Elsevier

The Lancet

Volume 377, Issue 9778, 14–20 May 2011, Pages 1663-1672
The Lancet

Articles
Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG)

https://doi.org/10.1016/S0140-6736(11)60355-3Get rights and content

Summary

Background

Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects.

Methods

This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ0thalassaemia, were aged 9–18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on 99Tc spleen scan) and renal function (glomerular filtration rate by 99mTc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2–4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00006400.

Findings

96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m2, p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia.

Interpretation

On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia.

Funding

The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.

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

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