Butts 2014

Methods	International RCT (264 centres, 33 countries), Phase III
Participants	Number of participants: 1513 (Feb 22, 2007 to Nov 15, 2011) Number randomised: Experimental group (cyclophosphamide and tecemotide): 1006 Control group (saline and placebo): 507 Number evaluated: Experimental group: 829, age (median and range): 61.0 (19.0 to 89.0) years Control group: 410, age (median and range): 61.5 (24,0 to 83.0) years Diagnosis: patients with unresectable stage III non‐small‐cell lung cancer Inclusion: eligible patients should be: aged 18 years or older with histologically or cytologically unresectable stage III non‐small‐cell lung cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Stage was confirmed and documented by CT, MRI, or PET. All histological subtypes of non‐small‐cell lung cancer were included.
Interventions	Experimental group: 3 days before administration of study drug, one dose of intravenous cyclophosphamide (300 mg/m², maximum dose 600 mg) was administered to participants, initial therapy consisted of eight consecutive weekly subcutaneous injections of tecemotide (806 μg lipopeptide). Control group: 3 days before administration of study drug, a corresponding intravenous saline infusion was given to participants, initial therapy consisted of eight consecutive weekly subcutaneous injections of placebo. In the absence of progressive cancer or toxicity, maintenance tecemotide or placebo every 6 weeks was continued until disease progression.
Outcomes	Duration of follow‐up (median): experimental group: 39.9 months (IQR 21.2 to 48.7), control group: 37.7 months (IQR 19.9 to 49.7) overall response, adverse events, time‐to‐disease progression, time‐to‐disease progression, safety.
Notes	Merck KGaA, the study sponsor, designed the trial in collaboration with the investigators, developed the protocol and statistical analysis plan, provided the study drug, co‐ordinated the management of study sites and the clinical data management, did statistical analyses, and participated in the interpretation of data
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	a computerized interactive voice response system was used for randomisation and allocation
Allocation concealment (selection bias)	Low risk	a computerized interactive voice response system was used for randomisation and allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"interactive voice randomisation system staff assigned patients and were not involved in the rest of the trial. To maintain blinding, tecemotide and placebo for the primary and maintenance treatment phases were packaged in identical containers"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	'With the exception of a designated unblinded statistician on the data monitoring board, interactive voice randomisation system staff, a designated pharmacist, and a study monitor for cyclophosphamide drug accountability records, the randomisation code was masked from the sponsor and other individuals monitoring the trial.'
Incomplete outcome data (attrition bias) All outcomes	Low risk	1239 randomised participants were included in analysis (81.9%)
Selective reporting (reporting bias)	Low risk	Previous protocol was available
Other bias	Low risk	No obvious potential source of bias