Phase 3 Safety and Efficacy Study of ART-123 in Subjects With Severe Sepsis and Coagulopathy

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects With Severe Sepsis and Coagulopathy.

The purpose of the study is to evaluate if ART-123 given to patients who have severe sepsis can decrease mortality.

Study Overview

• Status: Completed
• Conditions: Severe Sepsis; Coagulopathy
• Intervention / Treatment: Drug: ART-123; Drug: Placebo

Detailed Description

Study is to evaluate if ART-123 given to patients who have severe sepsis complicated by at least one organ dysfunction and coagulopathy can decrease mortality.

• Study Type: Interventional
• Enrollment (Actual): 816
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5004BAL
    • Hospital Italiano de Cordoba
• Australia
  • New South Wales
    • Randwick, New South Wales, Australia
      • Prince of Wales Hospital
  • Queensland
    • Herston, Queensland, Australia
      • Royal Brisbane and Women's Hospital
    • Woolloongabba, Queensland, Australia
      • Princess Alexandra Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Bendigo, Victoria, Australia
      • Bendigo Hospital
    • Clayton, Victoria, Australia
      • Monash Medical Centre
    • Dandenong, Victoria, Australia, 3175
      • Dandenong Hospital Monash Health
    • Footscray, Victoria, Australia
      • Western Hospital
    • Heidelberg, Victoria, Australia
      • Austin Health
    • Melbourne, Victoria, Australia, 3021
      • Sunshine Hospital
• Belgium
  • Antwerpen, Belgium
    • UZ Antwerpen
  • Arlon, Belgium
    • Cliniques Du Sud-Luxerbourg (CSL), Hospital Saint Joseph
  • Brussels, Belgium
    • Hopital Erasme
  • Brussels, Belgium
    • CHU Brugmann
  • Brussels, Belgium
    • UZ Brussel
  • Brussels, Belgium
    • Hôpitaux IRIS Sud
  • Brussels, Belgium
    • UCL St. Luc
  • Dinant, Belgium
    • Centre Hospitalier de Dinant
  • Gent, Belgium
    • UZ Gent
  • Ottignies, Belgium
    • Clinique Saint-Pierre
  • Yvoir, Belgium
    • UCL Mont-Godinne
• Brazil
  • Brasil, Brazil, 95010-005
    • Hospital Pompeia
  • MG
    • Belo Horizonte, MG, Brazil
      • Santa Casa de Misericordia de Belo Horizonte
  • SP
    • Sao Jose do Rio Preto, SP, Brazil
      • Fundação Faculdade Regional de Medicina São José do Rio Preto
• Bulgaria
  • Plovdiv, Bulgaria
    • Anesthesiology and Intensive Care Clinic, University Multiprofile Hospital For Active Treatment "Sveti Georgi", Plovdiv
  • Sofia, Bulgaria
    • Department of Anesthesiology and Intensive Care Multiprofile Hospital For Active Treatment "Tokuda Hospital Sofia", Sofia
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • 2 of 2
    • Calgary, Alberta, Canada, T2V 1PA
    • Calgary, Alberta, Canada, T3M 1M4
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • 2 of 2
    • Victoria, British Columbia, Canada, V8R-1J8
      • 1 of 2
    • Victoria, British Columbia, Canada, V8R1J8
  • Manitoba
    • Winnipeg, Manitoba, Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
  • Ontario
    • London, Ontario, Canada, N6A5W9
    • Ottawa, Ontario, Canada, KIH 8L6
      • 1 of 2
    • Ottawa, Ontario, Canada, KIH 8L6
      • 2 of 2
    • Windsor, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
• Croatia
  • Zagreb, Croatia
    • Clinical Hospital Center Zagreb, Medical ICU
  • Zagreb, Croatia
    • Clinical Hospital Dubrava, Department of Anesthesiology and resuscitation
  • Zagreb, Croatia
    • University Hospital Center Zagreb, Department of Anesthesiology, Reanimatology and Intensive Care Medicine
• Czechia
  • Brno, Czechia
    • University Hospital Brno, Department of Infectious Diseases
  • Hradec Kralove, Czechia
    • University Hospital Hradec Kralove, Department of Anaesthesiology, Resuscitation and Intensive Care
  • Prague 10, Czechia
    • University Hospital Kralovske Vinohrady, Department of Anesthesiology and Resuscitation
  • Prague 2, Czechia
    • General University Hospital in Prague, Department of Anaesthesiology, Resuscitation and Intensive Medicine
