The pediatric hydroxyurea phase III clinical trial (BABY HUG): Challenges of study design

Abstract

Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9 to 17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for two years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of two hundred. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity. (ClinicalTrials.gov number,NCT00006400)

Impact of hydroxyurea on clinical events in the BABY HUG trial

“…4 The trial began in October 2003 and was completed in September 2009. All children were taking prophylactic penicillin and received age-appropriate immunizations.…”

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

“…Further, the rates of severe cytopenias in the hydroxyurea group were comparable to the placebo group and there was no increased risk of serious bacterial infections in the most vulnerable age group, children less than 5 years of age [55]. However, evidence to support the primary hypothesis was lacking, namely hydroxyurea therapy would preserve splenic and renal function [56], the latter being a major determinant of earlier death in adults.…”

Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG Trial

“…Prevention of loss of splenic function is a primary endpoint. 1 After written informed consent in accordance with the Declaration of Helsinki, splenic filtrative function of children in BABY HUG was assessed by LS scan and compared with 2 surrogate biomarkers: pitted erythrocyte (PIT) counts by Nomarski optics and Howell-Jolly Bodies (HJBs) quantitated by flow cytometry. These pretreatment baseline data form the largest reported assessment of spleen function in young children with SCA by LS scan, define parameters of loss of function, and validate both biomarkers as accurate noninvasive measures of splenic function.…”