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.ResultsThe 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.ConclusionsThis 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
Highlights
We aimed at assessing the benefit-to-risk ratio of activated protein C and corticosteroids, given alone or in combination, in patients with septic shock
Septic shock is defined by a vasopressor requirement to maintain a mean arterial pressure ≥65 mmHg and serum lactate >2 mmol/l in the absence of hypovolemia
All randomized patients completed follow-up for the primary outcome and 180-day mortality data. This trial was designed to assess the role of Drotrecogin-alfa activated (DAA) and corticosteroids in adult septic shock
Summary
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. Septic shock is defined by a vasopressor requirement to maintain a mean arterial pressure ≥65 mmHg and serum lactate >2 mmol/l in the absence of hypovolemia [1] (it was defined by the need for vasopressors to restore cardiovascular homeostasis [2] at the time the protocol was planned). Its mortality and sequalae remain unacceptably high with roughly one out of two patients dying within 1 year and half of survivors suffering from cognitive decline [3]. Drotrecogin-alfa activated (DAA) was the only marketed therapy for sepsis after promising early findings [5].
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