Efficacy & Safety of Resatorvid in Adults With Severe Sepsis

• ClinicalTrials.gov Identifier: NCT00143611
• Recruitment Status: Completed
• First Posted: September 2, 2005
• Last Update Posted: February 2, 2012
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: August 31, 2005
• First Posted Date: September 2, 2005
• Last Update Posted Date: February 2, 2012
• Study Start Date: September 2005
• Actual Primary Completion Date: February 2007 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 5, 2009): 28-day All-cause Mortality. [ Time Frame: Day 28 ]
• Original Primary Outcome Measures (submitted: August 31, 2005): 28-day all-cause mortality

Current Secondary Outcome Measures (submitted: February 5, 2009)

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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sepsis

Intervention

• 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 Name: 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 Name: TAK-242
• Drug: Placebo
  Resatorvid placebo-matching injection, subcutaneously for thirty minutes; then resatorvid placebo-matching injection, subcutaneously over 96 hours.

Study Arms

• Experimental: Resatorvid 1.2 mg/kg/day
  Intervention: Drug: Resatorvid
• Experimental: Resatorvid 2.4 mg/kg/day
  Intervention: Drug: Resatorvid
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 8, 2007): 277
• Original Enrollment (submitted: August 31, 2005): 2930
• Actual Study Completion Date: February 2007
• Actual Primary Completion Date: February 2007 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czech Republic, Finland, Germany, Israel, Italy, Japan, Netherlands, New Zealand, Puerto Rico, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT00143611
• 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Takeda
• Original Responsible Party: Not Provided
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: VP Clinical Science; Takeda

• PRS Account: Takeda
• Verification Date: January 2012