Phase 3 randomised trial of eltrombopag versus standard first-line pharmacological management for newly diagnosed immune thrombocytopaenia (ITP) in children: study protocol

Abstract

IntroductionImmune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP.Methods and analysisRandomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×109/L during weeks 6–12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13–52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites.Ethics and disseminationThe study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023.Trial registration numberNCT03939637.

Update on the Use of Thrombopoietin-Receptor Agonists in Pediatrics

“…Indeed, the results of a multicenter, open-label, phase 3 RCT (NCT03939637) that compares eltrombopag to standard first-line management (steroids vs. immunoglobulins vs. Rho(D) immunoglobulin) in children (n ¼ 162) with newly diagnosed ITP ( 3 months from diagnosis) are expected in 2024. 54 The fact that eltrombopag binds to the transmembrane and juxtamembrane but not to the classical extracellular binding domains of the TPO-R makes this substance appealing for use in rare inherited thrombocytopenia, especially in CAMT. This group of congenital thrombocytopenias is characterized by ineffective megakaryopoiesis without typical features of syndromic conditions.…”

Therapeutic Outcomes of High Dose-Dexamethasone versus Prednisolone + Azathioprine, Rituximab, Eltrombopag, and Romiplostim Strategies in Persistent, Chronic, Refractory, and Relapsed Immune Thrombocytopenia Patients

“…The sample size for the study was determined based on the results from previous studies [38,[57][58][59], which have a power of 80-90%. In addition, the highest number of patients in previous randomized studies was 55 and 62 [60][61][62].…”

Eltrombopag and high-dose dexamethasone as first-line treatment in children with newly diagnosed primary immune thrombocytopenia

“…ITP is usually a self-limiting and mild disease, without life-threatening bleeding episodes or the need for hospitalization or treatment intervention [1,2]. Although most children with ndITP achieve remission spontaneously, others require therapy for minor or moderate bleedings and improvements in their health related quality of life [3,4]. The first-line treatment for ndITP includes corticosteroids, intravenous immunoglobulin, and anti-D globulin [1,3,5].…”

“…However, 10-20% of children with ITP do not respond to the recommended first-line therapies, going on to develop pITP or cITP. In addition, some patients become steroid--dependent or refractory, and this leads to adverse events and challenges in logistical and economic terms [4].…”

“…PINES is an ongoing phase III prospective randomized trial of eltrombopag's use in the management of ndITP in children [4]. Moreover, there has been convincing data from adult cohort studies suggesting that early aggressive and combined treatment protocols may be a good first-line therapeutic strategy for ndITP, resulting in sustained response rates [18,19].…”