by
Russell E. Ware;
Barry R. Davis;
William H. Schultz;
Robert Clark Brown;
Banu Aygun;
Sharada Sarnaik;
Isaac Odame;
Beng Fuh;
Alex George;
William Owen;
Lori Luchtman-Jones;
Zora R. Rogers;
Lee Hilliard;
Cynthia Gauger;
Connie Piccone;
Margaret T. Lee;
Janet L. Kwiatkowski;
Sherron Jackson;
Scott T. Miller;
Carla Roberts ;
Matthew M. Heeney;
Theodosia A. Kalfa;
Stephen Nelson;
Hamayan Imran;
Kerri Nottage;
Ofelia Alvarez;
Melissa Rhodes;
Alexis A. Thompson;
Jennifer A. Rothman;
Kathleen J. Helton;
Donna Roberts;
Jamie Coleman ;
Melanie J. Bonner;
Abdullah Kutlar;
Niren Patel;
John Wood;
Linda Piller;
Peng Wei;
Judy Luden;
Nicole A. Mortier;
Susan E. Stuber;
Naomi L.C. Luban;
Alan R. Cohen;
Sara Pressel;
Robert J. Adams
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.