Business Decision; No Safety Or Efficacy Concerns.

The purpose of this study is to determine the effect of resatorvid on subjects with sepsis.

Sepsis is a major cause of in-hospital death, with a higher mortality rate than events such as stroke and acute myocardial infarction, each with less than a 20% risk of death in the first 30 days. Sepsis is a clinical condition caused by the innate inflammatory host response to systemic infection that can result in organ failure and potentially death. Under certain circumstances, many components of the innate immune response that are normally involved with host defense can cause cell and tissue damage and subsequently multiple organ failure, the clinical hallmark of severe sepsis.

The host response to infection is characterized by the synthesis and release of proinflammatory cytokines. Cytokines are released by signals transmitted from the surface of inflammatory cells, after binding of pathogen-associated molecules to cell surface pattern recognition receptors known as toll-like receptors.

TAK-242 (resatorvid) is a toll-like receptor 4 inhibitor under clinical development for the treatment of patients with severe sepsis. Study participation is anticipated to be about 28 days, with an additional 9 month follow-up period.

Inclusion Criteria

• Suspected or proven bacterial or fungal infection for which patient is receiving parenteral antimicrobial therapy.

• Developed at least 3 of the 4 following systemic inflammatory response syndrome criteria within 36 hours prior to start of study drug administration:

  • A temperature from any site greater than 38°C (greater than 100.4°F) or a core temperature less than 36°C (less than 96.8°F).
  • Heart rate of greater than 90 beats per minute. If subject has a known medical condition (eg, heart block) or is receiving treatment (eg, beta blocker) that would prevent tachycardia, only 2 of the remaining 3 criteria for systemic inflammatory response syndrome must be met.
  • Respiratory rate of greater than 20 breaths per min or arterial partial pressure of carbon dioxide of less than 32 mm Hg or mechanical ventilation for an acute process.
  • A total white blood cell absolute count greater than 12,000 cells per mm3 or less than 4,000 cells/mm3; or a white blood cell differential count showing greater than 10% immature (band) forms.

• Has septic shock diagnosed within 36 hours prior to study drug administration..

• Has developed respiratory failure within 36 hours prior to study drug administration.

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria

• Received any investigational compound within 30 days (or 5 half-lives of the drug, whichever is longer) prior to the initiation of the study drug infusion or is participating in another investigational study, not including investigational compound, without prior approval from the Vanderbilt Coordinating Center or the sponsor.
• Currently receiving any immunosuppressive therapy (excluding glucocorticoids) such as methotrexate, azathioprine, anti tumor necrosis factor alpha, or a cancer related chemotherapeutic agent.
• Known history of glucose-6-phosphate dehydrogenase deficiency.
• Methemoglobin level of greater than or equal to 5% at pretreatment period or has a known history of methemoglobinemia.
• Moribund and death is considered imminent.
• Prior to the onset of sepsis, the subject would not otherwise have been expected to survive 28 days or to complete a functional recovery due to a pre-existing unstable medical condition (eg, a recent acute cerebral hemorrhage or infarct, a recent acute unstable myocardial infarction, severe traumatic injury).
• Poorly controlled or metastatic neoplasm.
• The participant, the participant's family or physician is not committed to full aggressive management or the presence of an unstable medical condition makes the receipt of full aggressive management support unlikely in the view of the coordinating center.
• Severe end stage chronic respiratory failure or lung disease that significantly impairs physical functioning equivalent to that of New York Heart Association functional classification III or IV.
• Documented history of moderate to severe chronic heart failure as defined by New York Heart Association functional classification III or IV.
• Received electrocardioversion for a pulse-less rhythm or chest compressions during their current hospitalization.
• Known to be immunocompromised such as subjects with human immunodeficiency virus and a CD4 count less than 50 mm3, primary immune deficiency or chronic lymphocytic leukemia.
• Chronic end stage hepatic failure or significant sequelae of chronic hepatic failure (eg, esophageal varices, jaundice, chronic ascites) or Child-Pugh hepatic impairment Classification C.
• In a chronic vegetative state or has a similar long-term neurological impairment, where continued aggressive care would be unlikely.
• Acute third degree burns involving more than 30% of body surface area within 120 hours of first qualifying organ failure.
• Known hypersensitivity to sulphonamides.
• Known hypersensitivity to components of resatorvid; for example, is allergic to eggs, egg products, or soybeans.

Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious adverse event) after the last dose of double-blind study drug

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.