Randomized, open-label, multicenter study to investigate the efficacy and safety of IVIg plus low-dose recombinant thrombopoietin in pregnant patients with corticosteroid or IVIg monotherapy-resistant ITP.

Primary immune thrombocytopenia (ITP) is a common autoimmune disease characterized by a low platelet count resulting from antibody-mediated platelet destruction and insufficient platelet production. ITP, with a prevalence of 1 in 1000-10 000 pregnancies, accounts for about 3% of all causes of thrombocytopenia in pregnancy and is reported to be the most common cause of thrombocytopenia in the first and early second trimesters. It is revealed that severe ITP is associated with devastating outcomes (e.g., postpartum hemorrhage, placental abruption, significant bleeding complication in both women patients and neonates, and even fetal death). It remains a challenge to manage pregnant patients with ITP. First-line treatment options in pregnant ITP patients include corticosteroids and intravenous immunoglobulin (IVIg) currently. However, previous studies reported that the response rate of pregnant ITP patients to corticosteroids was less than 40% and that to IVIg was 38%-56%, which was lower than that of nonpregnant ITP patients. The second-line treatment options are limited for pregnant ITP patients who have no response to the first-line treatments and no agreement has been reached about the optimum second-line treatment for pregnant ITP patients. In addition, single-agent therapy requires an increased dose of the agent and a long-term exposure, which is associated with an increased risk of treatment-related adverse effects. Therefore, the combination of agents sharing disparate mechanisms in the treatment of ITP might be a promising option to maximize efficacy while minimizing side effects.

Thrombopoietin (TPO) mimetics, including eltrombopag and romiplostim, are recommended to be used in the management of nonpregnant corticosteroid-resistant or relapsed ITP patients. However, they may pass through the placenta to have an influence on the fetus, which hinder their use in the management of pregnant ITP patients. Recombinant human thrombopoietin (rhTPO), a full-length and glycosylated TPO with a molecular weight of 90 000 Daltons developed by 3SBIO (Shenyang, China), has also been approved by the China State Food and Drug Administration as a second-line option for nonpregnant ITP patients. It could not cross the placenta theoretically with such a large molecular weight, and thus it has an apparent theoretical advantage over the two TPO mimetics since it would not impact the fetus. Previous data of a multicenter randomized phase 3 clinical trial on nonpregnant ITP patients resistant to corticosteroids showed that rhTPO increased platelet counts rapidly. A study investigating the application of rhTPO in pregnancy suggested rhTPO was a potentially effective and well-tolerated treatment option for ITP patients during pregnancy. A previous case report described a patient with refractory ITP who failed to response to monotherapy of IVIg and TPO mimetics, but responded rapidly with the combination of IVIg and TPO mimetics. It might be explained that the development of ITP was associated with increased platelet destruction and impaired platelet production, and the combination of IVIg and TPO mimetics directed to these two targets since IVIg could reduce platelet destruction whereas TPO mimetics could increase platelet production. Therefore, we conducted a multicenter, single-arm, open-label study to investigate the efficacy and safety of low dose rhTPO plus IVIg in pregnant corticosteroids/IVIg monotherapy-resistant ITP patients.

Inclusion Criteria:

• Patients have a diagnosis of primary ITP before or first onset during pregnancy; Patients ≥ 18 years; patients complicate with bleeding manifestations and/or have a platelet count < 30 × 10^9/L and failed to respond to initial treatment of corticosteroids or intravenous immunoglobulin (IVIg) monotherapy or relapsed during the tapering or discontinuation of corticosteroids.

Exclusion Criteria:

• Patients whose thrombocytopenia was secondary to cancer (solid tumor or leukemia), infections, preeclampsia, and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), and those who had primary immune deficiency, and other hematology or connective tissue diseases during follow-up; patients have heart, kidney, liver, or lung dysfunction; patients received chemotherapy or anticoagulants within 3 months before screening or other second-line ITP-specific treatments within 3 months before screening.

The study focuses on Pregnancy ITP, the gender of which is female.