Paracetamol (Acetaminophen) in stroke 2 (PAIS 2): Protocol for a randomized, placebo-controlled, double-blind clinical trial to assess the effect of high-dose paracetamol on functional outcome in patients with acute stroke and a body temperature of 36.5 degrees C or above

RationaleIn the first hours after stroke onset, subfebrile temperatures and fever have been associated with poor functional outcome. In the first Paracetamol (Acetaminophen) in Stroke trial, a randomized clinical trial of 1400 patients with acute stroke, patients who were treated with high-dose paracetamol showed more improvement on the modified Rankin Scale at three-months than patients treated with placebo, but this difference was not statistically significant. In the 661 patients with a baseline body temperature of 370 degrees C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 143; 95% confidence interval: 102-197). This relation was also found in the patients with a body temperature of 365 degrees C or higher (odds ratio 131; 95% confidence interval 101-168). These findings need confirmation. AimThe study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 365 degrees C or above on functional outcome. DesignThe Paracetamol (Acetaminophen) In Stroke 2 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial. We use a power of 85% to detect a significant difference in the scores on the modified Rankin Scale of the paracetamol group compared with the placebo group at a level of significance of 005 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 365 degrees C or above will be included within 12h of symptom onset. Patients will be treated with paracetamol in a daily dose of six-grams or matching placebo for three consecutive days. The Paracetamol (Acetaminophen) In Stroke 2 trial has been registered as NTR2365 in The Netherlands Trial Register. Study outcomesThe primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression. DiscussionIf high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.