Optimizing Dose and Limiting Laboratory Monitoring of Hydroxyurea in Africa: Design of the Promoting Utilization and Safety of Hydroxyurea Using Precision in Africa (PUSH-UP) Trial

Abstract

Background: More than 90% of the global burden of sickle cell anemia (SCA) occurs in sub-Saharan Africa (SSA) where efforts to expand newborn screening are likely to reduce early mortality. With an increasing number of infants diagnosed and surviving, it is critical to expand access to disease modifying therapy with hydroxyurea (HU) to reduce the risk of SCA complications. Despite increasing evidence demonstrating safety and effectiveness of HU in SSA, access to and use of HU remains limited. In high-resource settings, HU monitoring is performed through routine complete blood counts (CBCs) to monitor for hematologic toxicity and guide dose escalation. Unfortunately, in most SSA settings, access to CBCs is limited due to combination of lack of laboratory equipment, insufficient supply of reagents, or excess cost to the patient or healthcare system. The lack of capacity to perform a CBC is an insurmountable barrier in many SSA settings resulting in lack of access to this highly effective and lifesaving medication. There are some who argue that lower doses (10-15 mg/kg/day) in places where laboratory monitoring may not be readily available may reduce the theoretical risk of "toxicity." While this low dose strategy is likely to have some clinical benefit compared to no treatment at all, there is now sufficient evidence to demonstrate that higher doses of HU result in more significant clinical benefits without evidence that lower dosing prevents toxicity. In the US, we have recently developed and validated an individualized, pharmacokinetics (PK)-guided dosing strategy that optimizes the starting dose immediately without the need for dose escalation. The Prioritizing Utilization and Safety of Hydroxyurea Using Precision (PUSH-UP, ClinicalTrials.gov NCT05285917) trial is an NHLBI-funded clinical trial that will evaluate the utility and effectiveness of this individualized dosing strategy in addition to a limited laboratory monitoring strategy for children with SCA in Luanda, Angola. Study Design and Methods:The PUSH-UP trial is a randomized clinical trial of HU for 450 children aged 6 months through 12 years of age with SCA that will be performed at Hospital Geral dos Cajueiros, a national health reference center in Luanda, Angola. The primary aim of the study will determine the optimal dosing strategy, including a direct comparison of using an individualized, PK-guided starting dose to the more traditional, weight-based starting dose strategies. A second but equally important aim of the study will be to evaluate the safety of HU therapy with limited laboratory monitoring. The study will evaluate the feasibility and utility of measuring HU concentrations using a battery-powered HPLC machine (SmartLife LC™) and an automated individualized dose selection tool based on PK results. An important novel and real-world aspect of the trial is the use of only 500 mg capsules, the generic form of HU that is becoming increasingly available across many African countries. The study will utilize innovative dosing strategies, including every other day or 3-4 times per week dosing, with 500 mg capsules to achieve a safe daily dose in these young children. Following informed consent, prior to HU initiation, there will be a 3-month run-in period, followed by a 24-month treatment period. After initial dose selection and study arm assignment, there will be no dose escalations, to evaluate the most likely real-world scenarios where dose escalation is not feasible. Doses will be adjusted to account for weight-gain to maintain the same mg/kg dose throughout the study. CBCs will be performed monthly for 3 months before and 3 months after HU initiation of treatment to compare the incidence of hematologic "toxicities" and to test the hypothesis that there will be no increase in toxicity with HU treatment. After this, laboratory monitoring will be sparse, relying on clinical examination and point-of-care hemoglobin only without routine CBCs. The primary study endpoint will be SCA-related adverse events and secondary endpoints will include hematologic toxicities, infections and other non-SCA-related events to assess the safety of HU therapy with limited laboratory monitoring, and quality of life measures. Conclusions: The PUSH-UP trial will address important knowledge gaps related to hydroxyurea dosing and laboratory monitoring in low-resource settings that can be used to inform clinical guidelines in sub-Saharan Africa.