IRIS

Methods	A multicentre, double‐blind, placebo‐controlled clinical trial to test the effectiveness of pioglitazone for insulin resistant, non‐diabetic patients with a recent ischaemic stroke or TIA
Participants	People aged at least 40 years with qualifying ischaemic stroke or TIA during the 6 months before randomisation, as well as insulin resistance, defined as a value of more than 3.0 on the homeostasis model assessment of insulin resistance index. 3876 participants were randomised.
Interventions	Pioglitazone or matching placebo. The initial dose was 15 mg of pioglitazone daily or placebo. The dose was increased to 2 pills daily (30 mg of pioglitazone or placebo) at 4 weeks and to 3 pills daily (45 mg of pioglitazone or placebo) at 8 weeks. At 12 weeks, participants were started on 1 x 45 mg pioglitazone tablet or placebo tablet daily.
Outcomes	Fatal or non‐fatal stroke; fatal or non‐fatal myocardial infarction; heart failure resulting in hospitalisation or death; death from any cause; diabetes; and cognitive decline
Notes	Participants were contacted every 4 months with a median follow‐up of 4.8 years.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation was performed using a random permuted block design with variable block sizes stratified by site.
Allocation concealment (selection bias)	Low risk	To conceal the allocation sequence, randomisation lists were kept only at the central pharmacy and the statistical centre.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The Investigational Drug Service prepared medication bottles, including starter supplies, which were stored at the research sites. At the baseline visit, a structured interview was administered and the starter bottle with the participant's assigned randomisation number was dispensed.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Reviewers were blinded to treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	During a median follow‐up of 4.8 years, a total of 227 participants (5.9%) withdrew consent and 99 participants (2.6%) were lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Unclear risk	This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and monitored by an independent data and safety monitoring board appointed by NINDS. Pioglitazone and placebo were provided by Takeda Pharmaceuticals International.