The URICO-ICTUS study, a phase 3 study of combined treatment with uric acid and rtPA administered intravenously in acute ischaemic stroke patients within the first 4•5 h of onset of symptoms

Rationale Oxidative stress is a major contributor to brain damage in patients with ischaemic stroke. Uric acid (UA) is a potent endogenous antioxidant molecule. In experimental ischaemia in rats, the exogenous administration of uric acid is neuroprotective and enhances the effect of rtPA. Moreover, in acute stroke patients receiving rtPA within 3 h of stroke onset, the intravenous administration of uric acid is safe, prevents an early decline in uric acid levels and reduces an early increase in oxidative stress markers and in active matrix metalloproteinase nine levels. Aim To determine whether the combined treatment with uric acid and rtPA is superior to rtPA alone in terms of clinical efficacy in acute ischaemic stroke patients treated within the first 4 center dot 5 h of onset of symptoms. Study design Multicentre, interventional, randomised, double-blind and vehicle-controlled efficacy study with parallel assignment (1 : 1). Estimated enrolment: 420 patients over 3 years, starting in January 2010. Treatment arms included patients will receive a single intravenous infusion of 1 g of UA dissolved in a vehicle (500 ml of 0 center dot 1% lithium carbonate and 5% mannitol) (n=210) or vehicle alone (n=210). Inclusion and exclusion criteria: the study will include patients older than 18 years, treated with rtPA within the first 4 center dot 5 h of clinical onset and with a baseline National Institute of Health Stroke Scale score > 6 and < 25 and a modified Rankin Scale score < 2 before the ischaemic event. Patients with renal insufficiency, gout or asymptomatic hiperuricaemia treated with allopurinol will be excluded. Study outcomes The primary outcome measure is the proportion of patients achieving an modified Rankin Scale of 0 to 1 at 3 months after treatment or two in those patients with a prior qualifying modified Rankin Scale of 2. Secondary outcome measures include the final infarction volume measured at 72 h and the proportion of patients with symptomatic intracranial haemorrhage (>= 4 points of increase in the National Institute of Health Stroke Scale score).