Elsevier

The Lancet

Volume 373, Issue 9664, 21–27 February 2009, Pages 641-648
The Lancet

Articles
Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(09)60402-5Get rights and content

Summary

Background

Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that stimulates thrombopoiesis, leading to increased platelet production. This study assessed the efficacy, safety, and tolerability of once daily eltrombopag 50 mg, and explored the efficacy of a dose increase to 75 mg.

Methods

In this phase III, randomised, double-blind, placebo-controlled study, adults from 63 sites in 23 countries with chronic idiopathic thrombocytopenic purpura (ITP), platelet counts less than 30 000 per μL of blood, and one or more previous ITP treatment received standard care plus once-daily eltrombopag 50 mg (n=76) or placebo (n=38) for up to 6 weeks. Patients were randomly assigned in a 2:1 ratio of eltrombopag:placebo by a validated randomisation system. After 3 weeks, patients with platelet counts less than 50 000 per μL could increase study drug to 75 mg. The primary endpoint was the proportion of patients achieving platelet counts 50 000 per μL or more at day 43. All participants who received at least one dose of their allocated treatment were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00102739.

Findings

73 patients in the eltrombopag group and 37 in the placebo group were included in the efficacy population and were evaluable for day-43 analyses. 43 (59%) eltrombopag patients and six (16%) placebo patients responded (ie, achieved platelet counts ≥50 000 per μL; odds ratio [OR] 9·61 [95% CI 3·31–27·86]; p<0·0001). Response to eltrombopag compared with placebo was not affected by predefined study stratification variables (baseline platelet counts, concomitant ITP drugs, and splenectomy status) or by the number of previous ITP treatments. Of the 34 patients in the efficacy analysis who increased their dose of eltrombopag, ten (29%) responded. Platelet counts generally returned to baseline values within 2 weeks after the end of treatment. Patients receiving eltrombopag had less bleeding at any time during the study than did those receiving placebo (OR 0·49 [95% CI 0·26–0·89]; p=0·021). The frequency of grade 3–4 adverse events during treatment (eltrombopag, two [3%]; placebo, one [3%]) and adverse events leading to study discontinuation (eltrombopag, three [4%]; placebo, two [5%]), were similar in both groups.

Interpretation

Eltrombopag is an effective treatment for managment of thrombocytopenia in chronic ITP.

Funding

GlaxoSmithKline.

Introduction

Thrombocytopenia in patients with idiopathic thrombocytopenic purpura (ITP) is due to accelerated platelet destruction and suboptimum platelet production.1, 2, 3 The ensuing low platelet counts result in bleeding symptoms1 that range from mild, common events, such as petechiae and bruising, to rare, serious events, such as intracranial haemorrhage.4 Thrombopoietin is the primary cytokine stimulating thrombopoiesis. An important component of the pathophysiology of ITP is the absence of a substantial compensatory increase in thrombopoietin levels despite severe thrombocytopenia.

The primary goal of therapy for patients with chronic ITP is to keep the risk of bleeding to a minimum by increasing platelets to a safe level of at least 30 000–50 000 per μL with few treatment-associated toxic effects. Present treatment strategies have focused primarily on inhibition of platelet destruction (eg, glucocorticosteroids, intravenous immunoglobulins, intravenous anti-D, immunosuppressive drugs, splenectomy, and monoclonal antibodies directed at B cells). Although these treatments are often useful, not all patients respond to them, and they can be associated with undesirable side-effects.5, 6, 7

Stimulation of thrombopoiesis was explored with first-generation recombinant thrombopoietins that were tested in clinical trials primarily in healthy people and patients with chemotherapy-induced thrombocytopenia;8, 9 however, development of antibodies cross-reactive to endogenous thrombopoietin prevented their further use.8, 9 Second-generation agents were subsequently developed.

Eltrombopag is an oral, small molecule, non-peptide thrombopoietin-receptor agonist that interacts with the transmembrane domain of the thrombopoietin receptor. It stimulates the proliferation and differentiation of megakaryocytes in bone marrow, resulting in a dose-dependent increase in normally functioning platelets in preclinical studies10, 11, 12, 13 and in healthy volunteers.10, 13, 14, 15 Both eltrombopag16 and romiplostim,17, 18, 19 a thrombopoiesis-stimulating peptibody given by subcutaneous injection once per week, have shown efficacy in increasing platelet counts in patients with chronic ITP without undue toxic effects. Additionally, in a phase II study, eltrombopag has increased platelet counts in patients with thrombocytopenia secondary to hepatitis C virus.20

A phase II study in patients with chronic ITP showed that eltrombopag at doses of 50 mg and 75 mg induced a substantial platelet increase with a favourable safety profile.16 The objective of this phase III randomised study was to assess the efficacy, safety, and tolerability of once daily eltrombopag 50 mg in more than 100 adults with previously treated chronic ITP who were naive to thrombopoietic agents, and to explore the efficacy of a dose increase to 75 mg (if needed).

Section snippets

Patients

Patients were enrolled between Feb 6, and April 17, 2006, at 63 sites in 23 countries. Patients were required to be aged 18 years or older, have at least a 6-month history of ITP, have received at least one previous treatment for ITP, and have a pretreatment platelet count less than 30 000 per μL of blood. Patients could receive other ITP drugs as maintenance therapy (eg, glucocorticosteroids, azathioprine, danazol, ciclosporine A, and mycophenolate mofetil), and were eligible if the doses had

Results

Of 170 patients screened for this study, 114 were randomly assigned to treatment, none of whom had previously received a thrombopoietic agonist (figure 1). The reasons for ineligibility are shown in figure 1; the most common were a platelet count 30 000 per μL or more, laboratory values (eg, transaminases) out of normal range, and withdrawal of consent before randomisation.

Randomised patients had a median age of 48 years (range 19–84), nearly two-thirds were women, and three-quarters were white

Discussion

In this large, multicentre, randomised, placebo-controlled trial of eltrombopag treatment in chronic ITP, substantially more patients in the eltrombopag group achieved platelet counts of 50 000 per μL or greater than did those in the placebo group. Increases of platelet counts to 50 000 per μL or greater were seen within 2 weeks in more than half of patients given eltrombopag. In conjunction with the rise in platelet count, a prospective assessment showed a significant reduction in bleeding

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