Efficacy & Safety of Resatorvid in Adults With Severe Sepsis

A Pivotal, Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy And Safety of TAK-242 in Adults With Severe Sepsis

The purpose of this study is to determine the optimal dose of Resatorvid for reducing 28-day all-cause mortality in subjects with severe sepsis.

Study Overview

• Status: Completed
• Conditions: Sepsis
• Intervention / Treatment: Drug: Resatorvid; Drug: Resatorvid; Drug: Placebo

Detailed Description

Severe sepsis, defined as sepsis associated with acute organ dysfunction, remains a serious medical problem worldwide. In the United States alone, approximately 750,000 cases of severe sepsis occur each year, with the mortality rate ranging between 30% and 50% for severe sepsis patients with concomitant organ dysfunction. As the population ages, these numbers are expected to increase. The pathophysiology of severe sepsis is thought to involve the activation of a variety of inflammatory and procoagulant host responses to infection, which if unchecked, can lead to diffuse endovascular injury, multi-organ dysfunction, and ultimately death.

The host response to infection with microorganism and microorganism-derived molecules is characterized by the synthesis and release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins 1, 6 and 8 (IL-1, IL-6, and IL-8), by inflammatory cells, and by other markers of inflammation such as C-reactive protein. Inflammatory cells, such as macrophages, release these cytokines by signals transmitted from the surface of these cells after binding of pathogen-associated molecules to cell surface pattern recognition receptors known as toll-like receptors.

TAK-242 (resatorvid) is a small molecule suppressor of pathogen-induced release of inflammatory cytokines and acts by inhibiting TLR-4 mediated signaling. Because of its inhibitory effect on suppressing cytokine levels, resatorvid is being developed as a treatment for severe sepsis.

The study was ended after the DSMB determined there was insufficient cytokine suppression in the 150-subject analysis within Stage 1 of the study.

