SWiTCH 2012.
| Methods |
Trial design: RCT Trial grouping: parallel group Open Label: yes Cluster RCT: no Total duration of trial treatment was 30 months after randomisation, with a final trial visit scheduled 6 months after discontinuation of trial treatments Non‐inferiority trial |
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| Participants | Screened: N = 202; enrolled: N = 161; randomised: N = 134 Baseline characteristics RBC transfusions
Hydroxyurea
Included criteria: paediatric participants with severe forms of SCA (HbSS, HbS/βº‐thalassaemia, HbS/OArab;); age range of 5.0 ‐ 18.9 years, inclusive, at the time of enrolment; initial (primary) completed overt clinical stroke after the age 12 months with documented infarction on brain CT or MRI; at least 18 months of chronic monthly erythrocyte transfusions since primary stroke; transfusional iron overload, defined as a previously documented liver iron concentration ≥ 5.0 mg Fe per g of dry weight liver or serum ferritin ≥ 500 ng/mL on 2 independent measurements; adequate monthly erythrocyte transfusions with average HbS ≤ 45% (the upper limit of the established academic community standard) for the past 6 months before enrolment; parent or guardian willing and able to provide informed consent with verbal or written assent from the child (< 18 years of age), and subject willing and able to provide informed consent (≥ 18 years of age); ability to comply with trial‐related treatments, evaluations, and follow‐up Excluded criteria: inability to receive or tolerate chronic RBC transfusion therapy; inability to take or tolerate daily oral hydroxyurea; clinical and laboratory evidence of hypersplenism (temporary); abnormal laboratory values at initial evaluation (temporary); current participation in other therapeutic clinical trials; current use of other therapeutic agents for SCD (e.g. arginine, decitabine, magnesium); any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the investigator makes participation ill‐advised; inability or unwillingness to complete required screening studies, including blood tests, brain MRI/MRA, and liver biopsy; a sibling enrolled in SWiTCH |
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| Interventions |
RBC transfusions
Hydroxyurea
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| Outcomes |
Primary outcome: composite primary endpoint of secondary stroke recurrence rate and quantitative liver iron concentration. Secondary outcomes: non‐stroke neurological events, non‐neurological sickle cell clinical events, quality of life evaluation, and measures of organ function |
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| Identification |
Sponsorship source: National Heart, Lung, and Blood Institute grants U01‐HL078787 (R.E.W.) and U01‐HL078987 (R.W.H.) Country: USA Setting: 26 paediatric outpatients treating children with SCD Comments: declarations of interest: The authors declare no competing financial interests. Trial registration: ClinicalTrials.gov NCT00122980 Authors name: Russell E. Ware Institution: Center for Global Health, Baylor College of Medicine and Texas Children’s Hospital, Email: reware@bcm.edu Address: Russell E. Ware, MD, PhD, Director, Centerfor Global Health, Baylor College of Medicine and Texas Children’s Hospital, 1102 Bates St, Ste FC‐1145, Houston, TX 77030 |
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| Notes | "Study exit examinations were performed in 112 children (75%) who did not experience an adjudicated stroke and the examinations revealed few changes. Only 1 subject (alternative treatment) developed a new subcortical lacuna, consistent with silent infarction occurring during the study treatment period. Similarly, only 1 subject had progressive vasculopathy (evolved from grade 0 to grade 4); this subject was also in the alternative treatment arm." Analysis: because reduction in LIC was not superior on hydroxyurea/phlebotomy, the DSMB concluded that the composite primary endpoint would not be met and recommended trial closure. NHLBI closed SWiTCH. N = 40 did not complete treatment phase in transfusion/iron chelation arm and N = 43 did not complete treatment phase in hydroxyurea/phlebotomy arm Power calculation: not stated |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Judgement comment: method of sequence generation not reported |
| Allocation concealment (selection bias) | Unclear risk | Judgement comment: method of allocation concealment not reported |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Judgement comment: by the nature of the trial treatments used to prevent recurrent stroke (blood transfusions vs hydroxyurea), it is impractical to make SWiTCH a blinded (masked) trial |
| Blinding of outcome assessment (detection bias) SCI, stroke, and all‐cause mortality | Low risk | Judgement comment: the inclusive independent stroke adjudication process for all suspected new neurological events is a novel feature of the trial. Stroke recurrence is a primary endpoint but also is a critical safety endpoint for the SWiTCH trial. Accordingly, it was necessary to develop an inclusive process by which all potential stroke events were recognized and systematically adjudicated using a standardised protocol and masked consultants. Participants who develop any acute neurological change are promptly evaluated for possible stroke. In addition, site personnel are provided with a written script to use at each interval clinic visit, to ensure that subjects and families are asked each month about any signs and symptoms of stroke. After a new neurological event is suspected, the stroke adjudication process begins. The clinical history and neurological exam are reviewed by 3 independent neurologists without knowledge of the imaging findings. Simultaneously, the radiological evaluation is reviewed by 3 independent masked neuroradiologists without knowledge of the clinical history or neurological examination. Only after their independent consensus opinions are formed are these two opinions reconciled into a final stroke adjudication decision; a diagnosis of stroke requires new neurological findings with corresponding radiological changes |
| Blinding of outcome assessment (detection bias) All outcomes except SCI, stroke and all‐cause mortality | High risk | Judgement comment: the SWiTCH principal investigator was masked to all treatment‐specific results, including laboratory tests and clinical events. In addition, all investigators at the peripheral clinical sites are masked to trial treatment results outside of their own clinical centre |
| Incomplete outcome data (attrition bias) Stroke and SCI | Low risk | The primary statistical analyses of efficacy and safety will be performed on the ITT population, which consists of all subjects who were randomised to a trial treatment and for whom outcome data are available |
| Incomplete outcome data (attrition bias) All outcomes except stroke and SCI | Low risk | The primary statistical analyses of efficacy and safety will be performed on the ITT population, which consists of all subjects who were randomised to a trial treatment and for whom outcome data are available |
| Selective reporting (reporting bias) | High risk | Judgement comment: several secondary outcomes not reported (i.e. quality of life, growth and development, organ damage, transfusion‐related, chelation‐related and phlebotomy related complications) |
| Other bias | Unclear risk | Judgement comment: the DSMB concluded that the composite primary trial endpoint would not be met and recommended trial closure. NHLBI closed SWiTCH ‐ N = 40 did not complete treatment phase in transfusion/iron chelation arm and N = 43 did not complete treatment phase in hydroxyurea/phlebotomy arm. More participants had moya‐moya in the hydroxyurea arm (11 participants) than the transfusion arm (5 participants), it was not known if there was a difference between treatment arms in the number of participants with other types of severe vasculopathy |