Sepsis
Conditions
Keywords
severe sepsis, septic shock, Gram-negative infection, phospholipid emulsion
Brief summary
The primary objective is to estimate the size of the GR270773 treatment effect on 28-day all-cause mortality for two doses of GR270773 versus placebo in adult subjects with suspected or confirmed Gram-negative severe sepsis. GR270773 will be administered as a three-day continuous intravenous infusion.
Interventions
DRUGIntravenous GR270773- Phospholipid Emulsion
OTHERPlacebo
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Receiving parenteral antibiotic therapy for a suspected or confirmed Gram-negative infection. * Have at least one new hypoperfusion abnormality or at least one new onset organ failure resulting from the current septic episode. * Must be available and able to receive the first dose of study medication no more than 12 hours after the confirmation of a new hypoperfusion abnormality or new onset organ failure and within 36 hours after the initiation of new parenteral antibacterial therapy for the suspected or confirmed Gram-negative infection believed to be responsible for this episode of sepsis.
Exclusion criteria
* Subject is unlikely to remain in hospital for a minimum of three days (72 hours) following enrollment. * Subject has neutropenia (e.g., subject recently receiving cytotoxic chemotherapy with absolute neutrophil count \<500/mcL or expected to decline to \<500/mcL in the next 3 days). * Subject has known active hemolytic disease, immune hemolytic anemias, hemoglobinopathies (sickle cell anemia and thalassemia major). * Subject has a known bone marrow disorder of inadequate red cell production (eg, aplastic anemia, myelodysplasia). * Subject is at increased risk of complications from GR270773-related hemolysis due to the inability to increase cardiac function sufficiently to meet the demands for oxygen delivery. * Subject has a baseline hemoglobin (measured after adequate volume resuscitation) \<9.0 g/dL (5.59 mmol/L). * Subject is currently being treated with XIGRIS (Drotrecogin alfa (activated)) or its use is considered imminent (ie., a decision to treat with XIGRIS has been made). * Subject has a history of allergic reaction to eggs (or egg products), soybeans, INTRALIPID, or any component of GR270773. * Subject has been designated as 'not full support do not resuscitate' (DNR), or other equivalent status which prohibits the use of life supporting interventions (e.g., mechanical ventilation, dialysis/hemofiltration, or others) thereby limiting the treatment options available. Note: Subjects with advanced directives prohibiting only chest compression (CPR) are eligible for the study. * Subject has preexisting severe liver disease such as cirrhosis, primary biliary cirrhosis or known preexisting Child-Pugh class B or C liver dysfunction. * Subject is moribund (a state in which death is perceived to be imminent) or has a life expectancy of less than 3 months due to an underlying disease. * Subject is currently receiving one of the following prohibited concomitant medications; parenteral nutrition supplements containing lipid emulsions (e.g., INTRALIPID), amphotericin, liposomal amphotericin, or amphotericin B lipid complex.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With 28-Day All Cause Mortality | Day 1 (post-infusion) up to Day 28 Follow-up | Mortality was assessed by the number of participants who died between days 1 and 28. A summary of death details was given which included whether the participant died between days 1 and 28, whether the death was related sepsis, cause of death, the source of the information, and whether the cause of death was verified by a death record. Participants who had withdrawn from study and all study assessments and for whom survival at day 28 could not be confirmed was treated as deaths for the primary endpoint. The difference in all-cause 28-day mortality rates for each treatment group versus the placebo group in the ITT Population was calculated as placebo - treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With New Onset Organ Failure, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrolment | Baseline (Day 1, pre-infusion) up to Day 28 Follow-up | The new onset organ failure was defined as first time each of the following criteria were met after start of study medication up to Day 28. Respiratory failure: defined by requiring mechanical ventilation not less than 24 hours due to surgery. Renal failure: defined by requiring the initiation of hemodialysis or hemofiltration. Coagulopathy: defined by disseminated intravascular coagulation (DIC) requiring transfusion with platelets or fresh frozen plasma or anticoagulant therapy. Cardiovascular failure: defined by sustained hypotension requiring vasopressor support of dopamine \>5 microgram per kilogram per minute (µg/kg/min), epinephrine, norepinephrine, phenylephrine or vasopressin at any dose if used to increase blood pressure for \>=6 continuous h. Analysis was done treating the death as a new onset organ failure (counted in both the numerator and denominator). |
| Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Baseline (Day 1, pre-infusion) up to Day 28 Follow up | Respiratory failure: defined by requiring mechanical ventilation not less than 24 hours due to surgery. Renal failure: defined by requiring the initiation of hemodialysis or hemofiltration. Coagulopathy: defined by disseminated intravascular coagulation (DIC) requiring transfusion with platelets or fresh frozen plasma or anticoagulant therapy. Cardiovascular failure: defined by sustained hypotension requiring vasopressor support of dopamine \>5 microgram per kilogram per minute (µg/kg/min), epinephrine, norepinephrine, phenylephrine or vasopressin at any dose if used to increase blood pressure for \>=6 continuous h. For each organ failure type and the number of new onset organ failures per participants for each organ failure type, the denominator only included participants who did not have that type of organ failure at Baseline. At Baseline a participant could enter the study with a type of organ failure, that type of failure was not reported as a new onset organ failure. |
| Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Day 1 (pre-infusion) up to Day 28 Follow-up | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition or common toxicity criteria (CTC) grade 4 laboratory abnormalities of national cancer institute not associated with the underlying sepsis unless more severe than expected for the participants condition. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czechia, Estonia, Finland, France, Germany, Greece, Hong Kong, Hungary, India, Israel, Latvia, Malaysia, Netherlands, New Zealand, Portugal, Puerto Rico, Romania, Russia, Slovenia, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
The study was planned on 1845 participants, hospitalized with suspected or confirmed gram-negative severe sepsis, male or female \>=18 years of age at 235 centers across 31 countries from 02 September 2004 to 25 June 2007.
