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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.
Lancet. 2016 Feb 13; 387(10019):661-70.Lct

Abstract

BACKGROUND

For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions.

METHODS

TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307.

FINDINGS

Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions).

INTERPRETATION

For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke.

FUNDING

National Heart, Lung, and Blood Institute, National Institutes of Health.

Authors+Show Affiliations

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Electronic address: russell.ware@cchmc.org.University of Texas School of Public Health, Houston, TX, USA.Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Emory University, Atlanta, GA, USA.Cohen Children's Medical Center, New Hyde Park, NY, USA.Wayne State University, Detroit, MI, USA.Hospital for Sick Children, Toronto, ON, Canada.East Carolina University, Greenville, NC, USA.Baylor College of Medicine, Houston, TX, USA.Children's Hospital of the King's Daughters, Norfolk, VA, USA.Children's National Medical Center, Washington, DC, USA.UT Southwestern, Dallas, TX, USA.University of Alabama, Birmingham, AL, USA.Nemours Children's Clinic, Jacksonville, FL, USA.Case Western Reserve University, Cleveland, OH, USA.Columbia University, New York, NY, USA.Children's Hospital of Philadelphia, Philadelphia, PA, USA.Medical University of South Carolina, Charleston, SC, USA.State University of New York-Downstate, Brooklyn, NY, USA.University of South Carolina, Columbia, SC, USA.Boston Children's Hospital, Boston, MA, USA.Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA.University of South Alabama, Mobile, AL, USA.St Jude Children's Research Hospital, Memphis, TN, USA.University of Miami, Miami, FL, USA.University of Mississippi, Jackson, MS, USA.Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.Duke University Medical Center, Durham, NC, USA.St Jude Children's Research Hospital, Memphis, TN, USA.Medical University of South Carolina, Charleston, SC, USA.St Jude Children's Research Hospital, Memphis, TN, USA.Duke University Medical Center, Durham, NC, USA.Georgia Regents University, Augusta, GA, USA.Georgia Regents University, Augusta, GA, USA.Children's Hospital of Los Angeles, Los Angeles, CA, USA.University of Texas School of Public Health, Houston, TX, USA.University of Texas School of Public Health, Houston, TX, USA.Medical University of South Carolina, Charleston, SC, USA.Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Children's National Medical Center, Washington, DC, USA.Children's Hospital of Philadelphia, Philadelphia, PA, USA.University of Texas School of Public Health, Houston, TX, USA.Medical University of South Carolina, Charleston, SC, USA.

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26670617

Citation

Ware, Russell E., et al. "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." Lancet (London, England), vol. 387, no. 10019, 2016, pp. 661-70.
Ware RE, Davis BR, Schultz WH, et al. 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. Lancet. 2016;387(10019):661-70.
Ware, R. E., Davis, B. R., Schultz, W. H., Brown, R. C., Aygun, B., Sarnaik, S., Odame, I., Fuh, B., George, A., Owen, W., Luchtman-Jones, L., Rogers, Z. R., Hilliard, L., Gauger, C., Piccone, C., Lee, M. T., Kwiatkowski, J. L., Jackson, S., Miller, S. T., ... Adams, R. J. (2016). 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. Lancet (London, England), 387(10019), 661-70. https://doi.org/10.1016/S0140-6736(15)01041-7
Ware RE, et al. 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. Lancet. 2016 Feb 13;387(10019):661-70. PubMed PMID: 26670617.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ware,Russell E, AU - Davis,Barry R, AU - Schultz,William H, AU - Brown,R Clark, AU - Aygun,Banu, AU - Sarnaik,Sharada, AU - Odame,Isaac, AU - Fuh,Beng, AU - George,Alex, AU - Owen,William, AU - Luchtman-Jones,Lori, AU - Rogers,Zora R, AU - Hilliard,Lee, AU - Gauger,Cynthia, AU - Piccone,Connie, AU - Lee,Margaret T, AU - Kwiatkowski,Janet L, AU - Jackson,Sherron, AU - Miller,Scott T, AU - Roberts,Carla, AU - Heeney,Matthew M, AU - Kalfa,Theodosia A, AU - Nelson,Stephen, AU - Imran,Hamayun, AU - Nottage,Kerri, AU - Alvarez,Ofelia, AU - Rhodes,Melissa, AU - Thompson,Alexis A, AU - Rothman,Jennifer A, AU - Helton,Kathleen J, AU - Roberts,Donna, AU - Coleman,Jamie, AU - Bonner,Melanie J, AU - Kutlar,Abdullah, AU - Patel,Niren, AU - Wood,John, AU - Piller,Linda, AU - Wei,Peng, AU - Luden,Judy, AU - Mortier,Nicole A, AU - Stuber,Susan E, AU - Luban,Naomi L C, AU - Cohen,Alan R, AU - Pressel,Sara, AU - Adams,Robert J, Y1 - 2015/12/06/ PY - 2015/12/17/entrez PY - 2015/12/17/pubmed PY - 2016/3/8/medline SP - 661 EP - 70 JF - Lancet (London, England) JO - Lancet VL - 387 IS - 10019 N2 - BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/26670617/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(15)01041-7 DB - PRIME DP - Unbound Medicine ER -