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Clinical Trial
. 2019 May 28;321(20):1993-2002.
doi: 10.1001/jama.2019.5358.

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial

Jean-Louis Vincent  1 , Bruno Francois  2 , Igor Zabolotskikh  3 , Mradul Kumar Daga  4 , Jean-Baptiste Lascarrou  5 , Mikhail Y Kirov  6 , Ville Pettilä  7 , Xavier Wittebole  8 , Ferhat Meziani  9 , Emmanuelle Mercier  10 , Suzana M Lobo  11 , Philip S Barie  12 , Mark Crowther  13 , Charles T Esmon  14 , Jawed Fareed  15 , Satoshi Gando  16 , Kenneth J Gorelick  17 , Marcel Levi  18 , Jean-Paul Mira  19 , Steven M Opal  20 , Joseph Parrillo  21   22 , James A Russell  23 , Hidehiko Saito  24 , Kazuhisa Tsuruta  25 , Takumi Sakai  25 , David Fineberg  26 ; SCARLET Trial Group
Affiliations
Clinical Trial

Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial

Jean-Louis Vincent et al. JAMA. .

Abstract

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.

Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.

Design, setting, and participants: The SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.

Interventions: Patients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.

Main outcome and measures: The primary end point was 28-day all-cause mortality.

Results: Among 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.

Conclusions and relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.

Trial registration: ClinicalTrials.gov Identifier: NCT01598831.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Vincent reported receiving grants from Asahi Kasei Pharma America Corporation during the conduct of the study. Dr Francois reported personal fees from AKPA during the conduct of the study and personal fees from Inotrem, Combioxin, AstraZeneca, Am-Pharma, and Polyphor and grants from Biomerieux outside the submitted work. Dr Zabolotskikh reported grants from PSI Inc during the conduct of the study. Dr Kirov reported grants from PSI during the conduct of the study. Dr Lobo reported receiving personal fees for the conduct of the study as the principal investigator at FUNFARME. Dr Barie reported personal fees from AKPA America during the conduct of the study; personal fees from Pfizer, Portola, Allergan, Arsanis, and Tetraphase outside the submitted work. Dr Esmon reported personal fees from Asahi Kasei during the conduct of the study and Dr Esmon had a patent related to thrombin binding polypeptides (US Patent No. 6,239,101 B1) issued. Dr Fareed reported consulting for AKPA. Dr Gando reported personal fees from Asahi Kasei Pharma America during the conduct of the study. Dr Gorelick reported personal fees from Asah Kasei Pharma America and NGN Capital during the conduct of the study. Dr Levi reported receiving personal fees from Asahi Kasei as a member of the advisory board during the conduct of the study. Dr Mira reported grants and personal fees from Asahi Kasei during the conduct of the study and grants and personal fees from Roche outside the submitted work. Dr Opal reported grants from Asahi Kasei during the conduct of the study. Dr Parrillo reported personal fees from Asahi Kasei America during the conduct of the study. Dr Russell reported personal fees from AKPA during the conduct of the study; personal fees from Ferring, SIB Therapeutics LLC, La Jolla Pharmaceuticals, PAR Pharma, Cubist Pharmaceuticals, Grifols, and CytoVale outside the submitted work, had a patent to PCSK9 in sepsis licensed and a patent to vasopressin in sepsis licensed, reported receiving an investigator-initiated grant from Grifols that was provided to and administered by University of British Colombia, was a founder, director and shareholder in Cyon Therapeutics Inc, and is a shareholder in Molecular You Corporation. Dr Tsuruta reported a patent related to a medicament containing thrombomodulin for therapeutic treatment and/or improvement of sepsis (US Patent No. 9592275) issued. Dr Sakai is an employee of Asahi Kasei Pharma Corporation. Dr Fineberg is an employee of Asahi Kasei Pharma America. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow of Patients in a Study of the Effect of Thrombomodulin on Patients With Sepsis
aData were not collected on how many patients were approached. bOne patient randomized to the placebo group also was inadvertently given recombinant human thrombomodulin (rhsTM). This patient was analyzed in the placebo group for the efficacy analysis and in the rhsTM group for the adverse events analysis.
Figure 2.
Figure 2.. Kaplan-Meier Plots of Survival Time in Patients With Sepsis in a Study of the Effect of Thrombomodulin vs Placebo
Kaplan-Meier plots of survival time for the 2 treatment groups in A, the full analysis set population and B, in a subgroup (post hoc analysis) of patients with baseline INR greater than 1.4 and platelet counts greater than 30 × 109/L (n = 634) . Patients whose status was alive or unknown were censored at last available date. In the full analysis set population, the median (interquartile range) observation time was 28 (18-28) days for the recombinant human thrombomodulin (rhsTM) group and 28 (16-28) days for the placebo group. In the baseline coagulopathy subgroup, the median (interquartile range) observation time was 28 (17-28) days for the rhsTM group and 28 (13-28) days for the placebo group.
Figure 3.
Figure 3.. Coagulation Parameters Over Time in Patients With Sepsis in a Study of the Effect of Thrombomodulin vs Placebo
The box represents the 25% to 75% interquartile range (IQR). Whiskers indicate minimum and maximum values up to 1.5 times the interquartile range from the quartiles. The data for outliers are not shown. The arrows indicate study drug administration. rhsTM indicates recombinant human soluble thrombomodulin. aThe value prior to dosing on day 3.
See this image and copyright information in PMC

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