Pre-assignment details
A total of 1415 participant numbers were assigned during randomization process, five were duplicate randomization numbers and for other two, the participants did not provide informed consent, precluding them from enrollment. Out of 1408 participants, 29 did not receive study medication, remaining 1379 included in Intent-to-Treat (ITT) Population.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Eligible participants were administered matching placebo to low-dose GR270773 or high-dose GR270773, IV as a loading dose infused over 2 h followed by a maintenance dose administered as a continuous infusion for 70 h, for a total treatment period of 72 h. The low placebo rate consisted of a loading dose of 0.75 mL/kg/h for 2 h and a maintenance dose of 0.1 mL/kg/h for 70 h. The high placebo rate consisted of a loading dose of 1.5 mL/kg/h for 2 h and a maintenance dose of 0.15 mL/kg/h for 70 h. | 599 |
| Low GR270773 Eligible participants were administered low-dose GR270773 IV as a loading dose infused over 2 h followed by a maintenance dose administered as a continuous infusion for 70 h, for a total treatment period of 72 h. The study medication was administered as a sterile 100 mg/mL lipid emulsion for IV administration. The low dose emulsion consisted of a loading dose of 75 mg/kg/h which was equivalent to 0.75 mL/kg/h for 2 h and a maintenance dose of 10 mg/kg/h which was equivalent to 0.1 mL/kg/h for 70 h. The total dose was 850 mg/kg. | 598 |
| High GR270773 Eligible participants were administered high-dose GR270773 IV as a loading dose infused over 2 h followed by a maintenance dose administered as a continuous infusion for 70 h, for a total treatment period of 72 h. The study medication was administered as a sterile 100 mg/mL lipid emulsion for IV administration. The high dose emulsion consisted of a loading dose of 15 mg/kg/h which was equivalent to 1.5 mL/kg/h for 2 h and a maintenance dose of 15 mg/kg/h which was equivalent to 0.15 mL/kg/h for 70 h. The total dose was 1350 mg/kg. | 182 |
| Total | 1,379 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 9 | 6 |
| Overall Study | Do not resuscitate (DNR) | 0 | 0 | 1 |
| Overall Study | Enrollment in another study | 0 | 1 | 0 |
| Overall Study | Family decision | 0 | 1 | 0 |
| Overall Study | Hemohlobin stopping rule | 0 | 1 | 0 |
| Overall Study | Investigator decision to withdrew | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 1 | 1 |
| Overall Study | Patient transferred to another hospital | 2 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 |
| Overall Study | Subject withdrew but agreed follow up | 1 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 6 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | High GR270773 | Low GR270773 |
|---|---|---|---|---|
| Age, Continuous | 63.1 Years STANDARD_DEVIATION 16.41 | 63.2 Years STANDARD_DEVIATION 16.23 | 64.8 Years STANDARD_DEVIATION 15.47 | 62.8 Years STANDARD_DEVIATION 16.27 |
| Race/Ethnicity, Customized American Indian | 4 Participants | 6 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Arabic/North African | 7 Participants | 14 Participants | 1 Participants | 6 Participants |
| Race/Ethnicity, Customized Black | 16 Participants | 32 Participants | 2 Participants | 14 Participants |
| Race/Ethnicity, Customized East & South East Asian | 51 Participants | 109 Participants | 14 Participants | 44 Participants |
| Race/Ethnicity, Customized Japanese | 3 Participants | 6 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Missing | 2 Participants | 7 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized South Asian | 29 Participants | 63 Participants | 2 Participants | 32 Participants |
| Race/Ethnicity, Customized White/Caucasian | 484 Participants | 1139 Participants | 161 Participants | 494 Participants |
| Sex: Female, Male Female | 254 Participants | 573 Participants | 80 Participants | 239 Participants |
| Sex: Female, Male Male | 345 Participants | 806 Participants | 102 Participants | 359 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 85 / 599 | 70 / 598 | 33 / 182 |
| other Total, other adverse events | 160 / 599 | 183 / 598 | 60 / 182 |
| serious Total, serious adverse events | 213 / 599 | 235 / 598 | 77 / 182 |
Outcome results
Primary
Percentage of Participants With 28-Day All Cause Mortality
Mortality was assessed by the number of participants who died between days 1 and 28. A summary of death details was given which included whether the participant died between days 1 and 28, whether the death was related sepsis, cause of death, the source of the information, and whether the cause of death was verified by a death record. Participants who had withdrawn from study and all study assessments and for whom survival at day 28 could not be confirmed was treated as deaths for the primary endpoint. The difference in all-cause 28-day mortality rates for each treatment group versus the placebo group in the ITT Population was calculated as placebo - treatment.
