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Clinical Trial
. 2024 Sep 3;7(9):e2432444.
doi: 10.1001/jamanetworkopen.2024.32444.

Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial

Morten H Bestle  1   2 , Jakob Stensballe  3   4 , Theis Lange  5 , Niels E Clausen  6 , Peter Søe-Jensen  7 , Kristine Holst Pedersen  3 , Mikkel Gybel-Brask  3 , Maj-Brit N Kjær  8 , Christian Overgaard Steensen  8 , Diana Bertelsen Jensen  6 , Rune Gärtner  6 , Martin Schønemann-Lund  1 , Klaus T Kristiansen  9 , Anne Lindhardt  10 , Pär I Johansson  3 , Anders Perner  2   8
Affiliations
Clinical Trial

Iloprost and Organ Dysfunction in Adults With Septic Shock and Endotheliopathy: A Randomized Clinical Trial

Morten H Bestle et al. JAMA Netw Open. .

Abstract

Importance: Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality.

Objective: To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL.

Design, setting, and participants: This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included.

Interventions: Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours.

Main outcomes and measures: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days.

Results: Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed.

Conclusions and relevance: In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients.

Trial registration: ClinicalTrials.gov Identifier: NCT04123444.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bestle reported receiving personal fees from Copenhagen University Hospital–Rigshopitalet during the conduct of the study; receiving grants from the Novo Nordisk Foundation and Sygeforsikringen “danmark”; receiving contract research funds from Inotrem; and receiving personal fees from AM-Pharma outside the submitted work. Dr Lange reported receiving personal fees from Novo Nordisk and Leo Pharma outside the submitted work. Dr Pedersen reported receiving grants from Innovation Fund Denmark during the conduct of the study. Mrs Kjær reported receiving grants from The Novo Nordisk Foundation, Sygeforsikring “danmark,” Pfizer, and AM-Pharma, all outside the submitted work. Dr Johansson reported receiving grants from Innovation Fund Denmark and Independent Research Fund Denmark during the conduct of the study; and holding patents EP3278112B1 and US10527633B1 for the use of prostacyclin in patients with septic shock and endotheliopathy. Dr Perner reported receiving grants from the Novo Nordisk Foundation and Sygeforsikringen “danmark”; and receiving personal fees from Novartis outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Screening, Randomization, and Follow-up of Patients in the COMBAT-SHINE Trial
ICU indicates intensive care unit. aCorrectly included and therefore part of the full analyses but not the per-protocol analysis.
Figure 2.
Figure 2.. Time to Death Curves Censored at 90 Days for 278 Patients in the Intervention and Placebo Groups
Four participants who withdrew consent were recorded as alive at 90 days. Accordingly, no imputation was performed.
See this image and copyright information in PMC

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