Since 2014, NIH guidelines recommend hydroxyurea for the treatment of children affected with sickle cell anemia (SCA) as young as 9 months of age, although it remains clinically underutilized. One potential barrier is identifying the most effective dose. TREAT is a prospective study of hydroxyurea for children affected by SCA from 6 months to 16 years of age with the primary objective to develop and evaluate a population PK-based model to predict a personalized hydroxyurea maximum tolerable dose (MTD) through an individualized dosing strategy. A sparse sampling approach was developed to allow practical sampling from young children with SCA. Using the population PK model with Bayesian estimation and hydroxyurea concentrations measured at three specified time points, hydroxyurea exposure is estimated and a starting dose is calculated that approximates actual MTD to reduce both the time to maximum therapeutic effect and the need for dose modifications before achieving MTD.

TREAT has demonstrated the feasibility of individualized, PK-guided hydroxyurea therapy and suggests that early initiation of hydroxyurea for young children with SCA is both safe and effective, achieving HbF responses (>30-40%) beyond which has been seen with standard dosing. This precision medicine approach to hydroxyurea therapy suggests that it is possible to exceed the traditional therapeutic goals with individualized dosing and could be transformational for the treatment of young children with SCA. TREAT has recently been extended for three years with an award from the Doris Duke Charitable Foundation with plans to expand into a multisite research study.

The purpose of HELPS is to examine the pharmacokinetics and distribution of oral hydroxyurea when administered as a single dose to lactating women. The current package insert for hydroxyurea lists pregnancy and lactation as contraindications for treatment, however women with sickle cell disease have a high risk of maternal and fetal morbidity and mortality due to their underlying disease, so abrupt cessation of an effective disease-modifying treatment may not be justifiable. In addition, published case reports suggesting successful use during pregnancy and minimal transmission through breast milk warrant further data collection.

In this study, the following objectives are proposed for lactating women, either healthy volunteers or patients with SCA: (1) to obtain blood, saliva, urine, and breast milk samples for pharmacokinetics (PK) calculations on a scheduled collection and analysis strategy using HPLC and LC-MS/MS; (2) to calculate distribution ratios for hydroxyurea across compartments, especially plasma to milk; and (3) to create population PK profiles for hydroxyurea to help calculate potential infant drug exposure to gain more insight into the safety of hydroxyurea in the context of lactation.

Russell E. Ware, MD, PhD, has a strong interest in global health and has invested time, expertise and resources to benefit children with sickle cell disease in developing countries. The following international studies are currently under Ware’s guidance and direction:

Uganda Sickle Surveillance Study (US3)

US3 began as a newborn screening pilot study to assess the prevalence of sickle cell trait and disease across Uganda, using dried blood spots currently obtained through the EID Collection Program. The team from Cincinnati Children’s trained local investigators and technologists, and now over 200,000 samples have been tested to date. The initial US3 study was completed in 2015, after which targeted newborn screening for SCA began in the highest prevalence areas, and the preliminary analysis regarding genetic modifiers of SCA in the region is currently in progress. This model has inspired the development of two new screening programs: one in Northwest Tanzania (TS3) and one in Malawi (MS3).

Realizing Effectiveness Across Continents with Hydroxyurea (REACH)

This trial is a prospective Phase I/II open-label dose escalation trial of hydroxyurea for children with confirmed SCA between 1 and 10 years of age that will gather critical data regarding the feasibility, safety, and efficacy of open-label hydroxyurea in four countries within sub-Saharan Africa. This study began in 2014 and has patients enrolled and treated in Kenya, the Democratic Republic of Congo, Angola and Uganda, and the longer-term goal is to make hydroxyurea more widely available for children with SCA in Africa, particularly those identified with SCA through expanded newborn screening programs. In 2017, REACH was awarded NIH funding for five more years.

Novel Use Of Hydroxyurea in an African Region with Malaria (NOHARM)

NOHARM is a prospective Phase III randomized trial of hydroxyurea versus placebo in Uganda, testing the safety and efficacy of treatment of SCA in a malaria endemic location. NOHARM began in September 2014, enrolling 200 children between the ages of 1 to 4 over 12 months. In the first year, the incidence and severity of malaria was similar in both treatment arms and those on hydroxyurea had fewer SCA-related adverse events. The trial participants will be invited to continue open-label hydroxyurea therapy observed on either a fixed-dose or an escalated dose, which is an unconventional treatment approach for SCA in this region of the world.

Stroke Avoidance for Children in Republica Dominicana (SACRED): A Prospective Research Study to Reduce Stroke in Children with Sickle Cell Anemia

This prospective trial screens children 3-15 years of age with SCA for stroke risk using transcranial Doppler (TCD). All patients, including those who are already on hydroxyurea and transfusion therapy, will be included to obtain a cross-sectional description of TCD velocities in this patient population. Patients identified to have elevated TCD velocities between 170-199 cm/sec will be eligible for protocol-directed hydroxyurea therapy or dose optimization, and those with abnormal TCD velocities ≥200 cm/sec will commence with transfusion therapy per current practice guidelines at the clinical site. Participants will be followed for three years to help define the natural history of cerebrovascular disease in children with SCA in this setting.

Expanding Treatment for Existing Neurological Disease (EXTEND)

EXTEND is a large follow-up study beyond SCATE, a Phase III trial which compared 30 months of alternative therapy (hydroxyurea) to standard care (observation) in children with SCA and conditional (170 - 199cm/sec) TCD velocities. EXTEND is in Jamaica, where there is a high prevalence of children with conditional and abnormal TCD velocities. The study will provide open-label hydroxyurea for these children and directly address the research gap of how best to treat cerebrovascular disease in children with SCA without chronic transfusions.