Bohara 2014.

Study characteristics
Methods	Randomised controlled trial. Single centre in India.
Participants	61 participants aged 8 years and above with Hb E/ß thalassaemia with the phenotype of ß thalassaemia intermedia. Gender split: 31 males and 30 females. 10 mg/kg/day hydroxyurea group (n = 32) mean (SD) age 16.68 (6.05) years. 20 mg/kg/day hydroxyurea group (n = 29) mean (SD) age 16.17 (5.75) years.
Interventions	10 mg/kg/day hydroxyurea (designated control in this review) versus 20 mg/kg/day hydroxyurea. There were no participants on either placebo or standard care in the study. If any participant presented with adverse events (e.g. a fall in haemoglobin > 0.5 g/dL which led to a need for transfusion, ANC < 1.5 x 103/mL, platelet count < 50 x 103/mL, significant hepatic or renal dysfunction) hydroxyurea therapy was withheld for 1 week. Therapy (at 5 mg/kg/day lower than the dose at which the toxicity had occurred) to be restarted after the resolution of the toxicity. These participants then "resumed the therapy as per study protocol". For any participant deemed to be non‐responsive (when hydroxyurea caused a rise in haemoglobin of < 0.5 g/dl in 12 weeks or a drop in haemoglobin from pre‐hydroxyurea value), therapy was permanently withheld. This was the case for 5 participants from the 10 mg/kg/day group and 12 participants in 20 mg/kg/day group. The number of participants remaining on hydroxyurea on each arm declined markedly as the study progressed. At the end of the study, there were 25 participants still receiving the lower dose of hydroxyurea while 13 participants were still on the higher dose.
Outcomes	Haemoglobin and Hb F were measured at baseline, 6, 12 and 24 weeks. Adverse effects (neutropenia, thrombocytopenia, gastrointestinal disturbances and raised liver enzymes) were reported. Response rates (good response, intermediate response and no response) based on arbitrary criteria were also reported.
Notes	No funding statement. The trial was not registered prospectively on a clinical trials register. Available as published abstract and full text publication.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomised ... using a random number table."
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding of participants or trial personnel was not reported.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessors was not reported. Note: The primary outcomes were laboratory assessments and it is possible that they were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although not all participants received the intervention that they were assigned for the full duration of the trial, all enrolled participants were analysed in the group they were assigned to "irrespective of how long they received hydroxyurea therapy".
Selective reporting (reporting bias)	Unclear risk	In the methods section of the published report, participants were reported to have undergone an interview regarding their sense of well being and state of energy and this was not reported in the results. Comment: the authors were unsure whether this was evidence of reporting bias since this outcome, although related to QoL, was not one of our pre‐specified outcomes. No protocol was available and other evidence of selective reporting was detected.
Other bias	Low risk	The baseline characteristics between the 2 groups had no significant difference in age, gender, ß genotype, reticulocytes and mean haemoglobin, Hb F and Hb E. However, there was a significant difference in the mean of the MCV levels, judged to not influence response to hydroxyurea.

ANC: absolute neutrophil count
Hb E: haemoglobin E
Hb F: foetal haemoglobin
MCV: mean corpuscular volume
QoL: quality of life
SD: standard deviation