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

Russell E. Ware, Barry R. Davis, William H. Schultz, R. 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 RobertsMatthew M. Heeney, Theodosia A. Kalfa, Stephen Nelson, Hamayun 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

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalThe Lancet
Volume387
Issue number10019
DOIs
StatePublished - Feb 13 2016

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Hydroxyurea
Sickle Cell Anemia
Maintenance
Random Allocation
Stroke
Therapeutics
National Heart, Lung, and Blood Institute (U.S.)
Sickle Hemoglobin
Pediatric Hospitals
Maximum Tolerated Dose
Magnetic Resonance Angiography
Transient Ischemic Attack
National Institutes of Health (U.S.)
Neuroimaging
Blood Transfusion
Canada
Linear Models
Magnetic Resonance Imaging
Safety
Pain

ASJC Scopus subject areas

  • Medicine(all)

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

In: The Lancet, Vol. 387, No. 10019, 13.02.2016, p. 661-670.

Research output: Contribution to journalArticle

Ware, RE, Davis, BR, Schultz, WH, Brown, RC, Aygun, B, Sarnaik, S, Odame, I, Fuh, B, George, A, Owen, W, Luchtman-Jones, L, Rogers, ZR, Hilliard, L, Gauger, C, Piccone, C, Lee, MT, Kwiatkowski, JL, Jackson, S, Miller, ST, Roberts, C, Heeney, MM, Kalfa, TA, Nelson, S, Imran, H, Nottage, K, Alvarez, O, Rhodes, M, Thompson, AA, Rothman, JA, Helton, KJ, Roberts, D, Coleman, J, Bonner, MJ, Kutlar, A, Patel, N, Wood, J, Piller, L, Wei, P, Luden, J, Mortier, NA, Stuber, SE, Luban, NLC, Cohen, AR, Pressel, S & Adams, RJ 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', The Lancet, vol. 387, no. 10019, pp. 661-670. https://doi.org/10.1016/S0140-6736(15)01041-7
Ware, Russell E. ; Davis, Barry R. ; Schultz, William H. ; Brown, R. Clark ; Aygun, Banu ; Sarnaik, Sharada ; Odame, Isaac ; Fuh, Beng ; George, Alex ; Owen, William ; Luchtman-Jones, Lori ; Rogers, Zora R. ; Hilliard, Lee ; Gauger, Cynthia ; Piccone, Connie ; Lee, Margaret T. ; Kwiatkowski, Janet L. ; Jackson, Sherron ; Miller, Scott T. ; Roberts, Carla ; Heeney, Matthew M. ; Kalfa, Theodosia A. ; Nelson, Stephen ; Imran, Hamayun ; Nottage, Kerri ; Alvarez, Ofelia ; Rhodes, Melissa ; Thompson, Alexis A. ; Rothman, Jennifer A. ; Helton, Kathleen J. ; Roberts, Donna ; Coleman, Jamie ; Bonner, Melanie J. ; Kutlar, Abdullah ; Patel, Niren ; Wood, John ; Piller, Linda ; Wei, Peng ; Luden, Judy ; Mortier, Nicole A. ; Stuber, Susan E. ; Luban, Naomi L.C. ; Cohen, Alan R. ; Pressel, Sara ; Adams, Robert J. / 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. In: The Lancet. 2016 ; Vol. 387, No. 10019. pp. 661-670.
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title = "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",
abstract = "Summary 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.",
author = "Ware, {Russell E.} and Davis, {Barry R.} and Schultz, {William H.} and Brown, {R. Clark} and Banu Aygun and Sharada Sarnaik and Isaac Odame and Beng Fuh and Alex George and William Owen and Lori Luchtman-Jones and Rogers, {Zora R.} and Lee Hilliard and Cynthia Gauger and Connie Piccone and Lee, {Margaret T.} and Kwiatkowski, {Janet L.} and Sherron Jackson and Miller, {Scott T.} and Carla Roberts and Heeney, {Matthew M.} and Kalfa, {Theodosia A.} and Stephen Nelson and Hamayun Imran and Kerri Nottage and Ofelia Alvarez and Melissa Rhodes and Thompson, {Alexis A.} and Rothman, {Jennifer A.} and Helton, {Kathleen J.} and Donna Roberts and Jamie Coleman and Bonner, {Melanie J.} and Abdullah Kutlar and Niren Patel and John Wood and Linda Piller and Peng Wei and Judy Luden and Mortier, {Nicole A.} and Stuber, {Susan E.} and Luban, {Naomi L.C.} and Cohen, {Alan R.} and Sara Pressel and Adams, {Robert J.}",
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language = "English (US)",
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pages = "661--670",
journal = "The Lancet",
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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)

T2 - 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.

PY - 2016/2/13

Y1 - 2016/2/13

N2 - Summary 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.

AB - Summary 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.

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