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 Roberts, Matthew 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, 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 Roberts, Matthew 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

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.

Conflict of interest statement

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

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
TWiTCH CONSORT flow diagram showing the enrollment, randomisation, and follow-up of the TWiTCH study participants.
Figure 2
Figure 2
Laboratory parameters based on intention-to-treat population: Panel A = hemoglobin concentration; Panel B = mean corpuscular volume; Panel C = %HbS; Panel D = %HbF; Panel E = white blood cell (WBC) count; Panel F = absolute neutrophil count (ANC); Panel G = absolute reticulocyte count (ARC); Panel H = serum ferritin. Complete blood counts and reticulocytes were measured locally, while hemoglobin electrophoresis and ferritin were analysed centrally. Data are illustrated as mean ± 1 standard deviation. The Standard Treatment Arm is portrayed in dashes while the Alternative Treatment Arm is shown by the solid line. All parameters are significantly different at exit (p

Figure 3

Primary study endpoint analysis of…

Figure 3

Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are…

Figure 3
Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are portrayed as dashes while the Alternative (Hydroxyurea) Arm data are shown as a solid line. Panel A illustrates the TCD data using the mixed model statistical analysis, with baseline equivalence but divergence over time with lower velocities in the Alternative Arm. The curves are significantly different using the per-protocol non-inferiority comparison (p=8.82 × 10−16) and also by post-hoc analysis for superiority (p=0.023). Panel B illustrates the actual TCD velocity data in each arm as mean ± 1 standard deviation, including the number of participants evaluated at each 12-week time point. Panel C illustrates baseline (enrolment) and final (exit) maximum time-averaged mean TCD velocities for each participant. The lines at 170 and 200 cm/sec denote the normal and abnormal TCD boundaries, respectively. Open circles = Alternative Arm, Closed circles = Standard Arm.

Figure 3

Primary study endpoint analysis of…

Figure 3

Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are…

Figure 3
Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are portrayed as dashes while the Alternative (Hydroxyurea) Arm data are shown as a solid line. Panel A illustrates the TCD data using the mixed model statistical analysis, with baseline equivalence but divergence over time with lower velocities in the Alternative Arm. The curves are significantly different using the per-protocol non-inferiority comparison (p=8.82 × 10−16) and also by post-hoc analysis for superiority (p=0.023). Panel B illustrates the actual TCD velocity data in each arm as mean ± 1 standard deviation, including the number of participants evaluated at each 12-week time point. Panel C illustrates baseline (enrolment) and final (exit) maximum time-averaged mean TCD velocities for each participant. The lines at 170 and 200 cm/sec denote the normal and abnormal TCD boundaries, respectively. Open circles = Alternative Arm, Closed circles = Standard Arm.
Figure 3
Figure 3
Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are portrayed as dashes while the Alternative (Hydroxyurea) Arm data are shown as a solid line. Panel A illustrates the TCD data using the mixed model statistical analysis, with baseline equivalence but divergence over time with lower velocities in the Alternative Arm. The curves are significantly different using the per-protocol non-inferiority comparison (p=8.82 × 10−16) and also by post-hoc analysis for superiority (p=0.023). Panel B illustrates the actual TCD velocity data in each arm as mean ± 1 standard deviation, including the number of participants evaluated at each 12-week time point. Panel C illustrates baseline (enrolment) and final (exit) maximum time-averaged mean TCD velocities for each participant. The lines at 170 and 200 cm/sec denote the normal and abnormal TCD boundaries, respectively. Open circles = Alternative Arm, Closed circles = Standard Arm.
Figure 3
Figure 3
Primary study endpoint analysis of TCD velocities. The Standard (Transfusion) Arm data are portrayed as dashes while the Alternative (Hydroxyurea) Arm data are shown as a solid line. Panel A illustrates the TCD data using the mixed model statistical analysis, with baseline equivalence but divergence over time with lower velocities in the Alternative Arm. The curves are significantly different using the per-protocol non-inferiority comparison (p=8.82 × 10−16) and also by post-hoc analysis for superiority (p=0.023). Panel B illustrates the actual TCD velocity data in each arm as mean ± 1 standard deviation, including the number of participants evaluated at each 12-week time point. Panel C illustrates baseline (enrolment) and final (exit) maximum time-averaged mean TCD velocities for each participant. The lines at 170 and 200 cm/sec denote the normal and abnormal TCD boundaries, respectively. Open circles = Alternative Arm, Closed circles = Standard Arm.

