Antiphospholipid (aPL)-Positive, Thrombocytopaenia
Conditions
Keywords
antiphospholipid, thrombocytopaenia, sirolimus, rapamycin, mTOR inhibitor
Brief summary
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
Detailed description
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
Interventions
DRUGSirolimus
Sirolimus 1 mg (two pills) once daily during the 6-month double-blind phase; sirolimus 1.5 mg once daily during the optional 3-month open-label extension for eligible participants.
DRUGPlacebo
Matching placebo two pills once daily during the 6-month double-blind phase; sirolimus 1.5 mg once daily during the optional 3-month open-label extension for eligible participants.
Sponsors
Peking University First Hospital
North China Pharmaceutical Co.,Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants are randomized 1:1 to receive sirolimus 1.0 mg or matching placebo during a 6-month double-blind, parallel-group phase. Participants who do not achieve the primary endpoint at Month 6 may enter a 3-month open-label extension and receive sirolimus 1.5 mg.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants with overall response at Month 6 | Month 6 | Overall response is defined as achieving either complete response or partial response. Complete response is defined as platelet count \>=100 x 10\^9/L. Partial response is defined as platelet count \<100 x 10\^9/L with at least a 2-fold increase from baseline. Participants with missing Month 6 assessment or meeting prespecified treatment failure criteria will be counted as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants with overall response at Month 1 | Month 1 | Overall response is defined as achieving either complete response or partial response. Complete response is defined as platelet count \>=100 x 10\^9/L. Partial response is defined as platelet count \<100 x 10\^9/L with at least a 2-fold increase from baseline. Participants with missing Month 1 assessment or meeting prespecified treatment failure criteria will be counted as non-responders. |
| Percentage of participants with overall response at Month 3 | Month 3 | Overall response is defined as achieving either complete response or partial response. Complete response is defined as platelet count \>=100 x 10\^9/L. Partial response is defined as platelet count \<100 x 10\^9/L with at least a 2-fold increase from baseline. Participants with missing Month 3 assessment or meeting prespecified treatment failure criteria will be counted as non-responders. |
| Percentage of participants with complete response at Month 6 | Month 6 | Complete response is defined as platelet count \>=100 x 10\^9/L. |
| Percentage of participants with partial response at Month 6 | Month 6 | Partial response is defined as platelet count \<100 x 10\^9/L with at least a 2-fold increase from baseline. |
| Change from baseline in Global Antiphospholipid Syndrome Score (GAPSS) at Month 6 | Baseline and Month 6 | GAPSS will be calculated at baseline and Month 6 according to the prespecified scoring algorithm based on antiphospholipid antibody profile and cardiovascular risk factors. The outcome will be reported as the change in GAPSS from baseline to Month 6, calculated as Month 6 GAPSS minus baseline GAPSS. A negative value indicates a decrease in GAPSS. |
| Change from baseline in oral glucocorticoid dose at Month 6 | Baseline and Month 6 | Oral glucocorticoid dose will be converted to prednisone-equivalent dose and summarized as the change from baseline to Month 6. |
Countries
China
Contacts
CONTACTLanlan Ji
Outcome results
None listed