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.

Despite the high prevalence of obstructive sleep apnea (OSA) and overnight hypoxia in sickle cell disease (SCD) patients, there are few data on treatment safety and efficacy, with controversy about the optimal management of these complications. Auto-adjusting positive airways pressure (APAP) has been shown to improve attention span and reduce pain episodes in children with sickle cell anemia (SCA) in a pilot randomized trial and there is observational evidence that nocturnal oxygen therapy (NOT) used for a period of at least six months in patients with SCD and severe nocturnal hypoxia is safe and easy to use. The Prevention of Morbidity in Sickle Cell Disease (POMS 2a) study is a National Institute for Health Research (NIHR) funded pilot feasibility trial to compare APAP with NOT in adults and children with SCD to establish the most acceptable treatment strategy and to determine short term safety of both interventions. We also assessed the feasibility of using an iPad app to collect daily pain scores. Methods: This was a cross-over interventional trial. Inclusion criteria were: age over 8 years, diagnosis of HbSS and ability to give informed consent and use an iPad. Evidence of overnight hypoxia and/or OSA was not necessary for inclusion in the trial. Each intervention was administered for a week in randomized order with a week of baseline data collection and a week of washout between the interventions. Tablet technology was used to collect daily pain scores and a detailed qualitative interview was performed after both interventions. These transcripts were analysed manually by two researchers using content analysis. Physiological and safety data included blood tests (routine hematology and biochemistry testing), urine protein measurements, oximetry, quality of life (using PedsQL), spirometry and lung volume measurements, which were measured at baseline and after each intervention. Adherence data was downloaded from the APAP machine and was self-reported for NOT. Results: Ten adults (3 female, mean age 31.7 years, 4 on hydroxyurea) and eleven children (5 female, mean age 11.9 years, 7 on hydroxyurea) were enrolled. APAP adherence data was available on 8 adults who completed 3 to 7 nights of APAP for a mean of 6.13 hours (range 4.49-7.76). Data was not available on 2 patients. One patient completed 3 days of APAP and was admitted two days later with a painful crisis and subsequent acute chest syndrome, they were subsequently withdrawn from the trial. One adult developed a pain crisis on day 2 of NOT which was self managed at home. Data on APAP adherence was available on nine children who completed APAP therapy for 3-7 nights for a mean of 5.9 hours (range 1.94-9.05), there was no data on 1 child and one did not tolerate APAP and stopped after one night. This child was admitted with a pain crisis three days after stopping APAP. Detailed quantitative interviews were completed on 19 participants. The majority of participants showed a preference for APAP because the machine was smaller, easier to handle and less noisy and noted that they slept better when using the APAP machine and were less fatigued, but some participants found the mask uncomfortable. Patients reported that NOT had a calming effect on them but they also reported that it was very noisy and caused dry nose, throat and mouth. There was no significance difference in hemoglobin, reticulocyte count, creatinine, erythropoietin, albumin creatinine ratio, bilirubin or lactate dehydrogenase at baseline and after either intervention. One patient showed a decrease in absolute reticulocyte count from 128x109 l to 53x 109/l after NOT therapy, with no change in hemoglobin. Mean overall pain days per week were 2.31 at baseline, 1.57 during APAP, 1.47 during NOT and 2.08 during washout. There was no difference in spirometry and lung volume measurements between baseline and post intervention. Pulse oximetry and Quality of Life was unchanged between baseline and after both interventions Conclusion: There were no safety concerns, in particular there was no evidence of erythroid suppression or rebound pain after 7-day application of APAP or nocturnal oxygen therapy. Tablet technology was acceptable to patients with satisfactory levels of completion. In view of patient preference for APAP the steering group has decided to proceed with a phase 2b randomized trial of six months therapy with APAP versus standard care to assess its effects on pain, quality of life and cognitive function. Disclosures Howard: Pfizer: Consultancy; Novartis: Consultancy, Other: Travel Grant; Aes-Rx: Consultancy.

Inhibition of platelet activation may reduce vaso‐occlusion rates in patients with sickle cell disease (SCD). In the HESTIA4 (NCT03492931) study, 21 children with SCD received a single oral dose of the antiplatelet agent ticagrelor (0.1 mg/kg <6 months; 0.2 mg/kg ≥6 to <24 months). All patients had measurable ticagrelor plasma concentrations. Ticagrelor and active metabolite (AR‐C124910XX) exposure were comparable across all groups (<6 months, ≥6 to <12 months and ≥12 to <24 months). Ticagrelor was well tolerated. Palatability was generally acceptable. These data will be used to enable dose selection for further investigations of ticagrelor efficacy and safety in children with SCD.

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