STOP 1998.

Methods	Trial design: RCT Trial grouping: parallel group Open label: yes Cluster RCT: no Mean (SD) length of follow‐up: transfusion arm: 21.0 (5.7) months; standard care: 18.3 (7.0) months Analysis: 4 interim analyses and one final analysis were planned. The date of the first analysis changed from 20 months to 14 months after recruitment began
Participants	Participant flow: screened: N = 1934; eligible: N = 206 randomised: N = 130 Baseline characteristics RBC transfusions N (total number of participants): 63 Age: mean (SD): 8.2 (3.2) years Sex: M: 31 (49%) Sickle cell genotype N (%): not reported (trial included only HbSS or HbSβº) Ethnic origin: not reported HbS%: 87 ± 10 Baseline Hb mean (SD) g/dL: 72 (8) HbF%: 8.0 ± 5.2 Lesions on MRI: 19 (31%) in original paper; 18 out of 56 in Pegelow paper TCD velocity mean (SD): 223 (27) Alpha thalassaemia: 14 (22%) Standard care N (total number of participants): 67 Age mean (SD): 8.4 (3.3) years Sex: M: 29 (43%) Sickle cell genotype N (%): not reported (trial included only HbSS or HbSβº) Ethnic origin: not reported HbS%: 87 ± 7 Baseline Hb mean (SD) g/dL: 76 (7) HbF%: 9.4 ± 5.0 Lesions on MRI: 25 (38%) in original paper; 29 out of 71 in Pegelow paper TCD velocity mean (SD): 223 (28) Alpha thalassaemia: 7 (9%) Included criteria: children 2 ‐ 16 years of age and who had been given a diagnosis of SCA or sickle βº thalassaemia at high risk of stroke with a blood flow velocity of at least 200 cm per second on 2 TCD trials. Only children with an MRI at trial entry were included in the SCI analysis Excluded criteria: history of stroke, had an indication for or contraindication to long‐term transfusion, were receiving other treatments that affected the risk of stroke, were infected with HIV, had been treated for seizures, were pregnant, or had a serum ferritin concentration above 500 ng per mL Pretreatment: baseline Hb was higher in the standard care group. Alpha thalassaemia was more common RBC transfusion group
Interventions	Intervention characteristics RBC transfusions Description: In the transfusion arm the goal was to reach an HbS concentration < 30 percent of total haemoglobin within 21 days without exceeding a haemoglobin concentration of 120 g/L and a hematocrit of 36%. Exchange or simple transfusion were allowed: 63% were simple transfusions, 12% were exchange; 25% a combination of simple and exchange. RBC were delivered in a volume of approximately 10 to 15 mL per kg of packed cells per transfusion. RBC component: leucocyte‐depleted, negative for haemoglobin S. RBC matching: ABO, Rh and Kell antigensIron. Chelation: none. Potential participants with a ferritin level above 500 ng/mL were excluded from the trial. The intention was to exclude any child with a significant iron burden before initiation of treatment, thus avoiding clinically significant iron overload during the trial Standard care Description: concomitant care included penicillin prophylaxis, pneumococcal vaccination, folic acid supplementation, surgery, and treatment of acute illness, including the use of transfusion when needed for transient episodes but excluding the use of hydroxyurea or anti‐sickling agents. Vaccination against hepatitis B was required if appropriate
Outcomes	Primary outcome: cerebral infarction and intracranial haemorrhage Secondary outcomes: death, transfusion‐related adverse events
Identification	Sponsorship source: supported by Cooperative Agreements (U10 HL 52193 and U10 HL 52016) with the National Heart, Lung, and Blood Institute. Country: USA & Canada Setting: Paediatric outpatients treating children with sickle cell disease aged 2 ‐ 16 years of age with HbSS or HbSβº thalassaemia Comments: declarations of interest: None; published trial registration: No registration found; Authors name: Dr Robert J. Adams Institution: Department of Neurology, Medical College of Georgia Email: rjadams@mcg.edu Address: Department of Neurology, Medical College of Georgia, 1467 Harper St., HB‐2060, Augusta, GA 30912‐3200
Notes	Screening began in January 1995 and ended in November 1996. The trial was to run to December 1998 but was stopped in September 1997 "Estimates of stroke risk for patients randomized to standard care were obtained by fitting an exponential model to the follow‐up of TCD (1) patients follow‐up, it was estimated that 47% of patients in this group should develop stroke on study. Assuming transfusion prevents 70% of these strokes, 14% of the patients randomized to transfusion should have strokes on study. Taken together, these values imply that a sample size of 46 per treatment arm should provide the desired statistical power of 90% to detect a 70% reduction in stroke incidence at a type I error rate of 0.05 for a two‐sided test"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The DCC developed permuted blocks within which treatment allocations were randomly and evenly assigned. The blocks themselves were randomly assigned to each of the 12 Centers."