  • Usti nad Labem, Czechia
    • Masaryk´s Hospital Ustni nad Labem, o.z., Department of Infectious Diseases
• Finland
  • Helsinki, Finland
    • Helsingin Yliopistollinen Keskussairaala (HYKS) (Helsinki University Central Hospital (HUCH))
  • Jyväskylä, Finland
    • Keski-Suomen Keskussairaala (Central Finland Central Hospital)
  • Kuopio, Finland
    • Kuopion Yliopistollinen Sairaala (KYS) (Kuopio University Hospital)
  • Tampere, Finland
    • Tampereen Yliopistollinen Sairaala (Tampere University Hospital) (TAYS) - Keskussairaala (Central Hospital)
• France
  • Angers Cedex 9, France
    • CHU D'Anger
  • Dijon, France, 21000
    • CHU de Dijon, Hopital Bocage Central
  • Grenoble cedex 09, France
    • CH-Hôpital Albert Michallon
  • La Roche-Sur-Yon cedex 9, France
    • Centre Hospitalier Départemental de Vendée-Les Oudairies
  • Lille, France, 59037
    • CHRU Lille-Pole Reanimation
  • Limoges cedex, France
    • CHU Limoges
  • Nîmes Cedex 9, France
    • Centre Hospitalier Universitaire Nîmes
  • Paris, France
    • Hopital Cochin
  • Paris, France, 75013
    • La Pitié Salpétrière, Paris
  • Pessac, France, 33600
    • University Hospital of Bordeaux
  • Pierre-Bénite cedex, France
    • CH Lyon Sud
  • Strasbourg, France, 67000
    • Nouvel Hospital Civil
  • Toulon, France
    • Hôpital Sainte Musse
  • Tours, France
    • CHU Tours, Hopital Bretonneau
  • Cedex 3
    • Nice, Cedex 3, France, 23079
      • Archet 1 University Hospital of Nice
  • Nantes Cedex 01
    • Nantes, Nantes Cedex 01, France, 44093
      • Service de reanimation médicale. CHU Hotel Dieu
• Germany
  • Aachen, Germany, 54074
    • Universitätsklinikum der RWTH Aachen
  • Erfurt, Germany
    • HELIOS Klinikum Erfurt
  • Frankfurt am Main, Germany
    • Klinikum der Johann-Wolfgang Goethe-Universitat
• Hungary
  • Budapest, Hungary, 1115
    • Szent Imre Hospital, Anesthesiology and Intensive Care Unit
• India
  • Bangalore, India, 560099
    • Mazumdar Shaw Medical Centre (Unit of Narayana Health)
  • Belgaum, India, 590010
    • KLES Dr. Prabhakar Kore Hospital & Medical Research Centre
  • Mysore, India, 570004
    • JSS Hospital
  • Nagpur, India, 440010
    • Care Hospital
  • Pune, India, 411013
    • Noble Hospital
  • Delhi
    • New Delhi, Delhi, India
      • Maulana Azad Medical College and Associated L N Hospital
  • Gujarat
    • Ahmedabad, Gujarat, India
      • Shalby
    • Ahmedabad,, Gujarat, India, 380015
      • Shalby Hospital
  • Haryana
    • Gurgaon, Haryana, India, 122001
      • Artemis Hospital
  • Maharashtra
    • Pune, Maharashtra, India, 411013
      • Noble Hospital
    • Pune, Maharashtra, India, 411011
      • Ruby Hall Clinic
    • Pune, Maharashtra, India
      • King Edward Memorial Hospital & Research Centre
  • Odisha
    • Bhubaneswar, Odisha, India
      • Hi-tech Medical College & Hospital
  • Pune, Maharashtra
    • Pune, Pune, Maharashtra, India, 411043
      • Bharati Vidyapeeth Deemed University Medical College Bharti Hospital and Research Centre
  • Telangana State
    • Hyderabad, Telangana State, India, 500018
      • St. Theresa Hospital
• Israel
  • Ashkelon, Israel
    • Barzilai Medical Center
  • Haifa, Israel
    • Rambam Medical Center
  • Haifa, Israel
    • The Lady Davis Carmel Medical Center
  • Jerusalem, Israel
    • Shaare Zedek Medical Center
  • Petach Tikva, Israel
    • Rabin Medical Center
  • Rehovot, Israel
    • Kaplan Medical Center
• Korea, Republic of
  • Seongdu, Korea, Republic of
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of
    • Seoul National University Hospital
  • Seoul, Korea, Republic of
    • Asan Medical Center
  • Seoul, Korea, Republic of
    • Samsung Medical Center [Pulmonology]
• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Jeroen Bosch Ziekenhuis
  • Amsterdam, Netherlands
    • VUmc
  • Ede, Netherlands
    • Ziekenhuis Gelderse Vallei
