BABY HUG 2011
Methods	Study design: RCT Study grouping: parallel group
Participants	Baseline characteristics Hydroxyurea N: 96 Gender N (%): M: 44 (46%) Age mean (SD): 13.6 (2.7) months SCD genotype HbSS N (%): 94 (98%) SCD genotype: Hb Sβ 0 thalassaemia N (%): 2 (2%) Haemoglobin concentration (g/L) mean (SD): 90 (13) Percentage of haemoglobin as fetal haemoglobin mean (SD): 25.9% (8.5%) GFR (mL per min per 1.73 m2) mean (SD): 126 (39) Splenic sequestration N (%): 5 (5%) Hospitalisations N (%): 65 (68%) Pain events N (%): 25 (27%) Acute chest syndrome N (%): 3 (3%) Transfusions N (%): 10 (11%) Serum creatinine (mmol/L): 0.25 (0.09) Urine osmolality (mOsm/kg : 403.22 (151.63) Placebo N: 97 Gender N (%): M: 40 (41%) Age mean (SD): 13.5 (2.8) months SCD genotype HbSS N (%): 93 (96%) SCD genotype: Hb Sβ 0 thalassaemia N (%):4 (4%) Haemoglobin concentration (g/L) mean (SD): 92 (13) % of haemoglobin as fetal haemoglobin mean (SD): 26.0% (8.5) GFR (mL per min per 1.73 m2) mean (SD): 124 (30) Splenic sequestration N (%): 10 (11%) Hospitalisations N (%): 70 (73%) Pain events N (%): 26 (27%) Acute chest syndrome N (%): 5 (5%) Transfusions N (%): 17 (18%) Serum creatinine (mmol/L): 0.23 (0.07) Urine osmolality (mOsm/kg) : 408.32 (152.40) Inclusion criteria: participants aged 9 - 18 months were recruited between October 2003, and September 2007, at 13 trial centres in the USA; eligible participants had HbSS or Sβ0 thalassaemia, and were enrolled irrespective of clinical severity Exclusion criteria: transfusion within two months; height, weight, or head circumference less than the 5th percentile; MDI) less than 70; abnormal TCD velocity; chronic transfusion therapy; cancer; severe developmental delay (e.g. cerebral palsy or other mental retardation); grade III/IV intraventricular haemorrhage; stroke with neurological deficit; surgical splenectomy; participating in other clinical intervention trials; probable or known diagnosis of haemoglobin S-hereditary persistence of fetal haemoglobin; known HbSβ+ thalassaemia (haemoglobin A present); any condition or chronic illness, which in the opinion of the principal investigator, makes participation unadvised or unsafe; inability or unwillingness to complete baseline (pre-enrolment) studies, including blood or urine specimen collection, liver-spleen scan, abdominal sonogram, neurological examination, neuropsychological testing, or transcranial doppler ultrasound (interpretable study not required, but confirmed velocity greater than 200 cm/second results in ineligibility); previous or current treatment with hydroxyurea or another anti-sickling drug (additional exclusion criteria from trial registration NCT00006400).
Interventions	Hydroxyurea: 20 mg/kg/day; local pharmacists reconstituted powder with syrup and water to a concentration of 100 mg/mL, and dispensed a 35-day supply. There was no dose escalation Placebo: hydroxyurea and placebo powders had the same appearance and packaging and the liquid formulations had the same appearance and taste. Hydroxyurea and placebo were distributed to clinical centres in encoded kits
Outcomes	Co-primary outcomes: splenic and liver function (as measured by GFR) Secondary outcomes: investigations of the brain, lungs, hepatobiliary system, and growth and development; monitoring of height, weight, and head circumference; neuro-development assessment (Bayley Developmental and Vineland Adaptive Behavior Scales) ; adverse clinical events included known complications of sickle-cell anaemia, such as pain, dactylitis, acute chest syndrome, stroke, priapism, sepsis or bacteraemia, splenic sequestration, hospitalisation, and transfusion; SAEs
Identification	Sponsorship source: the US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development Country: USA Setting: 13 medical centres Authors name: Prof W C Wang MD Institution: St Jude Children’s Research Hospital, Memphis, TN, USA Email: winfred.wang@stjude.org Address: Hematology MS 800, Room R5036 St. Jude Children’s Research Hospital 262 Danny Thomas Place Memphis, TN 38105-3678
Notes	179 (93%) participants who completed at least 18 months of the trial and at least one exit assessment were analysed; 167 (86%) completed the full study. Hydroxyurea: 4 withdrawals: 3 lost to follow-up; 1 incorrect diagnosis; 91 analysed. Placebo: 9 withdrawals: 4 declined further participation; 2 moved; 2 lost to follow-up; 1 placed on chronic transfusion; 88 analysed
