title: 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 °C or above.
abstract: BACKGROUND
  In 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 37.0 °C or above, treatment with paracetamol increased the odds of functional improvement (odds ratio 1.43; 95% confidence interval: 1.02-1.97). This relation was also found in the patients with a body temperature of 36.5 °C or higher (odds ratio 1.31; 95% confidence interval 1.01-1.68). These findings need confirmation.
  
  
  OBJECTIVE
  The study aims to assess the effect of high-dose paracetamol in patients with acute stroke and a body temperature of 36.5 °C or above on functional outcome.
  
  
  METHODS
  The 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 0.05 and assume a treatment effect of 7%. Fifteen-hundred patients with acute ischemic stroke or intracerebral hemorrhage and a body temperature of 36.5 °C or above will be included within 12 h 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.
  
  
  RESULTS
  The primary outcome will be improvement on the modified Rankin Scale at three-months as analyzed by ordinal logistic regression.
  
  
  CONCLUSIONS
  If high-dose paracetamol will be proven effective, a simple, safe, and extremely cheap therapy will be available for many patients with acute stroke worldwide.
authors.affiliation: Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Inger R
authors.initials: IR
authors.lastname: de Ridder
authors.forename: Frank Jan
authors.initials: FJ
authors.lastname: de Jong
authors.forename: Heleen M
authors.initials: HM
authors.lastname: den Hertog
authors.forename: Hester F
authors.initials: HF
authors.lastname: Lingsma
authors.forename: H Maarten A
authors.initials: HM
authors.lastname: van Gemert
authors.forename: A H C M L Tobien
authors.initials: AH
authors.lastname: Schreuder
authors.forename: Annemieke
authors.initials: A
authors.lastname: Ruitenberg
authors.forename: E Lisette
authors.initials: EL
authors.lastname: Maasland
authors.forename: Ritu
authors.initials: R
authors.lastname: Saxena
authors.forename: Peter
authors.initials: P
authors.lastname: Oomes
authors.forename: Jordie
authors.initials: J
authors.lastname: van Tuijl
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koudstaal
authors.forename: L Jaap
authors.initials: LJ
authors.lastname: Kappelle
authors.forename: Ale
authors.initials: A
authors.lastname: Algra
authors.forename: H Bart
authors.initials: HB
authors.lastname: van der Worp
authors.forename: Diederik W J
authors.initials: DW
authors.lastname: Dippel
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use*; D058633:Antipyretics / Q000627:therapeutic use*; D001831:Body Temperature / Q000187:drug effects; D002985:Clinical Protocols; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005334:Fever / Q000188:drug therapy* / Q000209:etiology*; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D020521:Stroke / Q000150:complications* / Q000188:drug therapy
chemical_list: D058633:Antipyretics; D000082:Acetaminophen
keywords: body temperature; functional outcome; inflammation; paracetamol; stroke