Clinical trial NCT00143611: Efficacy & Safety of Resatorvid in Adults With Severe Sepsis
Official title: A Pivotal, Multicenter, Multinational, Randomized, Double-Blind, Placebo-Controlled Study To Evaluate The Efficacy And Safety of TAK-242 in Adults With Severe Sepsis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis
Keywords: Shock, Septic
Sepsis Syndrome
Respiratory Insufficiency
SIRS (Systemic Inflammatory Response Syndrome)
Respiratory Failure
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2005-09-02
Enrollment: 277
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 28-day All-cause Mortality.
timeFrame: Day 28
Secondary outcomes:
measure: Change from Baseline in Organ Failure Assessment
timeFrame: Day 28
measure: Mean Systemic Inflammatory Response
timeFrame: Day 28
measure: Mean Vasopressor-free days
timeFrame: Day 28
measure: Mean Ventilator-free days
timeFrame: Day 28
measure: Mean Intensive Care Unit free days
timeFrame: Day 28
measure: Mean Discharge Status.
timeFrame: Day 28
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Mobile
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Scottsdale
country: United States
state: Arizona
city: Escondido
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Orange
country: United States
state: California
city: Poway
country: United States
state: California
city: San Diego
country: United States
state: California
city: Colorado Springs
country: United States
state: Colorado
city: New Haven
country: United States
state: Connecticut
city: Newark
country: United States
state: Delaware
city: Atlantis
country: United States
state: Florida
city: Bay Pines
country: United States
state: Florida
city: Jacksonville
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Sarasota
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Augusta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Peoria
country: United States
state: Illinois
city: Indianapolis
country: United States
state: Indiana
city: Des Moines
country: United States
state: Iowa
city: Louisville
country: United States
state: Kentucky
city: Shreveport
country: United States
state: Louisiana
city: Portland
country: United States
state: Maine
city: Baltimore
country: United States
state: Maryland
city: Springfield
country: United States
state: Massachusetts
city: Kalamazoo
country: United States
state: Michigan
city: Kansas City
country: United States
state: Missouri
city: St. Louis
country: United States
state: Missouri
city: Butte
country: United States
state: Montana
city: Englewood
country: United States
state: New Jersey
city: Buffalo
country: United States
state: New York
city: New York
country: United States
state: New York
city: Rochester
country: United States
state: New York
city: Greensboro
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Akron
country: United States
state: Ohio
city: Columbus
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Greenville
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Fort Worth
country: United States
state: Texas
city: Galveston
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Lubbock
country: United States
state: Texas
city: Bellevue
country: United States
state: Washington
city: Adelaide
country: Australia
city: Fremantle
country: Australia
city: Heidelberg
country: Australia
city: Linz
country: Austria
city: Wien
country: Austria
city: Aalst
country: Belgium
city: Antwerpen
country: Belgium
city: Brussel
country: Belgium
city: Bruxelles
country: Belgium
city: Genk
country: Belgium
city: Gent
country: Belgium
city: Liege
country: Belgium
city: Ottignies
country: Belgium
city: Yvoir
country: Belgium
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Victoria
country: Canada
state: British Columbia
city: Winnipeg
country: Canada
state: Manitoba
city: Halifax
country: Canada
state: Nova Scotia
city: London
country: Canada
state: Ontario
city: Brno
country: Czech Republic
city: Havlickuv Brod
country: Czech Republic
city: Hradec Kralove
country: Czech Republic
city: Opava
country: Czech Republic
city: Pilsen
country: Czech Republic
city: Prague
country: Czech Republic
city: Helsinki
country: Finland
city: Joensuu
country: Finland
city: Kokkola
country: Finland
city: Kuopio
country: Finland
city: Lappeenranta
country: Finland
city: Oulu
country: Finland
city: Seinajoki
country: Finland
city: Tampere
country: Finland
city: Turku
country: Finland
city: Berlin
country: Germany
city: Dresden
country: Germany
city: Erfurt
country: Germany
city: Jena
country: Germany
city: Krefeld
country: Germany
city: Ludwigshafen
country: Germany
city: Mannheim
country: Germany
city: Munchen
country: Germany
city: Wuppertal
country: Germany
city: Afula
country: Israel
city: Ashkelon
country: Israel
city: Haifa
country: Israel
city: Holon
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Petach-Tikva
country: Israel
city: Zerifin
country: Israel
city: Lecco
country: Italy
city: Monza
country: Italy
city: Pavia
country: Italy
city: Chiba
country: Japan
city: Fukuoka
country: Japan
city: Hiroshima
country: Japan
city: Hokkaido
country: Japan
city: Iwate
country: Japan
city: Kumamoto
country: Japan
city: Kyoto
country: Japan
city: Osaka
country: Japan
city: Shizuoka
country: Japan
city: Tokyo
country: Japan
city: Yamaguchi
country: Japan
city: Apeldoorn
country: Netherlands
city: Groningen
country: Netherlands
city: Leeuwarden
country: Netherlands
city: Nijmegen
country: Netherlands
city: Rotterdam
country: Netherlands
city: s-Hertogenbosch
country: Netherlands
city: Tilburg
country: Netherlands
city: Auckland
country: New Zealand
city: Christchurch
country: New Zealand
city: Hastings
country: New Zealand
city: Tauranga
country: New Zealand
city: San Juan
country: Puerto Rico
city: Barcelona
country: Spain
city: Getafe
country: Spain
city: Madrid
country: Spain
city: Valladolid
country: Spain
city: Vitoria
country: Spain
city: Gavle
country: Sweden
city: Goteborg
country: Sweden
city: Karlstad
country: Sweden
city: Kristianstad
country: Sweden
city: Linkoping
country: Sweden
city: Lund
country: Sweden
city: Stockholm
country: Sweden
city: Uppsala
country: Sweden
city: Brighton
country: United Kingdom
city: Glasgow
country: United Kingdom
city: Leeds
country: United Kingdom
city: Livingston
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Takeda
name: VP Clinical Science
role: STUDY_DIRECTOR
References:
citation: 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.