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The randomisation sequence was pre-decided by a randomisation schedule developed for each clinical site by the medical co-ordinating centre. Double-blind randomisation was done with an automated telephone response system and the use of a random three digit kit number for each enrolled participant.”
Allocation concealment (selection bias)	Low risk	“The kit number, which was linked to the assignment sequence, was used by the drug distribution centre to ship the appropriate study drug to the clinical site pharmacy. Hydroxycarbamide and placebo powders had the same appearance and packaging and the liquid formulations had the same appearance and taste. Hydroxyurea and placebo were distributed to clinical centres in encoded kits.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Hydroxyurea and placebo were distributed to clinical centres in encoded kits. Local pharmacists reconstituted powder with syrup and water to a concentration of 100 mg/mL, and dispensed a 35-day supply. As in the HUSOFT trial, there was no dose escalation. Participants, caregivers, and medical coordinating centre staff were masked to treatment allocation.”
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	“An unmasked so-called primary endpoint person monitored laboratory values and assisted in clinical management. Masked readings of splenic uptake on 9 9 m Tc-sulphur colloid liver-spleen scans were categorised qualitatively as normal, decreased (but present), or absent.” While the Methods state “double blind randomisation”, it is not clear whether this is at the level of the outcome assessors as well as at the level of the drug administration. The statement about an unmasked primary endpoint assessor monitoring laboratory values is suggestive of a risk of bias; however; they may have only monitored for safety, whereas the splenic readings were done by someone who was blinded to the study drug allocation. It is not clear whether the assessor of the GFR was blinded or not
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	States that all participants randomly assigned to a treatment group were analysed for the co-primary endpoints - but also ’Total number of participants assessed for each endpoint. N differs from the number reported in table one because only entry values that are paired with exit values from the same participants are included. Both co-primary endpoints are per protocol analysis and only include participants with paired entry and exit values. There were approximately 25% of participants with no entry/exit GFR values. ’All other outcomes reported as intention to treat’
Selective reporting (reporting bias)	Low risk	All of the outcomes stated in the methods were reported in the results
Other bias	Low risk	No other sources of bias were detected from the Baby Hug trial
Foucan 1998
Methods	Study design: RCT Study grouping: parallel group
Participants	Baseline characteristics ACEI (captopril) N: 12 Gender N (%): M: 5 Age mean (SD): 30 (8) years SCD genotype HbSS N (%): 12 (100) SCD genotype: Hb Sβ 0 thalassaemia n (%): 0 Haemoglobin concentration (g/L) mean (SD): 80 (10) Percentage of haemoglobin as fetal haemoglobin mean (SD): 8 (6) GFR (mL per min per 1·73 m2) mean (SD): 113 (24) Splenic sequestration N (%): - Hospitalisations N (%): - Pain events N (%): - Acute chest syndrome N (%): - Transfusions N (%): - Serum creatinine (mg/dL): 67 (17) Urine osmolality (mOsm/kg : - Systolic blood pressure mean (SD): 121 (11) Diastolic blood pressure mean (SD): 63 (7) Microalbuminuria (mg/day): 121 (66 ) Placebo N: 10 Gender N (%): M: 2 Age mean (SD): 28 (6) years SCD genotype HbSS N (%): 10 (100) SCD genotype: Hb Sβ 0 thalassaemia N (%): 0 Haemoglobin concentration (g/L) mean (SD): 80 (10) Percentage of haemoglobin as fetal haemoglobin mean (SD): 11 (4) GFR (mL per min per 1·73 m2) mean (SD): 129 (21) Splenic sequestration N (%): - Hospitalisations N (%): - Pain events N (%): - Acute chest syndrome N (%): - Transfusions N (%): - Serum creatinine (mg/dL): 58 (10) Urine osmolality (mOsm/kg : - Systolic blood pressure mean (SD): 118 (8) Diastolic blood pressure mean (SD): 61 ( 6) Microalbuminuria (mg/day): 107 (86) Inclusion criteria: homozygous for haemoglobin SS; 18 years of age or older; diagnosis of sickle cell anaemia based on clinical and biological data including haemoglobin electrophoresis;urinary albumin excretion between 30 and 300 mg per 24 hours on three separate occasions during the 6-month period preceding the study Exclusion criteria: non-HbSS genotype; age < 18 years; hypertension (blood pressure > 140/90 mm Hg); evidence of heart, kidney, liver, or systemic disease; pregnant; taking anti-inflammatory or antihypertensive medications Pre-treatment: no statistical differences.
