Sepsis
Conditions
Keywords
Systemic Inflammatory Response Syndrome, Septic Shock, Septicemia, Drug Therapy
Brief summary
The purpose of this study is to determine the effect of resatorvid on subjects with sepsis.
Detailed description
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.
Interventions
DRUGResatorvid
Resatorvid 1.2 mg/kg emulsion, injection for 30 minutes and resatorvid 2.4 mg/kg per-day emulsion, injection, continuous infusion for 96 hours.
DRUGPlacebo
Resatorvid placebo-matching emulsion, injection for 30 minutes and resatorvid placebo-matching emulsion, injection, continuous infusion for 96 hours.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | Day 28 | Mortality regardless of cause at Day 28 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ICU Free Days | Day 28 | Number days participant was not in ICU |
| Vasopressor Free Days. | Day 28 | Number days participant did not need vasopressors. |
| Ventilator Free Days. | Day 28 | Number days participant was not on Ventilattor support. |
Countries
Japan
Participant flow
Recruitment details
Participants took part in the sudy at 11 centers in Japan and 1 center in the United States from 26 February 2008 to 20 February 2009 (day the decision was taken to terminate the study) .
Pre-assignment details
Participants who met 3 of the 4 systemic inflammatory response syndrome (SIRS) criteria and receiving parentaeral antimicrobial therapy for bacterial or fungal infection prior to enrollment and met the key organ failure criteria within 36 hours of planned study drug administration were randomized to receive resatorvid or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Resatorvid 2.4 mg/kg/Day Resatorvid 1.2 mg/kg given as a 30-minute loading dose followed by 2.4 mg/kg/day given as a continuous infusion for 96 hours | 6 |
| Placebo Placebo given as a 30-minute loading dose followed by a continuous infusion for 96 hours. | 11 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Randomized but not treated | 1 | 0 |
Baseline characteristics
| Characteristic | Resatorvid 2.4 mg/kg/Day | Total | Placebo |
|---|---|---|---|
| Age Continuous | 76.7 years STANDARD_DEVIATION 5.28 | 77.4 years STANDARD_DEVIATION 11.14 | 77.8 years STANDARD_DEVIATION 13.56 |
| Age, Customized 18 - <45 | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 45 - <60 | 0 Participants | 1 Participants | 1 Participants |
| Age, Customized 60 - <75 | 2 Participants | 5 Participants | 3 Participants |
| Age, Customized ≥75 | 4 Participants | 11 Participants | 7 Participants |
| Body Mass Index | 21.46 kg/m2 STANDARD_DEVIATION 3.97 | 22.19 kg/m2 STANDARD_DEVIATION 5.36 | 22.59 kg/m2 STANDARD_DEVIATION 6.12 |
| Ethnicity Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity Not Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity Unknown or Not Reported | 6 Participants | 16 Participants | 10 Participants |
| Height | 158.3 cm STANDARD_DEVIATION 6 | 159.9 cm STANDARD_DEVIATION 6.9 | 160.7 cm STANDARD_DEVIATION 7.4 |
| Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race Asian | 6 Participants | 16 Participants | 10 Participants |
| Race Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race White | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 7 Participants |
| Smoking Classification Current smoker | 0 Participant | 3 Participant | 3 Participant |
| Smoking Classification Ex-smoker | 3 Participant | 7 Participant | 4 Participant |
| Smoking Classification Never smoked | 2 Participant | 6 Participant | 4 Participant |
| Smoking Classification Smoking history not available | 1 Participant | 1 Participant | 0 Participant |
| Weight | 54.27 kg STANDARD_DEVIATION 12.9 | 56.84 kg STANDARD_DEVIATION 15.4 | 58.24 kg STANDARD_DEVIATION 17.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 6 / 11 |
| serious Total, serious adverse events | 1 / 6 | 3 / 11 |
Outcome results
Primary
All-cause Mortality
Mortality regardless of cause at Day 28
Time frame: Day 28
Population: Participants who received study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resatorvid | All-cause Mortality | Number Alive | 4 Participants |
| Resatorvid | All-cause Mortality | Number participants Analyzed | 6 Participants |
| Resatorvid | All-cause Mortality | Number not alive | 2 Participants |
| Placebo | All-cause Mortality | Number participants Analyzed | 11 Participants |
| Placebo | All-cause Mortality | Number Alive | 8 Participants |
| Placebo | All-cause Mortality | Number not alive | 3 Participants |
Primary
All-cause Mortality
Mortality regardless of cause at Day 28
Time frame: Day 28
Population: Participants who received study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Resatorvid | All-cause Mortality | Percent Alive | 66.7 Percent of Participant |
| Resatorvid | All-cause Mortality | Percent Not alive | 33.7 Percent of Participant |
| Placebo | All-cause Mortality | Percent Alive | 72.7 Percent of Participant |
| Placebo | All-cause Mortality | Percent Not alive | 27.3 Percent of Participant |
Secondary
ICU Free Days
Number days participant was not in ICU
Time frame: Day 28
Population: This study was terminated early when 17 subjects had received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resatorvid | ICU Free Days | NA days |
| Placebo | ICU Free Days | NA days |
Secondary
Vasopressor Free Days.
Number days participant did not need vasopressors.
Time frame: Day 28
Population: This study was terminated early when 17 subjects had received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resatorvid | Vasopressor Free Days. | NA days |
| Placebo | Vasopressor Free Days. | NA days |
Secondary
Ventilator Free Days.
Number days participant was not on Ventilattor support.
Time frame: Day 28
Population: This study was terminated early when 17 subjects had received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Resatorvid | Ventilator Free Days. | NA Days |
| Placebo | Ventilator Free Days. | NA Days |