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Groningen, Netherlands
    • University Medical Center Groningen
  • Leeuwarden, Netherlands
    • Medisch Centrum Leeuwarden
  • Nijmegen, Netherlands
    • UMC St. Radboud
  • Rotterdam, Netherlands
    • Ikazia Ziekenhuis
• New Zealand
  • Auckland, New Zealand
    • Auckland District Health Board
  • Christchurch, New Zealand
    • Christchurch Hospital
  • Hastings, New Zealand
    • Hawkes Bay Regional Hospital Intensive Care Unit Omahu Road
  • Newtown, New Zealand, 6021
    • Wellington District Health Board
• Peru
  • Lima Province
    • Lima, Lima Province, Peru
      • Hospital Nacional Almenara Yrigoyen - EsSALUD
    • Lima, Lima Province, Peru
      • Hospital Nacional FAP
• Russian Federation
  • Arkhangelsk, Russian Federation
    • Arkhangelsk Regional Clinical Hospital
  • Arkhangelsk, Russian Federation
    • Volosevich City Clinical Hospital #1
  • Kemerovo, Russian Federation, 650000
    • City Clinical Hospital #3 n.a. M.A. Pogorbunskiy
  • Krasnodar, Russian Federation
    • Kuban State Medical University (Site Facility: Krasnodar Regional Clinical Hospital #2)
  • Krasnoyarsk, Russian Federation, 660022
    • Krasnoyarsk Regional Clinocal Hospital
  • Moscow, Russian Federation
    • Vishnevsky Institute of Surgery
  • Saint Petersburg, Russian Federation, 194354
    • St George City Hospital
  • Saint Petersburg, Russian Federation
    • City hospital #40
  • Sochi, Russian Federation, 354057
    • City Hospital #4
  • St. Petersburg, Russian Federation
    • Aleksandrovskaya City Hospital
  • St. Petersburg, Russian Federation
    • Mariinskaya City Hospital
  • St. Petersburg, Russian Federation
    • Mechnikov North-Western State Medical University n.a. I.I. Mechnikov
• Serbia
  • Nis, Serbia
    • Clinic for Infectious Diseases, Clinical Center Nis
• Spain
  • A Coruña, Spain
    • Complexo Hospitalario Universitario A Coruña
  • Barcelona, Spain
    • Hospital Universitario Mutua Terrassa Intensive Care
  • Barcelona, Spain
    • Servicio de Medicina Intensiva Hospital Universitario Valle de Hebron
  • Madrid, Spain
    • Hospital Clinico San Carlos
  • Sabadell, Spain
    • Hospital de Sabadell
  • Tarragona, Spain
    • Hospital Universitari de Tarragona Joan XXIII
• Taiwan
  • Taichung, Taiwan
    • Taichung Veterans General Hospital [Pulmonology]
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Tainan
    • Yongkang, Tainan, Taiwan
      • Chi Mei Medical Center Yong Kang
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Birmingham Heartlands Hospital
  • Hull, United Kingdom, HU3 2JZ
    • Hull Royal Infirmary
  • Liverpool, United Kingdom
    • Royal Liverpool University Hospital
  • Manchester, United Kingdom
    • Manchester Royal Infirmary
  • Plymouth, United Kingdom
    • Derriford Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
  • Arizona
    • Phoenix, Arizona, United States, 85008
  • Georgia
    • Atlanta, Georgia, United States, 30342
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
  • Indiana
    • Indianapolis, Indiana, United States, 46202
  • Kentucky
    • Hazard, Kentucky, United States, 41701
    • Louisville, Kentucky, United States, 40202
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital
    • Detroit, Michigan, United States, 48235
      • Sinai-Grace Hospital
    • Detroit, Michigan, United States, 48201
      • Harper Hospital - Wayne State University School of Medicine
  • Mississippi
    • Jackson, Mississippi, United States, 39216
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University in St. Louis
  • Montana
    • Butte, Montana, United States, 59701
  • New Jersey
    • Englewood, New Jersey, United States, 07631
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Columbus, Ohio, United States, 43215
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
  • Texas
    • Houston, Texas, United States, 77030
      • 2 of 2
  • Utah
    • Murray, Utah, United States, 84107