• Study Type: Interventional
• Enrollment (Actual): 277
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
  • Fremantle, Australia
  • Heidelberg, Australia
• Austria
  • Linz, Austria
  • Wien, Austria
• Belgium
  • Aalst, Belgium
  • Antwerpen, Belgium
  • Brussel, Belgium
  • Bruxelles, Belgium
  • Genk, Belgium
  • Gent, Belgium
  • Liege, Belgium
  • Ottignies, Belgium
  • Yvoir, Belgium
• Canada
  • Alberta
    • Calgary, Alberta, Canada
  • British Columbia
    • Vancouver, British Columbia, Canada
    • Victoria, British Columbia, Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
  • Ontario
    • London, Ontario, Canada
• Czech Republic
  • Brno, Czech Republic
  • Havlickuv Brod, Czech Republic
  • Hradec Kralove, Czech Republic
  • Opava, Czech Republic
  • Pilsen, Czech Republic
  • Prague, Czech Republic
• Finland
  • Helsinki, Finland
  • Joensuu, Finland
  • Kokkola, Finland
  • Kuopio, Finland
  • Lappeenranta, Finland
  • Oulu, Finland
  • Seinajoki, Finland
  • Tampere, Finland
  • Turku, Finland
• Germany
  • Berlin, Germany
  • Dresden, Germany
  • Erfurt, Germany
  • Jena, Germany
  • Krefeld, Germany
  • Ludwigshafen, Germany
  • Mannheim, Germany
  • Munchen, Germany
  • Wuppertal, Germany
• Israel
  • Afula, Israel
  • Ashkelon, Israel
  • Haifa, Israel
  • Holon, Israel
  • Jerusalem, Israel
  • Kfar Saba, Israel
  • Petach-Tikva, Israel
  • Zerifin, Israel
• Italy
  • Lecco, Italy
  • Monza, Italy
  • Pavia, Italy
• Japan
  • Chiba, Japan
  • Fukuoka, Japan
  • Hiroshima, Japan
  • Hokkaido, Japan
  • Iwate, Japan
  • Kumamoto, Japan
  • Kyoto, Japan
  • Osaka, Japan
  • Shizuoka, Japan
  • Tokyo, Japan
  • Yamaguchi, Japan
• Netherlands
  • Apeldoorn, Netherlands
  • Groningen, Netherlands
  • Leeuwarden, Netherlands
  • Nijmegen, Netherlands
  • Rotterdam, Netherlands
  • Tilburg, Netherlands
  • s-Hertogenbosch, Netherlands
• New Zealand
  • Auckland, New Zealand
  • Christchurch, New Zealand
  • Hastings, New Zealand
  • Tauranga, New Zealand
• Puerto Rico
  • San Juan, Puerto Rico
• Spain
  • Barcelona, Spain
  • Getafe, Spain
  • Madrid, Spain
  • Valladolid, Spain
  • Vitoria, Spain
• Sweden
  • Gavle, Sweden
  • Goteborg, Sweden
  • Karlstad, Sweden
  • Kristianstad, Sweden
  • Linkoping, Sweden
  • Lund, Sweden
  • Stockholm, Sweden
  • Uppsala, Sweden
• United Kingdom
  • Brighton, United Kingdom
  • Glasgow, United Kingdom
  • Leeds, United Kingdom
  • Livingston, United Kingdom
  • London, United Kingdom
• United States
  • Alabama
    • Birmingham, Alabama, United States
    • Mobile, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
    • Scottsdale, Arizona, United States
  • California
    • Escondido, California, United States
    • Los Angeles, California, United States
    • Orange, California, United States
    • Poway, California, United States
    • San Diego, California, United States
  • Colorado
    • Colorado Springs, Colorado, United States
  • Connecticut
    • New Haven, Connecticut, United States
  • Delaware
    • Newark, Delaware, United States
  • Florida
    • Atlantis, Florida, United States
    • Bay Pines, Florida, United States
    • Jacksonville, Florida, United States
    • Miami, Florida, United States
    • Orlando, Florida, United States
    • Sarasota, Florida, United States
  • Georgia
    • Atlanta, Georgia, United States
    • Augusta, Georgia, United States
  • Illinois
    • Chicago, Illinois, United States
    • Peoria, Illinois, United States
  • Indiana
    • Indianapolis, Indiana, United States
  • Iowa
    • Des Moines, Iowa, United States
  • Kentucky
    • Louisville, Kentucky, United States
  • Louisiana
    • Shreveport, Louisiana, United States
  • Maine
    • Portland, Maine, United States
  • Maryland
    • Baltimore, Maryland, United States
  • Massachusetts
    • Springfield, Massachusetts, United States
  • Michigan
    • Kalamazoo, Michigan, United States
  • Missouri
    • Kansas City, Missouri, United States
    • St. Louis, Missouri, United States
  • Montana
    • Butte, Montana, United States
  • New Jersey
    • Englewood, New Jersey, United States
  • New York
    • Buffalo, New York, United States
    • New York, New York, United States
    • Rochester, New York, United States
  • North Carolina
    • Greensboro, North Carolina, United States
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Akron, Ohio, United States
    • Columbus, Ohio, United States
  • Oklahoma
    • Oklahoma City, Oklahoma, United States
  • South Carolina
    • Greenville, South Carolina, United States
  • Tennessee
    • Nashville, Tennessee, United States
  • Texas
    • Fort Worth, Texas, United States
    • Galveston, Texas, United States
    • Houston, Texas, United States
    • Lubbock, Texas, United States
  • Washington
    • Bellevue, Washington, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has clinical evidence of infection defined as the presence of a known or probable source of infection requiring the initiation of parenteral antimicrobial therapy.

• Must meet at least 3 of the following 4 criteria for SIRS:

  • A core temperature greater than 38°C or less than 36°C.
  • A heart rate greater than 90 beats per minute.
  • A respiratory rate greater than 20 breaths/min or partial pressure of carbon dioxide in arterial blood less than 32 mm Hg or mechanical ventilation for an acute process.
  • A total white blood cell absolute count greater than 12,000 cells/mm3 or less than 4,000 cells/mm3, or a white blood cell differential count that showed greater than 10% immature (band) forms.
• Must have sepsis with shock and/or respiratory failure.

