Baseline data from the prioritizing utilization and safety of hydroxyurea using precision in Africa (PUSHUP) trial

Abstract Background: There are >500,000 infants born with sickle cell anemia (SCA) each year, mostly (>90%) in sub-Saharan Africa. Over the past decade, several high-impact clinical trials have clearly demonstrated both the safety and efficacy of hydroxyurea (HU) to treat children with SCA across sub-Saharan Africa. Despite this, HU remains highly underutilized and inaccessible for most children with SCA living in sub-Saharan Africa. Two primary remaining questions that limit expanded use are related to appropriate dosing strategy and the need for frequent laboratory monitoring with complete blood counts, which is either unavailable or cost prohibitive in many African settings. In the US, we have developed and validated an individualized, pharmacokinetics (PK)-guided dosing strategy that optimizes the starting dose immediately without the need for dose escalation and associated laboratory monitoring. The Prioritizing Utilization and Safety of Hydroxyurea Using Precision (PUSH-UP, ClinicalTrials.gov NCT05285917) trial is an NHLBI-funded prospective clinical trial that is evaluating the utility and effectiveness of this individualized dosing strategy in addition to a limited laboratory monitoring strategy for children with SCA in Luanda, Angola. Here, we report baseline data from this fully enrolled trial. Methods: PUSH-UP is a randomized clinical trial of HU for 400 children aged 6 months through 12 years of age with SCA at Hospital Geral dos Cajueiros in Luanda, Angola. The primary aim is to determine optimal dosing, including a direct comparison of an individualized, PK-guided starting dose to a weight-based (25 mg/kg) starting dose. A second but equally important aim is to evaluate the safety of HU with limited laboratory monitoring (no complete blood counts) during the second year of treatment. The study will evaluate the feasibility and utility of measuring HU concentrations using a battery-powered HPLC machine (SmartLife LC™) and an automated dose selection tool based on PK results. The study utilizes innovative dosing strategies, including every other day or 3-4 times per week dosing, with 500 mg capsules to achieve an approximation of the weight-based or PK-recommended dose. Following informed consent, prior to HU initiation, there is a 3-month run-in period, followed by a 24-month treatment period. The primary study endpoint will be SCA-related adverse events in each dosing arm and secondary endpoints will include hematologic toxicities and other non-SCA-related events to assess the safety of hydroxyurea therapy with limited laboratory monitoring (hemoglobin measurement only), rather than CBCs with WBC differential. Results: A total of 420 patients consented and 400 are included in this baseline analysis, excluding 8 who did not meet eligibility criteria, 10 lost to follow-up, and 2 deaths prior to initiating hydroxyurea. There are 200 participants (200M, 200F) randomized to each treatment arm with comparable baseline characteristics. The mean age of enrollment is 5.6 ± 3.1 years with an equal distribution greater than and less than 5 years of age, as intended by protocol. Baseline laboratory values were consistent with untreated SCA and not significantly different between arms: WBC: 13.0 ± 4.7 x109/L; Hemoglobin: 7.1 ± 1.0 g/dL; MCV 77 ± 8 fL; absolute neutrophil count: 6.8 ± 3.1 x109/L; absolute reticulocyte count: 164 ± 90 x109/L; fetal hemoglobin: 14.1 ± 6.7%. There was a history of frequent sickle cell complications among the cohort, including 316/400 (79%) who have had at least one prior hospitalization, 314/400 (78.5%) with dactylitis, 380/400 (95.0%) with pain 236/400 (59.0%) having received transfusion, 366/400 (91.5%) with a history of malaria, 54/400 (13.5%) with a history of splenic sequestration, and 9/400 (2.3%) with a history of overt stroke. Most (396/400=99%) were taking folic acid and 172/400 (43%) were taking prophylactic penicillin. All participants received pneumococcal vaccination. Pharmacokinetic testing was successful with a PK-guided dose determined for 93% of participants in the PK arm. Starting HU dose for the PK arm was 27.5 ± 3.8 mg/kg/day, compared to the starting dose of 23.2 ± 1.8 mg/kg for the weight-based arm. Conclusions: The PUSH-UP trial is now fully enrolled and aims to address important knowledge gaps related to HU dosing and laboratory monitoring in low-resource settings that can be used to inform HU dosing and monitoring guidelines in Angola and across sub-Saharan Africa.

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