ArticlesEfficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial
Introduction
Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder that is characterised predominantly by antibody-mediated platelet destruction.1, 2, 3, 4, 5, 6 Available therapies—such as corticosteroids, intravenous immunoglobulins, splenectomy, rituximab, and cyclophosphamide—primarily focus on reduction of this platelet destruction.7, 8 However, recent evidence suggests that decreased platelet production might also have a role in ITP.9, 10 For example, kinetic studies have shown that platelet production is not increased (contrary to expectations) in over three-quarters of thrombocytopenic patients with chronic ITP,11, 12 and thrombopoietin concentrations are normal or near normal in patients with this disease.13, 14, 15, 16, 17 Moreover, antiplatelet antibodies inhibit in-vitro growth of megakaryocyte precursor cells,9, 10 and bone marrow megakaryocytes in ITP can be apoptotic.18 Often, therapies aimed at reduction of platelet destruction are either ineffective or poorly tolerated. Therefore, treatments aimed at increasing platelet production, alone or in combination with existing therapies, provide an opportunity to improve outcomes in patients with this chronic disease.
Romiplostim (formerly know as AMG531) is a novel thrombopoiesis stimulating protein (peptibody) that binds to and activates the human thrombopoietin receptor despite having no sequence homology with human thrombopoietin.19, 20 Romiplostim produces a dose-dependent increase in platelet counts in healthy volunteers21 and improves platelet counts during short-term use in patients with chronic ITP.19, 22 In a small, randomised, placebo-controlled trial of weekly injections of romiplostim for 6 weeks (1 or 3 μg/kg) versus placebo, 12 of 16 ITP patients who were given romiplostim with baseline platelet counts of 30×109/L or less (50×109/L or less if on stable doses of corticosteroids) had their platelet counts at least doubled and increased to more than 50×109/L; mean peak platelet counts were 135×109/L and 241×109/L for 1 μg/kg and 3 μg/kg romiplostim, respectively.19 Romiplostim caused no major adverse events in these studies.19, 21, 22
We aimed to assess the efficacy, safety, and optimum dosing of romiplostim in the maintenance treatment of splenectomised and non-splenectomised patients with chronic ITP.
Section snippets
Study design and patients
We undertook two parallel prospective, multicentre, international phase III studies that were randomised, placebo-controlled, double-blind trials, lasting for 6 months. Study designs were identical except that one trial enrolled patients who had undergone splenectomy 4 weeks or more before entry, whereas the other enrolled patients who had not had a splenectomy.
Patients with ITP (according to American Society of Hematology guidelines)4 were enrolled into both studies from 35 sites in the USA
Results
Figure 1 shows the trial profile. All patients received at least one dose of investigational product. One non-splenectomised patient randomly assigned to placebo received three doses of romiplostim in error and was included in the safety analysis as a patient given romiplostim and in the efficacy analysis as a patient given placebo.
Table 1 shows baseline characteristics and patient demographics. All characteristics were comparable in the placebo and romiplostim treatment groups in both studies,
Discussion
In these two randomised, controlled trials, romiplostim was a well-tolerated and effective treatment for patients with ITP. Platelet increases were seen within 1–2 weeks and were sustained throughout 24 weeks of treatment in both splenectomised and non-splenectomised patients. The target platelet count was achieved within 2–3 weeks by over half of patients given romiplostim, with more than four-fifths achieving an overall platelet response and about half achieving a durable response (two-fifths
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