ArticlesHydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)
Introduction
Sickle-cell anaemia is characterised by haemoglobin polymerisation that results in sickle-shaped red blood cells, vaso-occlusion, haemolytic anaemia, and vasculo-endothelial dysfunction, causing pain, organ injury, and early mortality. Clinical symptoms begin in the first year of life, with a physiological decline in fetal haemoglobin concentration. Higher concentrations of fetal haemoglobin are associated with fewer pain crises1 and improved survival.2 Hydroxycarbamide is an antineoplastic drug that inhibits ribonucleotide reductase, increases fetal haemoglobin concentration in red blood cells, and has other potentially beneficial effects, including improved nitric oxide metabolism, reduced red cell–endothelial interaction, and decreased erythrocyte density.3 15 years ago the double-blind placebo-controlled Multi-Center Study of Hydroxyurea (MSH) in adults with severe sickle-cell anaemia showed that hydroxycarbamide substantially reduced episodes of pain and acute chest syndrome, admissions to hospital, and transfusions.4 Subsequently, smaller studies have shown similar benefits and few toxic effects in school-age children and adolescents.5
In 2000, the US National Heart, Lung, and Blood Institute (NHLBI) awarded a competitive contract to test in a clinical trial whether hydroxycarbamide given to infants with sickle-cell anaemia for 2 years slows or prevents organ damage. In a pilot trial (HUSOFT),6 very young children with sickle-cell anaemia tolerated a liquid hydroxycarbamide formulation (20 mg/kg per day), and had improved blood counts and fetal haemoglobin concentrations compared with predicted age-specific levels.6 After 2 years, splenic radionuclide uptake was absent in only 47% of children, although 80% absence was predicted, leading to the choice of splenic function as a primary endpoint for the Pediatric Hydroxyurea in Sickle Cell Anemia (BABY HUG) trial. Because glomerular filtration rate (GFR) is abnormally increased early in life in children with sickle-cell anaemia, and can lead to progressive renal dysfunction,7 we also assessed the effect of hydroxycarbamide on GFR as a primary endpoint.
We designed the BABY HUG trial to determine whether hydroxycarbamide safely prevents early damage to the spleen and kidneys in infants with sickle-cell anaemia. We also aimed to assess the effect of hydroxycarbamide on adverse clinical events, blood counts, additional aspects of organ function, and toxic effects.8
Section snippets
Patients
Participants aged 9–18 months were recruited between October, 2003, and September, 2007, at 13 trial centres in the USA. After written informed consent was obtained from their parents or guardians, potential study participants were assessed to establish eligibility and baseline status. An ombudsman was present at each site to promote understanding of the risks and demands of study participation. An unmasked so-called primary endpoint person monitored laboratory values and assisted in clinical
Results
193 infants with HbSS (n=187) or Sβ0thalassaemia (n=6), mean age 13·6 months (range 9–18), were randomly assigned to a treatment group at 13 clinical centres (figure 1). A temporary administrative clinical hold on all study activity occurred from March to June, 2006, because of a specified expiration date on one lot of treatment bottles. 179 (93%) participants who completed at least 18 months of the trial and at least one exit assessment were analysed; 167 (86%) completed the full study. 96
Discussion
Hydroxycarbamide was safe and resulted in a decrease in common but serious adverse events, especially pain and dactylitis, as well as improved laboratory parameters. Several secondary measures of spleen, kidney, and CNS function suggested benefit, but these results were not conclusive.
BABY HUG is, to our knowledge, the first randomised, double-blind trial of hydroxycarbamide in children with sickle-cell anaemia (panel 2). It differs from all other paediatric trials (except for the pilot HUSOFT
References (30)
How I use hydroxyurea to treat young patients with sickle cell anemia
Blood
(2010)- et al.
Hydroxyurea for treatment of severe sickle cell anemia: a pediatric clinical trial
Blood
(1996) - et al.
A two-year pilot trial of hydroxyurea in very young children with sickle-cell anemia
J Pediatr
(2001) - et al.
Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease
J Pediatr
(2000) - et al.
Biomarkers of splenic function in infants with sickle cell anemia: baseline data from the BABY HUG trial
Blood
(2011) - et al.
Acquired DNA mutations associated with in vivo hydroxyurea exposure
Blood
(2000) - et al.
Assessment of genotoxicity associated with hydroxyurea therapy in children with sickle cell anemia
Mutat Res
(2010) - et al.
Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease
Blood
(2004) - et al.
Prediction of adverse outcomes in children with sickle cell anemia: a study of the Dallas Newborn Cohort
Blood
(2008) - et al.
The effect of prolonged administration of hydroxyurea on morbidity and mortality in adult patients with sickle cell syndromes: results of a 17-year, single-center trial (LaSHS)
Blood
(2010)
Pain in sickle cell disease. Rates and risk factors
N Engl J Med
Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia
N Engl J Med
The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design
Pediatr Blood Cancer
Chemical and functional analysis of hydroxyurea oral solutions
J Pediatr Hematol Oncol
Cited by (607)
Adherence in adults with sickle cell disease: Using illness perception to understand the low adherence rate
2024, Revue Europeenne de Psychologie Appliquee