Hydroxyurea Optimization Through Precision Study

Study Overview
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Brief Summary
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Hydroxyurea Optimization through Precision Study (HOPS) is a prospective, multi-center, randomized trial that will directly compare a novel, individualized dosing strategy of hydroxyurea to standard weight-based dosing for children with SCA. The primary objective of the study is to evaluate whether a pharmacokinetics-based starting hydroxyurea dose thieves superior fetal hemoglobin response to to standard weight-based initial dosing. Patients will be recruited from the pediatric sickle cell clinic at Cincinnati Children's Hospital Medical Center and from additional pediatric sickle cell centers within the United States.

Detailed Description
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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.

Official Title
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Hydroxyurea Optimization Through Precision Study (HOPS): A Prospective, Multi-center, Randomized Trial of Personalized, Pharmacokinetics-guided Dosing of Hydroxyurea Versus Standard Weight-based Dosing for Children With Sickle Cell Anemia.

Conditions
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Sickle Cell Disease, Sickle Cell Anemia

Intervention / Treatment
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* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Arm<br>Participants randomized to the standard arm will receive a starting dose of hydroxyurea of 20 mg/kg/day. | Drug: Hydroxyurea<br>* 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.<br>|
| Experimental: Alternative Arm<br>Participants randomized to the alternative arm will receive a pharmacokinetic guided starting dose of hydroxyurea based on PK labs drawn at a baseline visit to target an area under the curve (AUC) of 115 mg*h/L in an attempt to approximate maximum tolerated dose (MTD). This dose will not exceed the maximum tolerated dose of 35 mg/kg/day. | Drug: Hydroxyurea<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal Hemoglobin (HbF) Response Following Six Months of 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) | 6 months after starting daily hydroxyurea therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| F Cells | In addition to traditional %HbF measurement, F cells will be measured at baseline, 6 months, and 12 months | Baseline, 6 and 12 months after initiating daily hydroxyurea therapy | 
| Gene Expression Patterns of Study Participants | 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. | 6 Months after initial Hydroxyurea therapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hydroxyurea, HbSS, HbSD, TREAT