Middleton 2000.

Study characteristics
Methods	Phase III parallel‐group RCT. Open label study.
Participants	Untreated metastatic melanoma. Participants randomised: 305.
Interventions	Two‐arm trial: Temozolomide 200 mg/m² orally, daily for 5 days every 28 days (N = 156); Dacarbazine 250 mg/m² IV daily for 5 days every 21 days (N = 149).
Outcomes	Progression‐free survival. Overall survival. Tumour response. Toxicity.
Notes	Cross‐over: not allowed. Quality of life: Temozolomide therapy significantly improved health‐related QoL (Kiebert 2003). Participants with brain metastasis: excluded. Median follow‐up: not available. Cost analysis: Temozolomide was associate with incremented cost‐effectiveness (Hillner 2000).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomised". Comment: There was insufficient information about the sequence generation process 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 no sufficient information to judge.
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.