Elsevier

The Lancet Haematology

Volume 2, Issue 8, August 2015, Pages e315-e325
The Lancet Haematology

Articles
Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study

https://doi.org/10.1016/S2352-3026(15)00114-3Get rights and content

Summary

Background

The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.

Methods

PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. Patients aged 1–17 years with immune thrombocytopenia lasting for 6 months or longer and platelets less than 30 × 109 per L who had received at least one previous treatment were enrolled. We enrolled patients into three cohorts consisting of patients aged 12–17, 6–11, and 1–5 years. We established patients' starting doses with an open-label, dose-finding phase with five patients in each cohort. During the dose-finding phase, patients aged 6–17 years started eltrombopag at 25 mg once per day (12·5 mg for those weighing <27 kg) and patients aged 1–5 years received 0·7 mg/kg per day to a maximum of 2 mg/kg unless otherwise approved. We permitted dose adjustments on the basis of platelet response up to a maximum dosage of 75 mg per day. Additional patients were then recruited and randomly assigned (2:1) to receive either eltrombopag or placebo tablets (or oral suspension formulation if aged 1–5 years) once per day for 7 weeks at the previously established doses. Starting doses for the double-blind phase were 37·5 mg/day for patients aged 12–17 years; 50 mg/day for patients weighing 27 kg or more (25 mg for east Asian patients) and 25 mg/day for patients weighing less than 27 kg (12·5 mg once per day for east Asian patients) for patients aged 6–11 years; and 1·5 mg/kg once per day (0·8 mg/kg once per day for east Asian patients) for patients aged 1–5 years. Randomisation was done by the GlaxoSmithKline Registration/Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who completed treatment were then enrolled into an open-label phase and all patients could receive up to 24 weeks of eltrombopag. The primary outcome was the proportion of patients achieving a platelet count of 50 × 109 per L or more at least once from weeks 1–6 (days 8 to 43) of the randomised phase of the study in the absence of rescue therapy. We assessed efficacy in the intent-to-treat population, which consisted of all patients assigned to treatment, and we assessed safety in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT00908037.

Findings

Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort, into the open-label dose-finding phase who did not progress into the double-blind phase. From March 17, 2010, to Jan 15, 2013, we randomly assigned 67 patients to treatment, with 45 patients assigned to receive eltrombopag (16 children aged 12–17 years, 19 aged 6–11 years, and ten aged 1–5 years) and 22 to receive placebo (eight children aged 12–17 years, nine aged 6–11 years, and five aged 1–5 years). However, two patients assigned to receive eltrombopag did not receive the study drug and one was lost to follow-up, and one patient assigned to receive placebo was given eltrombopag. From weeks 1 to 6, 28 (62%) patients who received eltrombopag, compared with seven (32%) who received placebo, achieved the primary endpoint of platelet count 50 × 109 per L or more at least once without rescue (odds ratio 4·31, 95% CI 1·39–13·34, p=0·011). The most common adverse events with eltrombopag were headache (13 [30%] patients receiving eltrombopag vs nine [43%] patients receiving placebo), upper respiratory tract infection (11 [25%] patients vs two [10%] patients), and diarrhoea (seven [16%] patients vs one [5%] patient). Grade 3 or 4 adverse events occurred in five (11%) patients receiving eltrombopag and four (19%) patients receiving placebo, and serious adverse events (four [9%] patients receiving eltrombopag and two (10%) patients receiving placebo) were similarly infrequent in both groups. No thrombotic events or malignancies occurred. Increased alanine aminotransferase concentrations caused two (3%) of 65 patients to discontinue eltrombopag in the open-label phase.

Interpretation

Our results showed that eltrombopag could be used to increase platelet counts and reduce clinically significant bleeding in children with persistent or chronic immune thrombocytopenia. Prevalence of increased liver laboratory values was similar to that seen in adults.

Funding

GlaxoSmithKline.

Introduction

Immune thrombocytopenia, which results from antibody-mediated platelet destruction and impaired platelet production, is a common cause of childhood thrombocytopenia.1, 2 Most patients have bruising and petechiae,3 but a few develop clinically significant bleeding, especially when platelet counts are less than 10–20 × 109 per L.3, 4, 5

For many children, immune thrombocytopenia improves spontaneously;4, 6 however, 13–36% of paediatric patients develop immune thrombocytopenia lasting for more than 6 months.6 The most severely affected children have very low platelet counts and ongoing bleeding, and are at risk of serious haemorrhage.

Despite the fact that consensus guidelines exist, treatment of persistent (ie, lasting for 3–12 months), and especially chronic (>12 months), immune thrombocytopenia in children is controversial because of the absence of evidence from randomised clinical trials.7, 8 Treatment options include long-term use of corticosteroids or intravenous immunoglobulin, rituximab, other immunosuppressive drugs, or splenectomy.8, 9, 10, 11, 12, 13, 14, 15 The side-effects from these treatments can be concerning, and responses, if seen, might only be transient.8, 9, 10, 11, 12, 13, 14, 15 However, immune thrombocytopenia can resolve spontaneously even during the chronic phase.6 Therefore, children are sometimes managed with a watch-and-wait approach, even for long periods of time. However, for these children, persistently low platelet counts might curtail normal childhood activities, which could affect their quality of life.16

Eltrombopag is an oral non-peptide thrombopoietin receptor agonist that leads to signal transduction through the JAK/STAT, MAPK, and AKT pathways, resulting in proliferation and differentiation of megakaryocytes and increased platelet production.17, 18 Eltrombopag is approved for chronic immune thrombocytopenia in adults; however, data are scarce for children with immune thrombocytopenia treated with thrombopoietin receptor agonists.19, 20

The PETIT study is the first randomised, double-blind, placebo-controlled trial in patients aged 1–17 years with immune thrombocytopenia lasting for 6 months or more (persistent or chronic immune thrombocytopenia). We aimed to investigate the efficacy and safety of 24 weeks of eltrombopag in these children.

Section snippets

Study design

PETIT was a three-part, randomised, multicentre, placebo-controlled study (figure 1) done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands. The study consisted of a dose-finding phase; a randomised, placebo-controlled double-blind phase; and an open-label phase.

The study protocol was approved by national, regional, or investigational centre ethics committee or institutional review boards accordingly. The trial protocol is available online.

Patients

Patients aged 1–17 years with a

Results

Between Oct 2, 2009, and June 22, 2011, we recruited 15 patients, with five patients in each age cohort (table 1), into the open-label dose-finding phase. Patients in the dose-finding phase did not enter the double-blind phase. Between March 17, 2010, and Jan 15, 2013, we assessed 82 additional patients for eligibility in the double-blind phase. Patients were enrolled in the double-blind starting with those aged 12–17 years, and the double-blind phase ran in parallel with the dose-finding phase

Discussion

Our results show that eltrombopag can be effective to increase platelet counts in children with persistent and chronic immune thrombocytopenia. The primary efficacy outcome was met: significantly more patients achieved a response, as defined as a platelet count of at least 50 × 109 per L without rescue therapy, with eltrombopag than with placebo during the 6 week randomised phase. Responses were similar (at about 60% of patients) in the three age cohorts. Clinical benefit was shown by

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