Wright 2014.

Methods	Multicentre randomised, double‐blind, placebo‐controlled phase III study
Participants	Adults who had severe, moderate‐to‐severe, or moderate TBI due to a blunt mechanism, with a GCS score of 4‐12. Participants were enrolled if the study treatment could be initiated within 4 h after injury.
Interventions	Both groups: the study drug (progesterone or placebo) was infused continuously through a dedicated intravenous catheter at a dose of 14.3 mL/h for 1 hour and then at 10 mL/h for 71 hours; the dose was then tapered by 2.5 mL/h every 8 hours, for a total treatment duration of 96 hours. Site pharmacists prepared the coded kit assigned by the randomisation algorithm by mixing a weight‐based dose (progesterone 0.05 mg/kg/mLinfusate) from the provided vials and a 250‐mL bag of fat‐emulsion vehicle (Intralipid 20%, Fresenius Kabi) every 24 hours.
Outcomes	Favourable outcome, as determined with the use of the stratified dichotomy of the GOS‐E score at 6 months after injury Mortality, DRS score and adverse events
Notes	Funding and support: Supported by grants from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NS062778, 5U10NS059032, and U01NS056975) and the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000454) and by the Emory Emergency Neurosciences Laboratory in the Department of Emergency Medicine, Emory School of Medicine, and Grady Memorial Hospital.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization was performed with the use of a combination of minimization and biased‐coin algorithms". (p 2459) Comment: probably done
Allocation concealment (selection bias)	Low risk	Quote: "Randomization was performed with the use of a combination of minimization and biased‐coin algorithms".(p 2459) Quote: "Study‐drug kits containing four vials of progesterone in ethanol (active treatment) or ethanol alone (placebo) were prepared by the Emory Investigational Drug Service. Drug kits and their contents were identical in appearance, and study assignments remained concealed from all site pharmacists and study teams".(p 2459) Comment: probably done
Blinding (performance bias and detection bias) Subjective outcome	Low risk	"Double blind." "Drug kits and their contents were identical in appearance, and study assignments remained concealed from all site pharmacists and study teams". (p 2459) Comment: probably done
Blinding (performance bias and detection bias) Mortality	Low risk	"Double blind" and review authors judged that the outcome and the outcome measurement were not likely to be influenced.
Incomplete outcome data (attrition bias) Mortality	Low risk	Missing outcome data balanced in numbers between progesterone group and placebo group.
Incomplete outcome data (attrition bias) Favorable outcome	Low risk	Data of 28 participants (6.3%) in progesterone group and 24 (5.5%) in placebo group were missing.
Selective reporting (reporting bias)	Low risk	The protocol for this trial was presented in Clinicaltrials.gov. It was clear that the published report included all expected outcomes.
Other bias	Unclear risk	The trial intended to enrol 1140 participants, but the trial was abandoned after 882 people had been assessed. The trial was because of futility: favourable outcomes were observed in 51% of participants who received progesterone after TBI, compared with 55.5% of controls. Stratification of the participants on the basis of injury severity did not reveal any effect of progesterone on recovery. We therefore assessed the risk of other bias to be unclear.