptor antagonist, intravenous immunoglobulin, immunosuppressants, B cell inhibitors (Belimumab or Talitacicept) and B cell depletion therapy (Rituximab or Obinutuzumab).

Exclusion Criteria:

• fulling the criteria of other connective tissue disease other than antiphospholipid syndrome
• received oral/intravenous antibiotics within 2 weeks before the enrollment.
• new onset of thrombosis within 4 weeks before the enrollment.
• apparent bleeding tendency.
• life or organ threatening manifestations, includes but not limit to catastrophic antiphospholipid syndrome and thrombotic microangiopathy.
• liver and renal dysfunction: ALT or AST more than three times of upper limit of normal range; eGFR<40mL/min/1.73m^2
• hematocytopenia: WBC<3.0×10^9/L, Hb<100g/L.
• uncontrollable hyperlipidemia: low density lipoprotein cholesterol>3.1 mmol/L, triglycerides>2.3 mmol/L after lipid lowering therapy.
• current active infection
• women in pregnancy and postpartum period