title: Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial.
abstract: BACKGROUND
  We aimed at assessing the benefit-to-risk ratio of activated protein C (drotrecogin-alfa activated, DAA) and corticosteroids, given alone or in combination, in patients with septic shock.
  
  
  METHODS
  We implemented an investigator-led, publicly funded, multicenter, randomized according to a 2 × 2 factorial design, placebo-controlled, double-blind trial in four parallel groups in which adults with persistent septic shock and no contraindication to DAA were assigned to either DAA alone (24 mg/kg/h for 96 h), or hydrocortisone (50 mg intravenous bolus q6 for 7 days) and fludrocortisone (50 µg once daily through the nasogastric tube for 7 days) alone, or their respective combinations, or their respective placebos. Primary endpoint was 90-day mortality rate. Follow-up duration was 6 months. Statistical analysis was planned to be performed in intent-to-treat once after all participants completed 180-day follow-up and according to the 2 × 2 factorial design.
  
  
  RESULTS
  The first patient was recruited in September 2008. The trial was suspended on October 25, 2011, owing to the withdrawal from the market of DAA. At this time, 411 patients had been enrolled. On May 17, 2012, the continuation of the trial on two parallel groups was approved by all legal authorities with the aim of investigating the benefit-to-risk ratio of corticosteroids. On June 30, 2014, the trial was suspended again by the study sponsor upon request of the independent data and safety monitoring board. Recruitment restarted on October 7, 2014, after any safety concern was ruled out. Finally, the trial was completed on June 23, 2015, with the recruitment of 1241 patients.
  
  
  CONCLUSIONS
  This report details the design, statistical plan and conduct of a randomized controlled trial of hydrocortisone and fludrocortisone in septic shock. Trial registration The trial was registered at ClinicalTrials.gov under NCT00625209.
authors.affiliation: General ICU, Service de Réanimation, Hôpital Raymond Poincaré, Laboratory of Infection and Inflammation, U1173, AP-HP, University of Versailles SQY and INSERM, 104 Boulevard Raymond Poincaré, 92380, Garches, France. djillali.annane@aphp.fr.
authors.forename: Djillali
authors.initials: D
authors.lastname: Annane
authors.affiliation: Service de Réanimation Médicale, Hôpital Henri Mondor, AP-HP, Créteil, France.
authors.forename: Christian Brun
authors.initials: CB
authors.lastname: Buisson
authors.affiliation: Service de Réanimation Médicale, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Cariou
authors.affiliation: Service d'Anesthésie Réanimation, Hôpital Nord, AP-HM, Marseille, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Martin
authors.affiliation: Service de Médecine Intensive et Réanimation, Hôpital Saint-Joseph, AP-HP, Université Paris Descartes, Paris Sorbonne Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Misset
authors.affiliation: Service de Pharmacologie, Centre d'Investigation Clinique INSERM 1414, CHU de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Renault
authors.affiliation: Département des Essais Cliniques, AGEPS, Paris, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Lehmann
authors.affiliation: Délégation à la Recherche Clinique, Hôpital Saint-Louis, AP-HP, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Millul
authors.affiliation: General ICU, Service de Réanimation, Hôpital Raymond Poincaré, Laboratory of Infection and Inflammation, U1173, AP-HP, University of Versailles SQY and INSERM, 104 Boulevard Raymond Poincaré, 92380, Garches, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Maxime
authors.affiliation: Service de Pharmacologie, Centre d'Investigation Clinique INSERM 1414, CHU de Rennes, Université de Rennes 1, Rennes, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Bellissant
keywords: Clinical trial; Corticosteroids; Design; Ethics; Septic shock