Optimizing Hydroxyurea Therapy in Children With Sickle Cell Anemia In Malaria Endemic Areas: The NOHARM Maximum Tolerated Dose (MTD) Study (NOHARM MTD)

The purpose of this study is to determine the long-term effects of hydroxyurea treatment on internal organs, the best dosing strategies for children with SCA in Africa, and to identify any genetic factors that affect how a child responds to the study medication. All children in this study will receive the research treatment, hydroxyurea. Hydroxyurea is used to prevent SCA pain episodes and is approved by the European Medicines Agency for adults, adolescents, and children over two-years-old with SCA. During quarterly visits, we will collect information about your child with the study medication, hydroxyurea. This study is being conducted by Dr. Russell Ware at Cincinnati Children's Hospital Medical Center (CCHMC) and his Co-Investigators including Professor Grace Ndeezi and Dr. Phillip Kasirye at the Mulago Hospital Sickle Cell Clinic, and the hydroxyurea medicine is supplied by the manufacturer.

The goal of this clinical trial is to assess the long-term risks and benefits of open-label dose-escalated oral hydroxyurea in a large cohort of Ugandan adolescents with sickle cell anemia (SCA). Additional objectives include investigation of hydroxyurea pharmacokinetics (PK) and pharmacodynamics (PD) in this population, and investigation of the drug's mechanisms of action through advanced genomics and multiomics analysis.

The main questions it aims to answer are:

Aim 1. To determine the safety and efficacy of maximum tolerated dose (MTD) vs. fixed dose (20 mg/kg/day) hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. For safety, we will compare adverse events and severe adverse events, including hematologic toxicities. For efficacy, we will assess hemoglobin level, fetal hemoglobin percentage (% HbF), and incidence of vaso-occlusive events such as pain crisis and acute chest syndrome.

Aim 2. To compare the clinical outcomes of MTD vs. fixed dose hydroxyurea treatment in children with SCA in a low-resource, malaria endemic setting. Clinical outcomes assessed will include growth and malaria incidence over a 24-month follow-up period, and differences in renal, splenic, and cerebrovascular function between study entry and 24-month follow-up.

Aim 3. To obtain long-term follow up data to assess laboratory and clinical effects as well as annual visits for organ function (liver, kidneys, spleen, brain) and growth/development.

Aim 4. Quantify the long-term benefits and risks of extended hydroxyurea treatment at MTD. We hypothesize that early and sustained hydroxyurea at MTD can (1) decrease the prevalence of organ damage; (2) improve growth and development; (3) preserve fertility; and (4) maintain a low risk for mutagenic genotoxicity. Protection against organ injury will be assessed in brain (Transcranial Doppler, MRI/MRA, and cerebral oxygenation); heart (echocardiogram); lungs (pulse oximetry, spirometry); kidney (length, glomerular filtration rate, albuminuria, and urine biomarkers); spleen (volume, erythrocyte micronuclei for filtrative function); bones (MRI for avascular necrosis, dual-energy X-ray absorptiometry for bone density); immunological competency (antibody titers to vaccines and malaria exposures); growth and development (standard auxologic measures, Tanner staging, growth hormones); fertility (sex hormones AMH/FSH/LH); and genotoxicity (clonal hematopoiesis, reticulocyte micronuclei).

Aim 5. Define and analyze hydroxyurea pharmacokinetics (PK) and pharmacodynamics (PD) profiles. We hypothesize that PK and PD hydroxyurea profiles will have substantial inter-patient variability. Both the Original Cohort and an untreated Comparator Cohort will undergo formal PK analysis using serial blood samples and a novel point-of-care assay to quantify hydroxyurea levels for calculating PK parameters and optimal dosing. With pharmacometrics analysis, these PK parameters will then be correlated with PD variables, including treatment responses (HbF) and hydroxyurea dose. These PK-PD associations will also be analyzed by age, hydroxyurea dose, and renal function.

Aim 6. Perform genomics analysis for genes influencing hydroxyurea treatment responses and modern multi-omics analysis with proteomics and metabolomics to help elucidate the drug's mechanism of action. We hypothesize that novel genetic variants affect key parameters such as optimal dose and HbF response. In addition to examining known or suspected target genes, we will use a univariate linear mixed model and genome-wide efficient mixed model association to analyze results of unbiased whole exome sequencing and genome-wide array data. We will also perform serial metabolomics and proteomics on samples collected before and during hydroxyurea treatment, to help identify useful biomarkers and signatures of treatment response, and elucidate pathways for hydroxyurea's mechanism of action.

Participants ages 11-16 years old will have information collected for up to 5 years which include:

• Physical Exam and Medical History
• Blood
• Urine Sample
• Near Infrared Spectroscopy
• Transcranial Doppler
• Pharmacokinetics Study
• Echocardiogram
• Spirometry
• Abdominal Ultrasound
• Brain MRI and MRA
• Hip and hand/wrist MRI
• Dual energy X-ray absorptiometry (DEXA)
• Quality of Life
• Physical Exam and Medical History
• Blood Sample
• Hydroxyurea medication

Children will take the maximum tolerated dose of hydroxyurea. A dose determined by pharmacokinetic-guided hydroxyurea initiation and subsequent optimization.