Efficacy & Safety of Resatorvid in Adults With Severe Sepsis

NCT ID: NCT00143611

Last Updated: 2012-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 277 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-09-30
• Study Completion Date: 2007-02-28

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.

Conditions

Sepsis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Resatorvid 1.2 mg/kg/day

Group Type: EXPERIMENTAL

Resatorvid

Intervention Type: DRUG

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.

Resatorvid 2.4 mg/kg/day

Group Type: EXPERIMENTAL

Resatorvid

Intervention Type: DRUG

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.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Resatorvid placebo-matching injection, subcutaneously for thirty minutes; then resatorvid placebo-matching injection, subcutaneously over 96 hours.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Placebo

Resatorvid placebo-matching injection, subcutaneously for thirty minutes; then resatorvid placebo-matching injection, subcutaneously over 96 hours.

Intervention Type: DRUG

Other Intervention Names

TAK-242; TAK-242

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

VP Clinical Science

Role: STUDY_DIRECTOR

Takeda

Locations

Birmingham, Alabama, United States

Mobile, Alabama, United States

Phoenix, Arizona, United States

Scottsdale, Arizona, United States

Escondido, California, United States

Los Angeles, California, United States

Orange, California, United States

Poway, California, United States

San Diego, California, United States

Colorado Springs, Colorado, United States

New Haven, Connecticut, United States

Newark, Delaware, United States

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

Atlanta, Georgia, United States

Augusta, Georgia, United States

Chicago, Illinois, United States

Peoria, Illinois, United States

Indianapolis, Indiana, United States

Des Moines, Iowa, United States

Louisville, Kentucky, United States

Shreveport, Louisiana, United States

Portland, Maine, United States

Baltimore, Maryland, United States

Springfield, Massachusetts, United States

Kalamazoo, Michigan, United States

Kansas City, Missouri, United States

St Louis, Missouri, United States

Butte, Montana, United States

Englewood, New Jersey, United States

Buffalo, New York, United States

New York, New York, United States

Rochester, New York, United States

Greensboro, North Carolina, United States

Winston-Salem, North Carolina, United States

Akron, Ohio, United States

Columbus, Ohio, United States

Oklahoma City, Oklahoma, United States

Greenville, South Carolina, United States

Nashville, Tennessee, United States

Fort Worth, Texas, United States

Galveston, Texas, United States

Houston, Texas, United States

Lubbock, Texas, United States

Bellevue, Washington, United States

Adelaide, , Australia

Fremantle, , Australia

Heidelberg, , Australia

Linz, , Austria

Vienna, , Austria

Aalst, , Belgium

Antwerp, , Belgium

Brussels, , Belgium

Genk, , Belgium

Ghent, , Belgium

Liège, , Belgium

Ottignies, , Belgium

Yvoir, , Belgium

Calgary, Alberta, Canada

Vancouver, British Columbia, Canada

Victoria, British Columbia, Canada

Winnipeg, Manitoba, Canada

Halifax, Nova Scotia, Canada

London, Ontario, Canada

Brno, , Czechia

Havlíčkův Brod, , Czechia

Hradec Králové, , Czechia

Opava, , Czechia

Pilsen, , Czechia

Prague, , Czechia

Helsinki, , Finland

Joensuu, , Finland

Kokkola, , Finland

Kuopio, , Finland

Lappeenranta, , Finland

Oulu, , Finland

Seinäjoki, , Finland

Tampere, , Finland

Turku, , Finland

Berlin, , Germany

Dresden, , Germany

Erfurt, , Germany

Jena, , Germany

Krefeld, , Germany

Ludwigshafen, , Germany

Mannheim, , Germany

München, , Germany

Wuppertal, , Germany

Afula, , Israel

Ashkelon, , Israel

Haifa, , Israel

Holon, , Israel

Jerusalem, , Israel

Kfar Saba, , Israel

Petah Tikva, , Israel

Ẕerifin, , Israel

Lecco, , Italy

Monza, , Italy

Pavia, , Italy

Chiba, , Japan

Fukuoka, , Japan

Hiroshima, , Japan

Hokkaido, , Japan

Kumamoto, , Japan

Kyoto, , Japan

Numakunai, , Japan

Osaka, , Japan

Shizuoka, , Japan

Tokyo, , Japan

Yamaguchi, , Japan

's-Hertogenbosch, , Netherlands

Apeldoorn, , Netherlands

Groningen, , Netherlands

Leeuwarden, , Netherlands

Nijmegen, , Netherlands

Rotterdam, , Netherlands

Tilburg, , Netherlands

Auckland, , New Zealand

Christchurch, , New Zealand

Hastings, , New Zealand

Tauranga, , New Zealand

San Juan, , Puerto Rico

Barcelona, , Spain

Getafe, , Spain

Madrid, , Spain

Valladolid, , Spain

Vitoria-Gasteiz, , Spain

Gävle, , Sweden

Gothenburg, , Sweden

Karlstad, , Sweden

Kristianstad, , Sweden

Linköping, , Sweden

Lund, , Sweden

Stockholm, , Sweden

Uppsala, , Sweden

Brighton, , United Kingdom

Glasgow, , United Kingdom

Leeds, , United Kingdom

Livingston, , United Kingdom

London, , United Kingdom

Countries

United States; Australia; Austria; Belgium; Canada; Czechia; Finland; Germany; Israel; Italy; Japan; Netherlands; New Zealand; Puerto Rico; Spain; Sweden; United Kingdom

References

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.

Reference Type: RESULT

PMID: 20562702 (View on PubMed)

Other Identifiers

2005-003561-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1127-5919

Identifier Type: REGISTRY

Identifier Source: secondary_id

DOH-27-0406-1213

Identifier Type: REGISTRY

Identifier Source: secondary_id

01-04-TL-242-011

Identifier Type: -

Identifier Source: org_study_id