Allocation concealment (selection bias)	Low risk	"After telephone verification that the patient was eligible and acquisition of written parental consent, the DCC ran a short randomization program and provided the Investigator with the trial group assignment." " Permuted blocks are used to blind Investigators to the potential treatment assignment of each patient while preserving approximate balance within and across Centers. The DCC provided the Clinical Center Investigator and patient with the treatment assignment."
Blinding of participants and personnel (performance bias) All outcomes	High risk	Judgement Comment: clinicians and participants were unblinded
Blinding of outcome assessment (detection bias) SCI, stroke, and all‐cause mortality	Low risk	A panel of physicians with no knowledge of the children’s treatment assignments who were not affiliated with the trial centres determined whether an event was a stroke. The primary endpoints were cerebral infarction and intracranial haemorrhage. "The protocol was intended to identify all neurologic events. A panel of physicians with no knowledge of the children’s treatment assignments who were not affiliated with the trial centres determined whether an event was a stroke."
Blinding of outcome assessment (detection bias) All outcomes except SCI, stroke and all‐cause mortality	High risk	Judgement comment: unblinded trial
Incomplete outcome data (attrition bias) Stroke and SCI	Unclear risk	Quote: "Only those subjects who had an MRI of the brain at the time of randomization were included in this analysis. Since the question being addressed was secondary to the trial, ITT analysis was not used; treatment classification was based on actual study experience. Five subjects randomized to the transfusion therapy arm were managed with standard care. The parents of 3 children refused transfusion therapy, another child was not compliant with monthly appointments, and 1 child who developed a delayed transfusion reaction could not be provided phenotypically matched blood. For this analysis, all 5 of these patients are considered to be in the standard care treatment arm." Judgement comment: this is a subgroup analysis that included only those with an MRI and done by treatment and not ITT
Incomplete outcome data (attrition bias) All outcomes except stroke and SCI	Low risk	Judgement comment: an ITT analysis was used, despite 12 participants crossing over between groups (2) or withdrawing from the trial (10). Reasons were provided. 10 participants from the transfusion group withdrew from the trial because of problems with compliance (n = 4), multiple alloantibodies (n = 1), ineligibility (n = 1) or other unspecified reasons (n = 4). Two participants from the standard care group crossed over to the transfusion group, one on the second day due to diagnosis of subacute intracerebral hematoma and the other after 12 months for treatment of leg ulcers
Selective reporting (reporting bias)	Unclear risk	Judgement comment: no protocol available and no prospective trial registration
Other bias	Unclear risk	Quote: "Since equipment or imaging programs were upgraded during the course of the study, the quality of later MRI studies was frequently better than those done earlier. As a result, some lesions seen on later studies could, in retrospect, be seen on those previously reported as showing no abnormality. In that case, the earlier result was changed to reflect the latest reading." Judgement comment: "Four interim analyses and one final analysis were planned, with the Lan–DeMets approximation of the O’Brien–Fleming stopping boundary. The date of the first analysis was changed from 20 months to 14 months after recruitment began." "Because of the high rate of stroke in the standard‐care group and the significant effect of transfusion found at the second interim analysis, the data safety and monitoring board recommended that the trial be stopped 16 months before the planned date of December 1998 so that transfusion could be offered to children in the standard‐care group." It is unclear if there could be an effect on the estimate with a change in readings; or early termination of the trial, even though recommended by the Safety committee