References

    1. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood. 1998;91:288–94.
    1. Hulbert ML, McKinstry RC, Lacey JL, et al. Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease. Blood. 2011;117:772–9.
    1. Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med. 1992;326:605–10.
    1. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusion in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339:5–11.
    1. Adams RJ for the STOP 2 Trial Investigators. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353:2769–78.
    1. Yawn BP, Buchanan GR, Afenyi-Annan AN, et al. Management of sickle cell disease. Summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033–48.
    1. Bernaudin F, Verlhac S, Arnaud C, et al. Impact of early transcranial Doppler screening and intensive therapy on cerebral vasculopathy outcome in a newborn sickle cell anemia cohort. Blood. 2011;117:1130–40.
    1. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332:1317–22.
    1. Wang WC, Ware RE, Miller ST, et al. for the BABY HUG Investigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG) Lancet. 2011;377:1663–72.
    1. Ware RE. How I use hydroxyurea to treat young patients with sickle cell anemia. Blood. 2010;115:5300–11.
    1. Gulbis B, Haberman D, Dufour D, et al. Hydroxyurea for sickle cell disease in children and for prevention of cerebrovascular events: the Belgian experience. Blood. 2005;105:2685–90.
    1. Zimmerman SA, Schultz WH, Burgett S, Mortier NA, Ware RE. Hydroxyurea therapy lowers transcranial Doppler flow velocities in children with sickle cell anemia. Blood. 2007;110:1043–7.
    1. Helton KJ, Adams RJ, Kesler KL, et al. Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: Results from the SWiTCH trial. Blood. 2014;124:891–8.
    1. Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am. 2008;55:483–501.
    1. Ware RE. Optimizing hydroxyurea therapy for sickle cell anemia. Am Soc Hematol Educ Program. in press.
    1. Aygun B, Mortier NA, Kesler K, et al. Therapeutic phlebotomy is safe in children with sickle cell anemia and can be effective treatment for transfusional iron overload. Br J Haematol. 2015;169:262–6.
    1. Reboussin DM, DeMets DL, Kyungmann K, Lan KK. Computations for group sequential boundaries using the Lan-DeMets spending function method. Control Clin Trials. 2000;21:190–207.
    1. Brambilla DJ, Miller ST, Adams RJ. Intra-individual variation in blood flow velocities in cerebral arteries of children with sickle cell disease. Pediatr Blood Cancer. 2007;49:318–22.
    1. Almeida CB, Souza LE, Leonardo FC, et al. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea. Blood. 2015;126:711–20.
    1. Raphael JL, Shetty PB, Lui H, Mahoney DH, Mueller BU. A critical assessment of transcranial Doppler screening rates in a large pediatric sickle cell center: opportunities to improve healthcare quality. Pediatr Blood Cancer. 2008;51:647–51.
    1. Reeves SL, Fullerton HJ, Dombkowski KJ, Boulton ML, Braun TM, Lisabeth LD. Physician attitude, awareness, and knowledge regarding guidelines for transcranial Doppler screening in sickle cell disease. Clin Pediatr. 2015;54:336–45.
    1. Aygun B, Wruck M, Schultz WH, et al. Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities. Am J Hematol. 2012;87:428–30.
    1. DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014;371:699–710.
    1. Kwiatkowski JL, Yim E, Miller S, Adams RJ for the STOP2 Study Investigators. Effect of transfusion therapy on transcranial Doppler ultrasonography velocities in children with sickle cell disease. Pediatr Blood Cancer. 2011;56:777–82.
    1. Ware RE, Schultz WH, Yovetich N, et al. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): A Phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. Pediatr Blood Cancer. 2011;57:1011–7.
    1. Ware RE, Zimmerman SA, Sylvestre PB, et al. Prevention of secondary stroke and resolution of transfusional iron overload in children with sickle cell anemia using hydroxyurea and phlebotomy. J Pediatr. 2004;145:346–52.
    1. Greenway A, Ware RE, Thornburg CD. Long-term results using hydroxyurea/phlebotomy for reducing secondary stroke risk in children with sickle cell anemia and iron overload. Am J Hematol. 2011;86:357–61.
    1. Flanagan JM, Frohlich DM, Howard TA, et al. Genetic predictors for stroke in children with sickle cell anemia. Blood. 2011;117:6681–4.
    1. Flanagan JM, Sheehan VA, Linder H, et al. Genetic mapping and exome sequencing identify 2 mutations associated with stroke protection in pediatric patients with sickle cell anemia. Blood. 2013;121:3237–45.
    1. Armstrong FD, Elkin TD, Brown RC, et al. for the BABY HUG Investigators. Developmental function in toddlers with sickle cell anemia. Pediatrics. 2013;131:e406–414.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren