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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.

SUBMITTER: Annane D

PROVIDER: S-EPMC4859323 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial.

Annane Djillali D Buisson Christian Brun CB Cariou Alain A Martin Claude C Misset Benoit B Renault Alain A Lehmann Blandine B Millul Valérie V Maxime Virginie V Bellissant Eric E

Annals of intensive care 20160506 1

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 27154719

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Project description:ImportanceThe combination of ascorbic acid, corticosteroids, and thiamine has been identified as a potential therapy for septic shock.ObjectiveTo determine whether the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock.Design, setting, and participantsRandomized, blinded, multicenter clinical trial of ascorbic acid, corticosteroids, and thiamine vs placebo for adult patients with septic shock. Two hundred five patients were enrolled between February 9, 2018, and October 27, 2019, at 14 centers in the United States. Follow-up continued until November 26, 2019.InterventionsPatients were randomly assigned to receive parenteral ascorbic acid (1500 mg), hydrocortisone (50 mg), and thiamine (100 mg) every 6 hours for 4 days (n = 103) or placebo in matching volumes at the same time points (n = 102).Main outcomes and measuresThe primary outcome was change in the Sequential Organ Failure Assessment (SOFA) score (range, 0-24; 0 = best) between enrollment and 72 hours. Key secondary outcomes included kidney failure and 30-day mortality. Patients who received at least 1 dose of study drug were included in analyses.ResultsAmong 205 randomized patients (mean age, 68 [SD, 15] years; 90 [44%] women), 200 (98%) received at least 1 dose of study drug, completed the trial, and were included in the analyses (101 with intervention and 99 with placebo group). Overall, there was no statistically significant interaction between time and treatment group with regard to SOFA score over the 72 hours after enrollment (mean SOFA score change from 9.1 to 4.4 [-4.7] points with intervention vs 9.2 to 5.1 [-4.1] points with placebo; adjusted mean difference, -0.8; 95% CI, -1.7 to 0.2; P = .12 for interaction). There was no statistically significant difference in the incidence of kidney failure (31.7% with intervention vs 27.3% with placebo; adjusted risk difference, 0.03; 95% CI, -0.1 to 0.2; P = .58) or in 30-day mortality (34.7% vs 29.3%, respectively; hazard ratio, 1.3; 95% CI, 0.8-2.2; P = .26). The most common serious adverse events were hyperglycemia (12 patients with intervention and 7 patients with placebo), hypernatremia (11 and 7 patients, respectively), and new hospital-acquired infection (13 and 12 patients, respectively).Conclusions and relevanceIn patients with septic shock, the combination of ascorbic acid, corticosteroids, and thiamine, compared with placebo, did not result in a statistically significant reduction in SOFA score during the first 72 hours after enrollment. These data do not support routine use of this combination therapy for patients with septic shock.Trial registrationClinicalTrials.gov Identifier: NCT03389555.

Project description:ObjectivesWe previously reported gene expression-based endotypes of pediatric septic shock, endotypes A and B, and that corticosteroid exposure was independently associated with increased mortality among pediatric endotype A patients. The Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial tested the efficacy of vasopressin as initial vasopressor therapy for septic shock among adult patients, when compared with norepinephrine. Patients who reached a prespecified dose of either vasopressor were further randomized to receive hydrocortisone or placebo. A proportion of patients in the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial had transcriptomic data generated at baseline using whole blood-derived messenger RNA. We used the publicly available transcriptomic data from the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial to assign the study subjects to pediatric septic shock endotype A or B, and tested the hypothesis that hydrocortisone treatment is associated with increased mortality among patients in endotype A.DesignSecondary analysis of publicly available transcriptomic data.SettingMultiple adult ICUs.PatientsAdults with septic shock randomized to hydrocortisone (n = 47) or placebo (n = 50).InterventionsRandomization to the Vasopressin vs Norepinephrine as Initial Therapy in Septic Shock trial experimental arms.Measurements and main resultsEndotype A patients receiving hydrocortisone had a mortality rate of 46%, whereas endotype A patients receiving placebo had a mortality rate of 22% (p = 0.105). In contrast, the mortality rates for endotype B patients receiving hydrocortisone or placebo were 19% and 22%, respectively. The odds of death were more than three times greater in endotype A patients receiving hydrocortisone than endotype A patients receiving placebo (p = 0.05).ConclusionsThis exploratory analysis provides further evidence that corticosteroid exposure may be associated with increased mortality among septic shock endotype A patients.

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Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial.

Publications

Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial.

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