Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial

• Authors: Russell E. Ware, Cincinnati Children’s Hospital Medical Center; Barry R. Davis, University of Texas; William H. Schultz, Cincinnati Children’s Hospital Medical Center; Robert Clark Brown, Emory University; Banu Aygun, Cohen Children’s Medical Center; Sharada Sarnaik, Wayne State University; Isaac Odame, Hospital for Sick Children; Beng Fuh, East Carolina University; Alex George, Baylor College of Medicine; William Owen, Children’s Hospital of the King’s Daughters; Lori Luchtman-Jones, Children’s National Medical Center; Zora R. Rogers, UT Southwestern; Lee Hilliard, University of Alabama; Cynthia Gauger, Nemours Children’s Clinic; Connie Piccone, Case Western Reserve University; Margaret T. Lee, Columbia University; Janet L. Kwiatkowski, Children’s Hospital of Philadelphia; Sherron Jackson, Medical University of South Carolina; Scott T. Miller, State University of New York-Downstate; Carla Roberts, University of South Carolina; Matthew M. Heeney, Boston Children’s Hospital; Theodosia A. Kalfa, Cincinnati Children’s Hospital Medical Center; Stephen Nelson, Children’s Hospitals and Clinics of Minnesota; Hamayan Imran, University of South Alabama; Kerri Nottage, St. Jude Children’s Research Hospital; Ofelia Alvarez, University of Miami; Melissa Rhodes, University of Mississippi; Alexis A. Thompson, Ann and Robert H. Lurie Children’s Hospital of Chicago; Jennifer A. Rothman, Duke University Medical Center; Kathleen J. Helton, St. Jude Children’s Research Hospital; Donna Roberts, Medical University of South Carolina; Jamie Coleman, St. Jude Children’s Research Hospital; Melanie J. Bonner, Duke University Medical Center; Abdullah Kutlar, Georgia Regents University; Niren Patel, Georgia Regents University; John Wood, Children’s Hospital of Los Angeles; Linda Piller, University of Texas School of Public Health; Peng Wei, University of Texas School of Public Health; Judy Luden, Medical University of South Carolina; Nicole A. Mortier, Cincinnati Children’s Hospital Medical Center; Susan E. Stuber, Cincinnati Children’s Hospital Medical Center; Naomi L.C. Luban, Children’s National Medical Center; Alan R. Cohen, Children’s Hospital of Philadelphia; Sara Pressel, University of Texas School of Public Health; Robert J. Adams, Medical University of South Carolina
• Journal Title: Lancet
• Volume: Volume 387, Number 10019
• Publisher: Elsevier: Lancet | 2016-02-13, Pages 661-670
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/S0140-6736(15)01041-7
• Subjects: Biology, Neuroscience; Health Sciences, Public Health
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, General & Internal; General & Internal Medicine; SILENT CEREBRAL INFARCTS; IRON OVERLOAD; DISEASE; STROKE; PREVENTION; ULTRASONOGRAPHY; PHLEBOTOMY; THERAPY; SWITCH; RATES; Sickle cell anaemia; Transcranial Doppler; Stroke; Hydroxyurea

Abstract

Background: For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods: TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings: Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation: For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.