Table 1.

Summary of randomized clinical trials evaluating role of hydroxyurea in management of SCD in SSA.

Study	Objectives	Endpoints	Key findings	References
REACH  (Realizing Effectiveness Across Continents with Hydroxyurea)  Study sites: Angola, Democratic Republic of the Congo, Kenya, Uganda	Investigate the feasibility, safety, and benefits of hydroxyurea treatment for children with SCD living in SSA	Feasibility (enrollment, retention and adherence), Safety (dose levels, toxic effects, malaria), Benefits (lab values, SCD related events, transfusions, and survival)	(1) Study retention rate 94.2% at 3 years (2) Hydroxyurea increased total hemoglobin and HbF (3) Rates of clinical AEs of SCD decreased with HU use (44.6 vs 98.3 events per 100 patient-years) (4) Fewer non-malarial infections, fewer malaria infections, fewer deaths	[80,81]
NOHARM  Novel use Of Hydroxyurea in an African Region with Malaria  Study site: Uganda	Determine the safety and efficacy of hydroxyurea in a malaria-endemic region	Incidence of clinical malaria, SCD-related AEs, clinical and laboratory effects, and hematological toxicities	(1) No difference in malaria incidence between children on hydroxyurea vs. placebo (hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms (2) SCD-related clinical events (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) were less frequent with hydroxyurea (45%) than placebo (69%; P = .001) (3) Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes (4) Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms	[82]
NOHARM MTD  Study site: Uganda	Compare risks and benefits of hydroxyurea dosing to determine dosing standards for children with SCD in SSA	Hemoglobin 9 g/dl or more Or HbF 20% or more after 24 months	(1) Hydroxyurea with dose escalation had superior clinical efficacy to that of fixed dose hydroxyurea, with equivalent clinical safety	[83]
SPIN  Stroke Prevention In Nigeria  Study site: Nigeria	Determine the adherence rate to daily hydroxyurea therapy in children with SCD and elevated TCD measurements Assess the safety of hydroxyurea therapy, as it relates to infection associated with hospitalization and mortality	Feasibility, Safety, Benefits	(1) Initial management of abnormal TCD measurements with moderate fixed-dose hydroxyurea (~20 mg/kg/day) was comparable to initial management with regular blood transfusion in the STOP trial and was superior to no treatment (2) Monthly CBC assessments for myelosuppression have limited clinical utility in LMICs with moderate-fixed-dose hydroxyurea (3) High enrollment and retention rate (100% in treatment group) noted (4) High adherence to hydroxyurea noted	[70,95]
SPRING  Hydroxyurea for primary stroke prevention in children with sickle cell anemia in Nigeria  Study site: Nigeria	Determine the incidence of stroke in children with SCA receiving moderate-dose hydroxyurea compared to those on low-dose hydroxyurea	Incidence of initial stroke or transient ischemic attack, All-cause hospitalization rate	(1) Equivalent stroke incidence rates noted in children with SCA with abnormal TCD velocities on moderate-dose and low-dose hydroxyurea (2) Decreased rate of in-hospital vaso-occlusive episodes and acute pain events at home noted when hydroxyurea dose was increased to moderate-dose from low-dose hydroxyurea	[84]