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR)
• Clinical objective evidence of bacterial infection and a known site of infection.
• Cardiovascular dysfunction or Respiratory Failure due to sepsis.
• Coagulopathy characterized by an INR >1.40 without other known causes.

Exclusion Criteria:

• Subject or Authorized Representative is unable to provide informed consent.
• Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study.
• Subject is of childbearing potential and does not have a negative pregnancy test.
• Subject is < 18 years of age.
• Subject has a known allergy to ART-123 or any components of the drug product.
• Subject is unwilling to allow transfusion of blood or blood products.
• Subject has an advance directive to withhold life-sustaining treatment.
• Subject has had previous treatment with ART-123.
• Body weight ≥ 175 kg.
• Platelets < 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis.
• Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or non-traumatic orthopedic surgery of the femur or pelvis) that is completed within 12 hours prior to first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures
• History of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent.
• Cerebral Vascular Accident (CVA) within 3 months prior to consent.
• Any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system.
• History of congenital bleeding diathesesor anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia).
• Significant gastrointestinal bleeding within 6 weeks prior to consent.
• Subject is diagnosed with a known medical condition associated with a hypercoagulable state.
• Child-Pugh score of 10-15 (Class C)
• Portosystemic hypertension or known history of bleeding esophageal varices.
• History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent.
• Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or gram stain consistent with bacterial infection.
• Subjects with renal dysfunction defined as (a) Chronic renal failure requiring renal replacement therapy (RRT), or (b) Acute renal failure with onset of oliguria (urine output < 0.3 ml/kg/hr) > 48 hours prior to first dose of study drug whether receiving RRT or not
• Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug.
• Life expectancy < 90 days.
• Current use of any chemotherapy agent likely to cause myeloablation (severe or complete depletion of bone marrow).
• Participation in another research study involving an investigational agent within 30 days prior to consent or projected study participation during the 28 days post study randomization.
• Confirmed or suspected endocarditis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days.
Active Comparator: ART-123	Drug: ART-123; Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days; Other Names: human recombinant thrombomodulin; thrombomodulin alfa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With 28-Day All-cause Mortality	28-Day All-cause Mortality	28 days
Number of Participants With On-Treatment Serious Major Bleeding Events	On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.)	Through Study Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Follow up All-cause Mortality at 3 Months	Follow up all-cause mortality at 3 months	3 months
Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction	Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days.	28 days
Number of Participants With Anti-drug Antibodies	Presence of Anti-drug antibodies up to 18 months	18 months

Collaborators and Investigators

• Sponsor: Asahi Kasei Pharma America Corporation
• Investigators: Study Director: David Fineberg, M.D., Asahi Kasei Pharma America Corporation

Publications and helpful links

General Publications

• Levi M, Vincent JL, Tanaka K, Radford AH, Kayanoki T, Fineberg DA, Hoppensteadt D, Fareed J. Effect of a Recombinant Human Soluble Thrombomodulin on Baseline Coagulation Biomarker Levels and Mortality Outcome in Patients With Sepsis-Associated Coagulopathy. Crit Care Med. 2020 Aug;48(8):1140-1147. doi: 10.1097/CCM.0000000000004426.
• Vincent JL, Francois B, Zabolotskikh I, Daga MK, Lascarrou JB, Kirov MY, Pettila V, Wittebole X, Meziani F, Mercier E, Lobo SM, Barie PS, Crowther M, Esmon CT, Fareed J, Gando S, Gorelick KJ, Levi M, Mira JP, Opal SM, Parrillo J, Russell JA, Saito H, Tsuruta K, Sakai T, Fineberg D; SCARLET Trial Group. Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial. JAMA. 2019 May 28;321(20):1993-2002. doi: 10.1001/jama.2019.5358.

Helpful Links

• Information on sepsis and treatment

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2012
• Primary Completion (Actual): April 5, 2018
• Study Completion (Actual): February 28, 2019

Study Registration Dates

• First Submitted: May 11, 2012
• First Submitted That Met QC Criteria: May 14, 2012
• First Posted (Estimate): May 15, 2012

Study Record Updates

• Last Update Posted (Actual): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 18, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: sepsis
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Hematologic Diseases; Hemorrhagic Disorders; Sepsis; Toxemia; Hemostatic Disorders; Blood Coagulation Disorders
• Other Study ID Numbers: 3-001