title: Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).
abstract: 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 Sβ(0)thalassaemia, 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 (99)Tc spleen scan) and renal function (glomerular filtration rate by (99m)Tc-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.
  
  
  RESULTS
  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 m(2), 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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA. winfred.wang@stjude.org
authors.forename: Winfred C
authors.initials: WC
authors.lastname: Wang
authors.forename: Russell E
authors.initials: RE
authors.lastname: Ware
authors.forename: Scott T
authors.initials: ST
authors.lastname: Miller
authors.forename: Rathi V
authors.initials: RV
authors.lastname: Iyer
authors.forename: James F
authors.initials: JF
authors.lastname: Casella
authors.forename: Caterina P
authors.initials: CP
authors.lastname: Minniti
authors.forename: Sohail
authors.initials: S
authors.lastname: Rana
authors.forename: Courtney D
authors.initials: CD
authors.lastname: Thornburg
authors.forename: Zora R
authors.initials: ZR
authors.lastname: Rogers
authors.forename: Ram V
authors.initials: RV
authors.lastname: Kalpatthi
authors.forename: Julio C
authors.initials: JC
authors.lastname: Barredo
authors.forename: R Clark
authors.initials: RC
authors.lastname: Brown
authors.forename: Sharada A
authors.initials: SA
authors.lastname: Sarnaik
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Howard
authors.forename: Lynn W
authors.initials: LW
authors.lastname: Wynn
authors.forename: Abdullah
authors.initials: A
authors.lastname: Kutlar
authors.forename: F Daniel
authors.initials: FD
authors.lastname: Armstrong
authors.forename: Beatrice A
authors.initials: BA
authors.lastname: Files
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Goldsmith
authors.forename: Myron A
authors.initials: MA
authors.lastname: Waclawiw
authors.forename: Xiangke
authors.initials: X
authors.lastname: Huang
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Thompson
mesh_terms: D056586:Acute Chest Syndrome / Q000209:etiology / Q000517:prevention & control; D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000986:Antisickling Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001772:Blood Cell Count; D002657:Child Development; D005260:Female; D005919:Glomerular Filtration Rate; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000627:therapeutic use*; D007223:Infant; D008297:Male; D009994:Osmolar Concentration; D010146:Pain / Q000209:etiology / Q000517:prevention & control; D013154:Spleen / Q000473:pathology / Q000503:physiopathology; D016284:Technetium Tc 99m Pentetate / Q000378:metabolism; D016896:Treatment Outcome; D017585:Ultrasonography, Doppler, Transcranial; D014481:United States; D014556:Urine / Q000737:chemistry
chemical_list: D000986:Antisickling Agents; D015415:Biomarkers; D006454:Hemoglobins; D016284:Technetium Tc 99m Pentetate; D006918:Hydroxyurea