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Author Notes:

Corresponding Author: Russell E. Ware MD PhD, 3333 Burnet Avenue, Cincinnati Children’s Hospital Medical Center, Cincinnati OH 45229, 513-803-4597 (phone), russell.ware@cchmc.org

AUTHORS & CONTRIBUTORS: REW, BRD, and RJA designed the study, supervised the trial, analysed the results, and wrote the first draft of the manuscript.

WHS, LP, JL, SES, and SP helped coordinate many critical aspects of the trial to ensure its safe and successful operational execution.

RCB, BA, SS, IO, BF, AG, WO, LLJ, ZRR, LH, CG, CP, MTL, JLK, SJ, STM, CR, MMH, TK, SN, IH, KN, OA, MR, AAT, and JR enrolled patients, collected data, and helped interpret the results.

KJH, DR, JC, MJB, AK, NP, JW, NAM, NLCL, and ARC performed critical laboratory analyses and consultation for specific aspects of the trial related to study treatments and protocol endpoints.

PW and BRD performed statistical analyses for the trial.

All authors participated in the editing of the manuscript and approved the final version, and fulfill authorship requirements as outlined in the ICMJE recommendations.

The authors wish to thank all of the staff at the Medical Coordinating Centre at Cincinnati Children’s Hospital and the Data Coordinating Centre at the University of Texas School of Public Health for their support throughout the study.

We acknowledge the assistance of Drs. Ronald Helms and Nancy Yovetich in the design of the study.

FerriScan® R2-MRI was graciously provided at discount by Resonance Health in Claremont, Australia.

We also appreciate the efforts of all healthcare providers, and especially the nursing staff, at each participating institution.

The authors provide special recognition for the eager participation and time commitments made by the children and families who enrolled in this study.

DECLARATION OF INTERESTS: Hydroxyurea is not approved by the US FDA for use in children with sickle cell anemia, and the TWiTCH trial was performed under FDA IND #67289 with cross-reference to FDA IND #111926.

Dr. Ware is a consultant for Bayer Pharmaceuticals and Global Blood Therapeutics; receives research support from Bristol Myers-Squibb, Addmedica, and Biomedomics Inc.; and serves on a Data and Safety Monitoring Board for Eli Lilly.

Dr. Odame serves as a consultant to Novartis, and sits on an Advisory Board to ApoPharma and Global Blood Therapeutics.

Dr. Owen serves on the Speaker’s Bureau of Novartis.

Dr. Rogers is a consultant to ApoPharma and on the Speaker’s Bureau for Bio-Rad Labs.

Dr. Kwiatkowski is a consultant for Shire and Sideris, and receives research funding from ApoPharma.

Dr. Heeney serves on the Scientific Advisory Board of Sancilio and Company.

Dr. Imran is on the Speaker’s Bureau of NovoNordisk.

Dr. Nottage is now employed by Janssen Pharmaceuticals, Inc.

Dr. Wood is a consultant to ApoPharma, Biomed Informations, ISIS Pharmaceuticals, Celgene, AMAG, and Pfizer; receives research support from AMAG and Philips Healthcare; and serves as a Medical Advisor for ApoPharma.

Dr. Cohen is a consultant to Novartis and serves on a Data and Safety Monitoring Board for an ApoPharma-sponsored clinical trial.

None of these disclosures is relevant to the results and conclusions of the TWiTCH trial.

Nothing to disclose: BRD, WHS, RCB, BA, SS, BF, AG, LLJ, LH, CG, CP, MTL, SJ, STM, CR, TAK, SN, OA, MR, AAT, JAR, KJH, DR, JC, MJB, AK, NP, LP, PW, JL, NAM, SES, NLCL, SP, RJA


Research Funding:

Funding: National Heart, Lung, and Blood Institute; NIH. TWiTCH was registered at ClinicalTrials.gov NCT01425307.

This clinical trial was supported by the National Heart, Lung and Blood Institute through grants R01 HL-095647 (REW) and R01 HL-095511 (BRD).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, General & Internal
  • General & Internal Medicine
  • Sickle cell anaemia
  • Transcranial Doppler
  • Stroke
  • Hydroxyurea

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

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Journal Title:



Volume 387, Number 10019


, Pages 661-670

Type of Work:

Article | Post-print: After Peer Review


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.

Copyright information:

© 2016 Elsevier Ltd.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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