Ticagrelor versus placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: Rationale and design of a randomized, double-blind, parallel-group, multicenter phase 3 study (HESTIA3)

Abstract

Background: An unmet need for therapies exists to reduce sickle cell disease (SCD) complications in pediatric patients. Activated platelets contribute to the formation of cellular aggregates during sickling and vaso-occlusive crises (VOCs). Ticagrelor is an oral, direct-acting, and reversible adenosine diphosphate P2Y 12 receptor antagonist that inhibits platelet activation and aggregation. Although ticagrelor was well tolerated in two phase 2 studies in children and young adults with SCD, larger and longer-term treatment studies are needed to assess ticagrelor's efficacy to reduce VOCs. HESTIA3 will evaluate the efficacy, safety, and tolerability of ticagrelor versus placebo over a minimum of 1 year (maximum 2 years) in pediatric patients with SCD. Methods: Approximately 180 patients (aged ≥ 2 to < 18 years) with SCD (≥ 2 VOCs in the prior year) from 18 countries will be randomized 1:1 to ticagrelor or placebo. Primary endpoint: number of VOCs (a composite endpoint of painful crises and/or acute chest syndrome); key secondary endpoints: hospitalizations, pain intensity and analgesic use during VOCs, acceptability of formulation, and health-related quality of life. The weight-based doses of ticagrelor are set by modeling and simulation. Platelet inhibition data, measured by the vasodilator-stimulated phosphoprotein assay, will be collected for exploratory purposes. Conclusions: HESTIA3 aims to demonstrate that using greater target platelet inhibition than previous studies on SCD, ticagrelor will decrease the frequency of VOC in pediatric patients.

Clinical Features and Outcome of Sickle Cell Disease in a Tertiary Center in Northern Lebanon: A Retrospective Cohort Study in a Local, Hospital-Associated Registry

“…Differences in definitions can make between-study comparisons difficult; however, because pain and ACS are the two most common reasons for hospitalization, often coexist, and together represent the major burden in sickle cell disease, combining these clinical events provides a better estimate of disease burden, which is the primary objective of this study. Additionally, some recently conducted clinical trials have used this description [26,27].…”

A dose‐ranging study of ticagrelor in children aged 3‐17 years with sickle cell disease: A 2‐part phase 2 study

“…Overall, no safety concerns were raised from treating pediatric patients with a broad range of single and repeated doses of ticagrelor during the study. The potential of ticagrelor to impact SCD‐related pain crises warrants further evaluation in this population, and a phase 3 study (HESTIA3) is planned …”

Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

“…27 Information garnered from recent studies of other novel therapies, including SUSTAIN (crizanlizumab), DOVE (prasugrel), HESTIA (ticagrelor), and several others have demonstrated that there are still a significant proportion of patients who either are not taking HU, or experience breakthrough VOCs while taking HU. [28][29][30] Chronic transfusion therapy Chronic transfusion therapy is used primarily to reduce the risk of stroke in high-risk individuals with SCD. 31,32 However, it can also be used to reduce the levels of circulating sickled RBCs, and thereby decrease the number of VOCs when used as prophylactic therapy.…”

“… 27 Information garnered from recent studies of other novel therapies, including SUSTAIN (crizanlizumab), DOVE (prasugrel), HESTIA (ticagrelor), and several others have demonstrated that there are still a significant proportion of patients who either are not taking HU, or experience breakthrough VOCs while taking HU. 28 – 30 …”