Efficacy & Safety of Resatorvid in Adults With Severe Sepsis
Efficacy & Safety of Resatorvid 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.
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.
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.