Exclusion Criteria

• If female, the subject is pregnant, nursing and the milk is intended to be ingested by the infant, or the participant plans to become pregnant, or nurse and the milk is intended to be ingested by the infant.
• Is receiving immunosuppressive therapy such as cyclosporine, azathioprine, or cancer-related chemotherapy.
• Has a granulocyte count of less than 1000/mm3 except if the decreased count was believed to be due to sepsis.
• Has documented or suspected acute myocardial infarction within the last 6 weeks prior to Pretreatment Period.
• Has a documented history of moderate to severe chronic heart failure as defined by New York Heart Association Functional Classification III or IV.
• Is known to be positive for human immunodeficiency virus with known CD4 count less than or equal to 50/mm3 or had known end-stage processes.
• Has a known history of glucose-6-phosphate dehydrogenase deficiency.
• Has a methemoglobin level greater than 5% at Pretreatment Period or had a known history of methemoglobinemia.
• Is moribund and death was considered imminent.
• Is classified as "Do Not Resuscitate", or "Do Not Treat", or the participant's family has not committed to aggressive management of the participant's condition.
• Is not expected to survive for 28 days and was not likely be given life support due to a pre-existing, uncorrectable medical condition.
• Has a known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites.
• Is in a chronic vegetative state or has a similar long-term neurological condition.
• Has known portal hypertension or Child-Pugh hepatic impairment class C.
• Has acute third degree burns involving more than 30% of body surface within 120 hours prior to Pretreatment Period.
• Has known hypersensitivity to sulfonamides.
• Has known hypersensitivity to components of resatorvid.
• Has participated in any other investigational study (drug or device) and/or taken any investigational drug within 30 days or 5 half-lives of the drug.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Resatorvid placebo-matching injection, subcutaneously for thirty minutes; then resatorvid placebo-matching injection, subcutaneously over 96 hours.
Experimental: Resatorvid 1.2 mg/kg/day	Drug: Resatorvid; Resatorvid 1.2 mg/kg, injection, subcutaneously for thirty minutes; then resatorvid 0.05 mg/kg/h (1.2 mg/kg/day), injection, subcutaneously over 96 hours.; Other Names: TAK-242; Drug: Resatorvid; Resatorvid 1.2 mg/kg, injection, subcutaneously for thirty minutes; then resatorvid 0.1 mg/kg/h (2.4 mg/kg/day), injection, subcutaneously over 96 hours.; Other Names: TAK-242
Experimental: Resatorvid 2.4 mg/kg/day	Drug: Resatorvid; Resatorvid 1.2 mg/kg, injection, subcutaneously for thirty minutes; then resatorvid 0.05 mg/kg/h (1.2 mg/kg/day), injection, subcutaneously over 96 hours.; Other Names: TAK-242; Drug: Resatorvid; Resatorvid 1.2 mg/kg, injection, subcutaneously for thirty minutes; then resatorvid 0.1 mg/kg/h (2.4 mg/kg/day), injection, subcutaneously over 96 hours.; Other Names: TAK-242

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
28-day All-cause Mortality.	Day 28

Secondary Outcome Measures

Outcome Measure	Time Frame
Change from Baseline in Organ Failure Assessment	Day 28
Mean Systemic Inflammatory Response	Day 28
Mean Vasopressor-free days	Day 28
Mean Ventilator-free days	Day 28
Mean Intensive Care Unit free days	Day 28
Mean Discharge Status.	Day 28

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Rice TW, Wheeler AP, Bernard GR, Vincent JL, Angus DC, Aikawa N, Demeyer I, Sainati S, Amlot N, Cao C, Ii M, Matsuda H, Mouri K, Cohen J. A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med. 2010 Aug;38(8):1685-94. doi: 10.1097/CCM.0b013e3181e7c5c9.

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): February 1, 2007
• Study Completion (Actual): February 1, 2007

Study Registration Dates

• First Submitted: August 31, 2005
• First Submitted That Met QC Criteria: August 31, 2005
• First Posted (Estimate): September 2, 2005

Study Record Updates

• Last Update Posted (Estimate): February 2, 2012
• Last Update Submitted That Met QC Criteria: January 31, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Drug Therapy; Shock, Septic; Respiratory Insufficiency; Respiratory Failure; Sepsis Syndrome; SIRS (Systemic Inflammatory Response Syndrome)
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: 01-04-TL-242-011; 2005-003561-16 (EudraCT Number); U1111-1127-5919 (Registry Identifier: WHO); DOH-27-0406-1213 (Registry Identifier: SANCTR)