Beretta 1976.

Study characteristics
Methods	Phase III parallel‐group RCT. Open label study.
Participants	Untreated metastatic melanoma. Randomised participants: 450.
Interventions	Four‐arm study: Dacarbazine 100 mg/m² IV daily days 1 to 5, vincristine 1.4 mg/m² IV days 1 and 15, Carmustine 100 mg/m² IV day 1 (N = 207); Dacarbazine 100 mg/m² IV daily days 1 to 5, vincristine 1.4 mg/m² IV days 1 and 15, hydroxyurea 10 mg/kg IV days 7, 10, 13, 17, 21, 24 (N = 122); Dacarbazine 100 mg/m² IV daily days 1 to 5, actinomycin D 0.05 mg/m² IV days 1 and 15, Carmustine 100 mg/m² IV day 1 (N = 98); Dacarbazine 100 mg/m² IV daily days 1‐5, actinomycin D 0.05 mg/m² IV days 1 and 15, Hydroxyurea 10 mg/kg IV days 7, 10, 13, 17, 21, 24 (N = 23).
Outcomes	Overall survival. Tumour response. Toxicity.
Notes	Cross‐over: not reported. Quality of life: not reported. Participants with brain metastasis: included. Median follow‐up: not available.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomly allocated". Comment: There was insufficient information to permit judgment.
Allocation concealment (selection bias)	Unclear risk	There was insufficient information to permit judgment.
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	There was insufficient information to permit judgment.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	There was insufficient information to permit judgment.
Selective reporting (reporting bias)	High risk	One arm (D) was closed early and participants' data were not analysed.
Other bias	Unclear risk	There was insufficient information to permit judgment.