Interventions	Intervention characteristics ACEI (captopril): medication intervention: captopril for 6 months. The initial dose was 6.25 mg/day (¼ of a tablet of 25 mg once-a-day) during the first month, 12.5 mg/day (¼ of a tablet twice a day) during the second and the third months, and 25 mg/day (½ of a tablet twice-a-day) after the third month Placebo: medication intervention: indistinguishable placebo for 6 months
Outcomes	Outcomes: efficacy of ACE inhibitors in the progression of albuminuria and their effects on blood pressure in people with sickle cell anemia
Identification	Sponsorship source: supported by grants from the Programme Hospitalier de Recherche Clinique (PHRC), France Country: France (Guadeloupe) Setting: outpatients in one hospital Comments: Centre Hospitalo Universitaire (CHU) of Pointe-a‘-Pitre in Guadeloupe in 1996 Authors name: Lydia Foucan Institution: University Hospital, Pointe-a-Pitre, Guadeloupe; the Sickle Cell Center of Guadeloupe Email: lydia.foucan@chu-guadeloupe.fr Address: Departement d’Information Medicale et Sante Publique, Centre Hospitalier Universitaire de Pointe-a-Pitre 97159, Guadeloupe, French West Indies
Notes	Blood pressure was measured by the automated oscillometric method (Dynamap) after 5 minutes of rest in a half-sitting position. Systolic pressure, diastolic pressure, and mean arterial pressure (mBP) were measured as the average of three measurements taken at 5-minute intervals We contacted the lead author of Foucan 1998 for additional data on creatinine clearance and also to confirm the actual number of participants that are included in the proteinuria analysis, at the time of review publication we had not received a response
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Judgement comment: no description of randomisation.
Allocation concealment (selection bias)	Unclear risk	Judgement comment: no description of allocation concealment.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: “Patients were randomly assigned to two groups, and received captopril or an indistinguishable placebo” Judgement comment: participants may have been blinded to treatment - but not clear if dosing was done similarly in both arms No description or statement regarding blinding of personnel.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Judgement comment: no description if outcome assessment was blinded
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	“All patients were included in an intention-to-treat analysis.” Judgement comment: 1 in the captopril group had an unusual pain in the shoulder and discontinued treatment on the sixth day, and 1 in the placebo group was unavailable for follow-up after the first month. These 2 participants were included in the results for as long as they participated.Does not appear that they were included in 6-month analysis even though state intention-to-treat. Very small sample size so all results should be included
Selective reporting (reporting bias)	High risk	“Creatinine clearance was calculated by the modified Cockroft and Gault formula (10, 11). All measurements were repeated at baseline and at 1, 3, and 6 months.” “creatinine concentrations and creatinine clearance remained constant throughout the study in both groups (data not shown).” Judgement comment: creatinine clearance important marker of kidney progression but data not shown
Other bias	High risk	Judgement comment: this is a small sample size and likely not powered to detect any differences. Also follow-up is too short to assess longer-term AEs or actual effects on kidney disease progression

ACE: angiotensin converting enzyme

AEs: adverse events

GFR: glomerular filtration rate

MDI: mental developmental index

RCT: randomised controlled trial

SAEs: serious adverse events

SD: standard deviation

TCD: transcranial doppler ultrasound