Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study

doi:10.1016/S0140-6736(10)60959-2

The Lancet

Volume 377, Issue 9763, 29 January–4 February 2011, Pages 393-402

https://doi.org/10.1016/S0140-6736(10)60959-2 Get rights and content

Summary

Background

Eltrombopag is an oral thrombopoietin receptor agonist for the treatment of thrombocytopenia. We aimed to compare the response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.

Methods

We undertook a phase 3, double-blind, placebo-controlled study in adults with previously treated immune thrombocytopenia of more than 6 months' duration who had baseline platelet counts lower than 30 000 per μL. Patients were randomly allocated (in a 2:1 ratio) treatment with local standard of care plus 50 mg eltrombopag or matching placebo once daily for 6 months. Randomisation was done centrally with a computer-generated randomisation schedule and was stratified by baseline platelet count (≤15 000 per μL), use of treatment for immune thrombocytopenia, and splenectomy status. Patients, investigators, and those assessing data were masked to allocation. Dose modifications were made on the basis of platelet response. Patients were assessed for response to treatment (defined as a platelet count of 50 000–400 000 per μL) weekly during the first 6 weeks and at least once every 4 weeks thereafter; the primary endpoint was the odds of response to eltrombopag versus placebo. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, number NCT00370331.

Findings

Between Nov 22, 2006, and July 31, 2007, 197 patients were randomly allocated to treatment groups and were included in the intention-to-treat analysis (135 eltrombopag, 62 placebo). 106 (79%) patients in the eltrombopag group responded to treatment at least once during the study, compared with 17 (28%) patients in the placebo group. The odds of responding were greater in patients in the eltrombopag group compared with those in the placebo group throughout the 6-month treatment period (odds ratio 8·2, 99% CI 3·59–18·73; p<0·0001). 37 (59%) patients receiving eltrombopag reduced concomitant treatment versus ten (32%) patients receiving placebo (p=0·016). 24 (18%) patients receiving eltrombopag needed rescue treatment compared with 25 (40%) patients receiving placebo (p=0·001). Three (2%) patients receiving eltrombopag had thromboembolic events compared with none in patients on placebo. Nine (7%) eltrombopag-treated patients and two (3%) in the placebo group had mild increases in alanine aminotransferase concentration, and five (4%) eltrombopag-treated patients (vs none allocated to placebo) had increases in total bilirubin. Four (7%) patients taking placebo had serious bleeding events, compared with one (<1%) patient treated with eltrombopag.

Interpretation

Eltrombopag is effective for management of chronic immune thrombocytopenia, and could be particularly beneficial for patients who have not responded to splenectomy or previous treatment. These benefits should be balanced with the potential risks associated with eltrombopag treatment.

Funding

GlaxoSmithKline.

Introduction

In chronic immune thrombocytopenia, previously known as idiopathic thrombocytopenic purpura,¹ antiplatelet antibodies accelerate platelet destruction and simultaneously prevent the release of platelets from megakaryocytes, resulting in mild to serious bleeding.1, 2, 3, 4 The primary goal of treatment for this disorder is to prevent bleeding by increasing the platelet count to a stable, safe range with the fewest possible treatment-associated adverse effects.2, 3, 5 Most treatments (eg, corticosteroids, immunoglobulins, and splenectomy) mainly reduce destruction of antibody-coated platelets; however, treatment is not always effective and can be restricted by adverse effects.² By contrast, the novel thrombopoietic receptor agonists, eltrombopag6, 7 and romiplostim,8, 9, 10, 11 stimulate platelet production.¹² Romiplostim has shown efficacy in chronic immune thrombocytopenia.8, 9, 10, 11 Eltrombopag is an oral, small-molecule, non-peptide thrombopoietin receptor agonist that has shown efficacy and safety in patients with chronic immune thrombocytopenia in two 6-week placebo-controlled studies6, 7 and two open-label studies.13, 14 Eltrombopag also increases platelet counts in patients with other thrombocytopenic disorders, including thrombocytopenia related to hepatitis C virus infection and its treatment¹⁵ and chemotherapy-induced thrombocytopenia.¹⁶ We aimed to compare the platelet response to once daily eltrombopag versus placebo in patients with chronic immune thrombocytopenia during a 6-month period.

Section snippets

Patients

Patients were enrolled in this double-blind, placebo-controlled, phase 3 study between Nov 22, 2006, and July 31, 2007, from 75 sites in 23 countries. The ethics committee at each institution approved the protocol and amendments, and all patients provided written informed consent before enrolment. This study was undertaken in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and local laws and regulations. Eligible patients were aged 18 years and older and had

Results

Of 285 patients screened, 197 were randomly allocated treatment (62 placebo, 135 eltrombopag; figure 1). Demographic and baseline disease characteristics were similar between treatment groups (table 1). Baseline platelet counts were 15 000 per μL or lower in 97 (49%) patients, and 71 (36%) had not achieved a sustained response to splenectomy. 17 patients discontinued treatment early because of adverse events: 13 patients in the eltrombopag group (alanine aminotransferase increases [four];

Discussion

Our results showed that eltrombopag maintained platelet counts between 50 000 per μL and 400 000 per μL, reduced risk of bleeding, and substantially improved health-related quality of life in patients with chronic immune thrombocytopenia during 6 months of treatment. By contrast, platelet counts remained low in patients receiving placebo despite use of rescue treatment in 40% of patients. Patients responded to eltrombopag throughout the 6 months of treatment, irrespective of splenectomy status.

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ArticlesEltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients

Results

Discussion

Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group

Blood

Current options for the treatment of idiopathic thrombocytopenic purpura

Semin Hematol

Chronic idiopathic thrombocytopenic purpura: present strategy, guidelines and new insights

Neth J Med

The pathogenesis of immune thrombocytopaenic purpura

Br J Haematol

How I treat idiopathic thrombocytopenic purpura (ITP)

Blood

Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura

N Engl J Med

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

Lancet

AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP

N Engl J Med

Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP

Blood

Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial

Lancet

An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura

Br J Haematol

Novel thrombopoietic agents: a review of their use in idiopathic thrombocytopenic purpura

Drugs

Efficacy and safety of repeated intermittent treatment with eltrombopag in patients with chronic idiopathic thrombocytopenic purpura

Blood

Safety and efficacy of long-term treatment with oral eltrombopag for chronic idiopathic thrombocytopenic purpura

Blood

Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C

N Engl J Med

Efficacy and safety of eltrombopag, a novel, oral platelet growth factor on platelet counts in patients with cancer receiving carboplatin/paclitaxel chemotherapy

Support Care Cancer

Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology

Blood

Guidelines for the investigation and management of idiopathic thrombocytopenic purpura in adults, children and in pregnancy

Br J Haematol

How to score version two of the SF-36 health survey

Articles
Eltrombopag for management of chronic immune thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study