Amato 2010

Methods	Study design: 2‐arm, parallel‐group, double‐blind, placebo‐controlled RCT. Study dates: recruitment from October 2006 to March 2008, follow‐up to March 2009, range of follow‐up 12 to 29 months. Setting: multicentre, international, phase III. Countries: France, Germany, Israel, Poland, Romania, Russia, Spain, UK, Ukraine, US.
Participants	Inclusion criteria: people with histologically confirmed advanced or metastatic clear‐cell RCC with prior nephrectomy who required first‐line treatment, aged ≥ 18 years, measurable disease, KPS ≥ 80%, MSKCC 0‐2, life expectancy > 12 weeks. Exclusion criteria: cerebral metastases, prior exposure to MVA‐5T4, known allergy to vaccinia vaccinations or egg proteins, pregnancy. Sample size:732. Age (years, median with range): group 1: 58 (18 to 86); group 0: 58 (24 to 85). Sex (M/F, %): group 1: 69.6/30.4; group 0: 65.1/34.9. Prognostic factors: performance status (KPS 80/90/100, %): 30/44/26; prior nephrectomy (%): 99.9; prior systemic therapies (%): 0; risk prognosis favourable/intermediate/poor (Motzer 2002) (%): 58/42/1.
Interventions	Group 1 (n = 365): MVA‐5T4 (modified vaccinia Ankara encoding the tumour antigen 5T4). Group 0 (n = 367): placebo. Both as IM injection into the deltoid muscle at weeks 1, 3, 6, 9, 13, 17, 21, 25, 33, 41, 49, 57, 65. Cointerventions (standard‐of‐care according to local practice): SC low‐dose IL‐2 (n = 170): initial dose of 250,000 U/kg/dose with an upper limit of 22 MU/dose days 1 to 5 of week 1 + 125,000 U/kg/dose with an upper limit of 11 MU/dose days 1 to 5 of weeks 2 to 6 every 6 weeks; IFN‐α (n = 377): SC injection 3 times/week on days 1, 3 and 5 of each week at a dose level that reflected local practice between 9 million IU and 18 million IU every 1 week; sunitinib (n = 185): 50 mg oral dose taken days 1 to 28 every 6 weeks.
Outcomes	OS (primary outcome) How measured: active follow‐up. Time points measured: censored to March 2009. Time points reported: Kaplan‐Meier survival curves over up to 30 months, HR (with 95% CI), median. Subgroups: risk prognosis and standard of care (no comparison group 1 vs group 0 reported). AEs, grade ≥ 3 (primary safety outcome) How measured: NCI‐CTC (treatment‐emergent SAE all, grade 3, 4, 5). Time points measured and reported: not reported. Subgroups: not reported. QoL not evaluated. PFS (secondary outcome) How measured: not reported. Time points measured: week 26. Time points reported: not reported. Subgroups: not reported. Tumour remission (secondary outcome) How measured: complete response, partial response, stable disease. Time points measured and reported: week 26. Subgroups: not reported.
Funding sources	Sponsored by Oxford BioMedica.
Declarations of interest	RH, WHS, SN: named inventors on several Oxford BioMedica patents. REH: minor consultancy role for Oxford BioMedica.
Notes	Trial registration: NCT00397345, at the recommendation of the data safety monitoring board, the sponsor terminated the administration of MVA‐5T4/placebo to participants in July 2008 due to little or no prospect of demonstrating a significant survival benefit.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Stratification for standard of care, severity of disease and geographic location.
Allocation concealment (selection bias)	Unclear risk	No information provided.
Blinding of participants and personnel (performance bias) Subjective outcomes	Low risk	No performance bias assumed due to blinding of participants and study personnel.
Blinding of participants and personnel (performance bias) Objective outcomes	Low risk	No performance bias assumed due to blinding of participants and study personnel.
Blinding of outcome assessment (detection bias) Subjective outcomes	Low risk	No detection bias on OS assumed due to blinding of participants, study personnel and outcome assessors.
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	No detection bias on OS assumed due to blinding of participants, study personnel and outcome assessors.
Incomplete outcome data (attrition bias) (OS and PFS)	Low risk	No attrition bias on OS and PFS assumed, analysis with active follow‐up on survival data after termination of drug administration with no further description, no differences in censoring detected.
Incomplete outcome data (attrition bias) (safety)	Low risk	No attrition bias on safety outcomes assumed, assessment on the basis of all participants as randomized.
Incomplete outcome data (attrition bias) (tumour remission)	Low risk	No attrition bias on tumour remission assumed, assessment on the basis of all participants as randomized.
Incomplete outcome data (attrition bias) (QoL)	Unclear risk	Not evaluated.
Selective reporting (reporting bias)	High risk	PFS was mentioned as secondary outcome, but no information provided.
Other bias	High risk	Safety monitoring board recommended stopping in July 2008 because there was little prospect of demonstrating a significant benefit in OS, second‐line therapies in 32% of placebo and 29% of MVA‐5T4 patients.