Hydroxycarbamide in very young children with sickle-cell anaemia

A multicentre, randomised, controlled trial (BABY HUG)

Winfred C. Wang, Russell E. Ware, Scott T. Miller, Rathi V. Iyer, James F. Casella, Caterina P. Minniti, Sohail Rana, Courtney D. Thornburg, Zora R. Rogers, Ram V. Kalpatthi, Julio C. Barredo, R. Clark Brown, Sharada A. Sarnaik, Thomas H. Howard, Lynn W. Wynn, Abdullah Kutlar, F. Daniel Armstrong, Beatrice A. Files, Jonathan C. Goldsmith, Myron A. Waclawiw & 2 others Xiangke Huang, Bruce W. Thompson

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)1663-1672
Number of pages10
JournalThe Lancet
Volume377
Issue number9778
DOIs
StatePublished - May 14 2011

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Sickle Cell Anemia
Randomized Controlled Trials
Placebos
Acute Chest Syndrome
Fetal Hemoglobin
Pentetic Acid
Spleen
Random Allocation
Glomerular Filtration Rate
Hemoglobins
National Institute of Child Health and Human Development (U.S.)
National Heart, Lung, and Blood Institute (U.S.)
Doppler Transcranial Ultrasonography
Sickle Hemoglobin
Pain
Intention to Treat Analysis
Hydroxyurea
Poisons
Neutropenia
Leukocyte Count

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Wang, W. C., Ware, R. E., Miller, S. T., Iyer, R. V., Casella, J. F., Minniti, C. P., ... Thompson, B. W. (2011). Hydroxycarbamide in very young children with sickle-cell anaemia: A multicentre, randomised, controlled trial (BABY HUG). The Lancet, 377(9778), 1663-1672. https://doi.org/10.1016/S0140-6736(11)60355-3

Hydroxycarbamide in very young children with sickle-cell anaemia : A multicentre, randomised, controlled trial (BABY HUG). / Wang, Winfred C.; Ware, Russell E.; Miller, Scott T.; Iyer, Rathi V.; Casella, James F.; Minniti, Caterina P.; Rana, Sohail; Thornburg, Courtney D.; Rogers, Zora R.; Kalpatthi, Ram V.; Barredo, Julio C.; Brown, R. Clark; Sarnaik, Sharada A.; Howard, Thomas H.; Wynn, Lynn W.; Kutlar, Abdullah; Armstrong, F. Daniel; Files, Beatrice A.; Goldsmith, Jonathan C.; Waclawiw, Myron A.; Huang, Xiangke; Thompson, Bruce W.

In: The Lancet, Vol. 377, No. 9778, 14.05.2011, p. 1663-1672.

Research output: Contribution to journalArticle

Wang, WC, Ware, RE, Miller, ST, Iyer, RV, Casella, JF, Minniti, CP, Rana, S, Thornburg, CD, Rogers, ZR, Kalpatthi, RV, Barredo, JC, Brown, RC, Sarnaik, SA, Howard, TH, Wynn, LW, Kutlar, A, Armstrong, FD, Files, BA, Goldsmith, JC, Waclawiw, MA, Huang, X & Thompson, BW 2011, 'Hydroxycarbamide in very young children with sickle-cell anaemia: A multicentre, randomised, controlled trial (BABY HUG)', The Lancet, vol. 377, no. 9778, pp. 1663-1672. https://doi.org/10.1016/S0140-6736(11)60355-3
Wang, Winfred C. ; Ware, Russell E. ; Miller, Scott T. ; Iyer, Rathi V. ; Casella, James F. ; Minniti, Caterina P. ; Rana, Sohail ; Thornburg, Courtney D. ; Rogers, Zora R. ; Kalpatthi, Ram V. ; Barredo, Julio C. ; Brown, R. Clark ; Sarnaik, Sharada A. ; Howard, Thomas H. ; Wynn, Lynn W. ; Kutlar, Abdullah ; Armstrong, F. Daniel ; Files, Beatrice A. ; Goldsmith, Jonathan C. ; Waclawiw, Myron A. ; Huang, Xiangke ; Thompson, Bruce W. / Hydroxycarbamide in very young children with sickle-cell anaemia : A multicentre, randomised, controlled trial (BABY HUG). In: The Lancet. 2011 ; Vol. 377, No. 9778. pp. 1663-1672.
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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 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.",
author = "Wang, {Winfred C.} and Ware, {Russell E.} and Miller, {Scott T.} and Iyer, {Rathi V.} and Casella, {James F.} and Minniti, {Caterina P.} and Sohail Rana and Thornburg, {Courtney D.} and Rogers, {Zora R.} and Kalpatthi, {Ram V.} and Barredo, {Julio C.} and Brown, {R. Clark} and Sarnaik, {Sharada A.} and Howard, {Thomas H.} and Wynn, {Lynn W.} and Abdullah Kutlar and Armstrong, {F. Daniel} and Files, {Beatrice A.} and Goldsmith, {Jonathan C.} and Waclawiw, {Myron A.} and Xiangke Huang and Thompson, {Bruce W.}",
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TY - JOUR

T1 - Hydroxycarbamide in very young children with sickle-cell anaemia

T2 - A multicentre, randomised, controlled trial (BABY HUG)

AU - Wang, Winfred C.

AU - Ware, Russell E.

AU - Miller, Scott T.

AU - Iyer, Rathi V.

AU - Casella, James F.

AU - Minniti, Caterina P.

AU - Rana, Sohail

AU - Thornburg, Courtney D.

AU - Rogers, Zora R.

AU - Kalpatthi, Ram V.

AU - Barredo, Julio C.

AU - Brown, R. Clark

AU - Sarnaik, Sharada A.

AU - Howard, Thomas H.

AU - Wynn, Lynn W.

AU - Kutlar, Abdullah

AU - Armstrong, F. Daniel

AU - Files, Beatrice A.

AU - Goldsmith, Jonathan C.

AU - Waclawiw, Myron A.

AU - Huang, Xiangke

AU - Thompson, Bruce W.

PY - 2011/5/14

Y1 - 2011/5/14

N2 - 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.

AB - 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.

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