Hydroxyurea Optimization Through Precision Study

The trial will recruit patients who have decided to initiate hydroxyurea therapy. All participants will have pharmacokinetics studies performed at baseline, following a 20 mg/kg oral dose of hydroxyurea. Pharmacokinetic sampling will use a sparse sampling approach, requiring collection of blood at 3 time points (15 minutes, 60 minutes, 180 minutes) following the hydroxyurea dose. Enrolled participants will be randomized to receive either hydroxyurea using a starting dose of 20 mg/kg/day (Standard Arm) or a personalized PK-guided dose (Alternative Arm) to target an area under the curve (AUC) of 115 mg*h/L based to approximate hydroxyurea exposure seen when patients are escalated to maximum tolerated dose (MTD).

Following randomization and selection of the initial dose, participants in both arms will follow the same procedures of laboratory medication holds for hematological toxicity. The primary endpoint is fetal hemoglobin (HbF) six months following the initiation of hydroxyurea therapy with the hypothesis that participants starting with a PK-guided dose will achieve HbF at least 5% greater than those starting with a 20 mg/kg dose. Based upon the estimated number of new hydroxyurea starts at each site, it is anticipated that it will take 24 months to enroll the 116 participants required to achieve sufficient power to assess the primary endpoint. The study will conclude for each participant 12 months following hydroxyurea initiation.

• Hydroxyurea (Drug): The alternative arm will use PK data to choose a starting hydroxyurea dose to achieve an AUC of 115 mg*h/L to approximate maximum tolerated dose. On the standard arm, participants will start at the traditional, weight-based dose of 20 mg/kg/day. Following selection of the starting dose, all participants will follow the same dose escalation and laboratory monitoring procedures.

Primary outcomes

• Fetal Hemoglobin (HbF) Response Following Six Months of Hydroxyurea Therapy [6 months after starting daily hydroxyurea therapy]: The primary outcome will be HbF response six months after starting hydroxyurea therapy with the hypothesis that participants in the Alternative Arm (PK-guided starting dose) will have at least 5% higher HbF than the Standard Arm (20 mg/kg starting dose)

Secondary outcomes

• F Cells [Baseline, 6 and 12 months after initiating daily hydroxyurea therapy]: In addition to traditional %HbF measurement, F cells will be measured at baseline, 6 months, and 12 months
• Gene Expression Patterns of Study Participants [6 Months after initial Hydroxyurea therapy]: The epigenomic signature and gene expression patterns of study participants receiving hydroxyurea therapy at MTD. MTD is defined as a stable dose without any dose increases (except to account for weight gain), holds, or decreases within 8 weeks with laboratory criteria within the target range. This outcome will explain the mechanisms that yield high HbF responses.

Sex: All, ages: 6 Months to 21 Years

Inclusion Criteria:

* Diagnosis of sickle cell anemia (HbSS, HbSD, HbS/β0-thalassemia, or similarly severe SCA genotype)
* Age 6 months to 21 years at the time of enrollment
* Clinical decision by patient, family, and healthcare providers to initiate hydroxyurea therapy

Exclusion Criteria:

* Current treatment with chronic, monthly blood transfusions or erythrocytapheresis
* Treatment with hydroxyurea within the past 3 months
* Hemoglobin SC disease, HbS/β+-thalassemia
* Current treatment with other investigational sickle cell medications
* Current known pregnancy or lactation

• Results publication: Meier ER, Creary SE, Heeney MM, Dong M, Appiah-Kubi AO, Nelson SC, Niss O, Piccone C, Quarmyne MO, Quinn CT, Saving KL, Scott JP, Talati R, Latham TS, Pfeiffer A, Shook LM, Vinks AA, Lane A, McGann PT. Hydroxyurea Optimization through Precision Study (HOPS): study protocol for a randomized, multicenter trial in children with sickle cell anemia. Trials. 2020 Nov 27;21(1):983. doi: 10.1186/s13063-020-04912-z. PMID 33246482

• Patrick Niss, MD, Principal investigator, Lifespan