Maio 2010.

Study characteristics
Methods	Phase III parallel‐group RCT. Open label study. Multicentre trial.
Participants	Untreated metastatic melanoma. Randomised participants: 488.
Interventions	Five‐arm study: DIT1.6: Dacarbazine 800 mg/m² IV on day 1, IFN 3 mU SC daily on days 11 to 18, thymosin‐α 1.6 mg SC daily on days 8 to 11 and 15 to 18 (N = 97); DIT3.2: Dacarbazine 800 mg/m² IV on day 1, IFN 3 mU SC daily on days 11 to 18, thymosin‐α 3.2 mg SC daily on days 8 to 11 and 15 to 1 (N = 97); DIT6.4: Dacarbazine 800 mg/m² IV on day 1, IFN 3 mU SC daily on days 11 to 18, thymosin‐α 6.4 mg SC daily on days 8 to 11 and 15 to 1 (N = 98); DT: Dacarbazine 800 mg/m² IV on day 1, thymosin‐α 3.2 mg SC daily on days 8 to 11 and 15 to 1 (N = 99); DI: Dacarbazine 800 mg/m² IV on day 1, IFN 3 mU SC daily on days 11 to 18 (N = 97).
Outcomes	Progression‐free survival. Overall survival. Tumour response. Toxicity.
Notes	Cross‐over: not allowed. Quality of life: not reported. Participants with brain metastasis: excluded. Median follow‐up: not available.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Patients were randomly assigned". "The randomization list was produced by the Internal Quality Control Unit of Biostatistics and Data Management". Comment: Randomisation method was adequate.
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was blinded and centralized". Comment: This method ensured low risk of selection bias.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	As an open label study, no blinding of participants or personnel was possible. However, we believe that in this setting (metastatic melanoma), with the treatments tested and outcomes assessed, the knowledge of which intervention was received or administered (rather than the intervention itself), could not affect the outcomes under investigation. Therefore, we judged the risk of performance bias as low.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Independent, blinded evaluation of tumor images was performed by Fondazione Biomedica Europea." Comment: It was unclear if this method ensured low the risk of detection bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Missing outcome data were balanced across intervention groups, with similar reasons for missing data across groups.
Selective reporting (reporting bias)	Low risk	No differences between protocol and published report.
Other bias	Low risk	The study appeared to be free of other sources of bias.