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A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients With Sepsis and Suspected Disseminated Intravascular Coagulation*

Vincent, Jean-Louis MD, PhD, FCCM1; Ramesh, Mayakonda K. MS2; Ernest, David MBBS3; LaRosa, Steven P. MD4; Pachl, Jan MD, PhD5; Aikawa, Naoki MD, DMSc, FACS6; Hoste, Eric MD, PhD7; Levy, Howard MB, BCh, PhD8; Hirman, Joe PhD9; Levi, Marcel MD, PhD10; Daga, Mradul MD, FCCP11; Kutsogiannis, Demetrios J. MD, MHS12; Crowther, Mark MD, MSc, FRCPC13; Bernard, Gordon R. MD14; Devriendt, Jacques MD15; Puigserver, Joan Vidal MD16; Blanzaco, Daniel U. MD17; Esmon, Charles T. PhD18; Parrillo, Joseph E. MD19; Guzzi, Louis MD, FCCM20; Henderson, Seton J. MB, ChB21; Pothirat, Chaicharn MD, FCCP22; Mehta, Parthiv MD23; Fareed, Jawed PhD, FAHA24; Talwar, Deepak MD, DM, DNB25; Tsuruta, Kazuhisa PhD26; Gorelick, Kenneth J. MD, FCCP27; Osawa, Yutaka MPharm26; Kaul, Inder MD, MPH26

doi: 10.1097/CCM.0b013e31828e9b03
Feature Articles

Objectives: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation.

Design: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial.

Setting: Two hundred and thirty-three ICUs in 17 countries.

Patients: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score.

Interventions: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity.

Measurements and Main Results: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran–Mantel–Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline.

Conclusions: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

1Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.

2Department of Surgery, Victoria Hospital, Bangalore Medical College and Research Institute, Bangalore, Karnataka, India.

3Department of Medicine, Monash University, Monash Medical Center, Clayton, Victoria, Australia.

4Division of Infectious Disease, Beverly Hospital/Lahey Health, Beverly, MA.

5Department of Anesthesiology and Critical Care Medicine, Charles University Prague and Faculty Hospital Kralovske Vinohrady, Prague, Czech Republic.

6Department of Emergency & Critical Care Medicine, School of Medicine, Keio University, Shinjukuku, Tokyo, Japan.

7Department of Intensive Care Medicine, Ghent University Hospital, Ghent University, Research Foundation-Flanders, Ghent, Belgium.

8Howard Levy Consulting LLC, Hopewell, NJ.

9Pacific Northwest Statistical Consulting, Woodinville, WA.

10Department of Vascular Medicine and Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands.

11Department of Medicine, Maulana Azad Medical College, New Delhi, India.

12Division of Critical Care Medicine, Faculty of Medicine and Dentistry, The University of Alberta, Royal Alexandra Hospital, Edmonton, Alberta, Canada.

13Department of Medicine, McMaster University and St Joseph’s Hospital, Hamilton, Canada.

14Department of Medicine, Vanderbilt University, Nashville, TN.

15Department of Intensive Care, CHU Brugmann, Brussels, Belgium.

16Servei d’urgències, Hospital Universitari Son Espases, Palma de Mallorca, Spain.

17Department of Intensive Care, Hospital San Martín, Paraná, Argentina.

18Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, OK.

19Chairman, Heart and Vascular Hospital, Hackensack University Medical Center; Professor of Medicine, New Jersey Medical School of Rutgers University, Hackensack, NJ.

20Florida Hospital, Orlando, FL.

21Department of Intensive Care, Christchurch Hospital, Christchurch, New Zealand.

22Division of Pulmonary and Critical Care, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

23Mehta Hospital & Cardiopulmonary Care Centre, Ahmedabad, India.

24Pathology and Pharmacology, Loyola University Medical Center, Maywood, IL.

25Metro Hospitals, Noida, India.

26Asahi Kasei Pharma America Corporation, Waltham, MA.

27Zymo Consulting Group LLC, Newtown Square, PA.

* See also p. 2221.

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Supported, in part, by Asahi-Kasei Pharma America Corporation.

Dr. Vincent was a member of the ART-123 advisory committee, was compensated for his time as a consultant for Artisan Pharma, and received grant support from Artisan Pharma. Dr. LaRosa has received consulting honoraria from Artisan Pharma, ExThera Medical, and Agennix AG. Dr. Aikawa received consultation fees from Asahi-Kasei for the Japanese P-3 and P-4 studies and expenses from Artisan Pharma for attending PAB meeting in July 17, 2009. Dr. Levy is a paid consultant for Artisan Pharma. Dr. Hirman is a paid consultant for Asahi-Kasei Pharma America. Dr. Levi was a member of the ART-123 advisory committee and was compensated for his time as a consultant for Artisan Pharma. Dr. Crowther discloses having sat on advisory boards for Leo Pharma, Pfizer, Bayer, Boehringer Ingelheim, Alexion, CSL Behring, Portola, Viropharm, and AKP America; has prepared educational materials for Pfizer, Octapharm, and CSL Behring; holds a Career Investigator award from the Heart and Stroke Foundation of Ontario, and the Leo Pharma Chair in Thromboembolism Research at McMaster University; and has received funding for presentations from Leo Pharma, Bayer, Celgene, and CSL Behring. Dr. Bernard was a member of the ART-123 advisory committee and was compensated for his time as a consultant for Artisan Pharma. Dr. Esmon serves as a consultant for Portola Pharmaceuticals, Bayer HealthCare Pharmaceuticals, and Asahi Kasei Pharma America Corporation. He holds a patent for monoclonal antibodies against activated protein C and has a patent pending on histones for therapeutic use and biomarkers for prognosis. Dr. Parrillo was a member of the ART-123 advisory committee and was compensated for his time as a consultant for Artisan Pharma. Dr. Guzzi has received honoraria as a speaker for GlaxoSmithKline, Hospira, and EKR Therapeutics. Dr. Fareed is a consultant to Polymedix, Mitsubishi, Asahi-Kasei and Gentium, has received grant support from Sanofi-Aventis, Medefil and honoraria from Pharmaceutical Strategic Initiatives. Dr. Tsuruta owned stocks of Asahi Kasei Corporation which is the holding company of Asahi Kasei Group, study sponsors. Dr. Gorelick is a paid consultant to ArtisanPharma and an option holder in Artisan Pharma. He is a consultant to NGN Capital, which held stock in Artisan Pharma. He is a consultant to Asahi Kasei Pharma America. Mr. Osawa is an employee of Artisan Pharma, a former body of Asahi Kasei Pharma America Corporation but has no equity in the company. Dr. Kaul was an employee of Artisan Pharma, who sponsored this study and was offered company stock options. Artisan Pharma was bought out by Asahi Kasei Pharma and the surviving entity became Asahi Kasei Pharma America. He has no equity position in this new company but remains an employee. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins