Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia Emily R. Meier
Indiana Hemophilia and Thrombosis Center Susan E. Creary
Nationwide Children’s Hospital Matthew M. Heeney
Boston Children’s Hospital Min Dong
Cincinnati Children’s Hospital Medical Center Abena O Appiah‐Kubi
Cohen Children’s Medical Center Stephen C. Nelson
Children’s Hospital and Clinics of Minnesota Omar Niss
Cincinnati Children’s Hospital Medical Center Connie Piccone
Case Western Reserve University School of Medicine Maa-Ohui Quarmyne
Children’s Healthcare of Atlanta Charles T. Quinn
Cincinnati Children’s Hospital Medical Center Kay L. Saving
University of Illinois Peoria John P. Scott
Medical College of Wisconsin Ravi Talati
Cleveland Clinic Children’s Hospital Teresa S. Latham
Cincinnati Children’s Hospital Medical Center Amanda Pfeiffer
Cincinnati Children’s Hospital Medical Center Lisa M. Shook
Cincinnati Children’s Hospital Medical Center Alexander A. Vinks
Cincinnati Children’s Hospital Medical Center Adam Lane
Cincinnati Children’s Hospital Medical Center Patrick McGann ( firstname.lastname@example.org )
Cincinnati Children’s Hospital Medical Center https://orcid.org/0000-0001-6198-4785
Keywords: Sickle cell anemia, pharmacokinetics, hydroxyurea, pediatrics
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Abstract Background : Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the United States and millions worldwide. Hydroxyurea is the primary disease- modifying therapy for the SCD, with proven bene�ts to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a �xed dose, resulting in inadequate hydroxyurea exposure and suboptimal bene�ts for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory bene�ts than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and bene�ts of this PK-guided dosing approach in a multi-center trial.
Methods : HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the United States, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10μL of blood collected at 3 time-points over 3 hours. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea.
Discussion: HOPS will answer important questions about the clinical feasibility, bene�ts, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response.
Trial registration: ClinicalTrials.gov, NCT03789591. Registered on December 28, 2018.
Background Sickle cell disease (SCD) is a devastating, inherited disorder of hemoglobin, affecting over 100,000 persons in the United States and millions worldwide.1-3 The most severe forms of SCD, primarily HbSS and HbS/β0-thalassemia, account for a majority of the global cases of SCD and are collectively referred to as sickle cell anemia (SCA). Without early diagnosis and appropriate disease-modifying treatment, SCA results in signi�cant morbidity and early mortality. The life-threatening clinical complications of SCA, including acute splenic sequestration crisis and stroke, frequently occur within the �rst decade of life.4,5