Time frame: Day 1 (post-infusion) up to Day 28 Follow-up
Population: ITT Population was defined as all randomized participants from all three stages who receive any study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With 28-Day All Cause Mortality | 26.9 Percentage of participants |
| Low GR270773 | Percentage of Participants With 28-Day All Cause Mortality | 25.8 Percentage of participants |
| High GR270773 | Percentage of Participants With 28-Day All Cause Mortality | 31.3 Percentage of participants |
p-value: 0.329Chi-squared
p-value: 0.879Chi-squared
Secondary
Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE
An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in this definition or common toxicity criteria (CTC) grade 4 laboratory abnormalities of national cancer institute not associated with the underlying sepsis unless more severe than expected for the participants condition.
Time frame: Day 1 (pre-infusion) up to Day 28 Follow-up
Population: ITT Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any SAE | 213 Participants |
| Placebo | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any AE | 423 Participants |
| Placebo | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any fatal SAE | 85 Participants |
| Low GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any SAE | 235 Participants |
| Low GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any AE | 442 Participants |
| Low GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any fatal SAE | 70 Participants |
| High GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any AE | 144 Participants |
| High GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any fatal SAE | 33 Participants |
| High GR270773 | Assessment of Safety/Tolerability by Determining the Number of Participants With Any Adverse Events (AE), Serious Adverse Events (SAE) and Fatal SAE | Any SAE | 77 Participants |
Secondary
Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment
Respiratory failure: defined by requiring mechanical ventilation not less than 24 hours due to surgery. Renal failure: defined by requiring the initiation of hemodialysis or hemofiltration. Coagulopathy: defined by disseminated intravascular coagulation (DIC) requiring transfusion with platelets or fresh frozen plasma or anticoagulant therapy. Cardiovascular failure: defined by sustained hypotension requiring vasopressor support of dopamine \>5 microgram per kilogram per minute (µg/kg/min), epinephrine, norepinephrine, phenylephrine or vasopressin at any dose if used to increase blood pressure for \>=6 continuous h. For each organ failure type and the number of new onset organ failures per participants for each organ failure type, the denominator only included participants who did not have that type of organ failure at Baseline. At Baseline a participant could enter the study with a type of organ failure, that type of failure was not reported as a new onset organ failure.
Time frame: Baseline (Day 1, pre-infusion) up to Day 28 Follow up
Population: ITT Population. Organ failure occurring during the 28 days post-enrollment that was not in failure at enrollment. Participants who died prior to observing a new failure are excluded from analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Respiratory failure, n= 297, 333, 99 | 50 Participants |
| Placebo | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Cardiovascular failure, n= 150, 161, 43 | 33 Participants |
| Placebo | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Renal failure, n= 460, 474, 138 | 40 Participants |
| Placebo | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Coagulopathy, n= 344, 355, 107 | 36 Participants |
| Low GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Coagulopathy, n= 344, 355, 107 | 41 Participants |
| Low GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Respiratory failure, n= 297, 333, 99 | 61 Participants |
| Low GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Renal failure, n= 460, 474, 138 | 47 Participants |
| Low GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Cardiovascular failure, n= 150, 161, 43 | 48 Participants |
| High GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Coagulopathy, n= 344, 355, 107 | 16 Participants |
| High GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Cardiovascular failure, n= 150, 161, 43 | 15 Participants |
| High GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Renal failure, n= 460, 474, 138 | 22 Participants |
| High GR270773 | Number of Participants With New Onset Organ Failure of Respiratory Failure, Cardiovascular Failure, Renal Failure and Coagulopathy, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrollment | Respiratory failure, n= 297, 333, 99 | 23 Participants |
Secondary
Number of Participants With New Onset Organ Failure, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrolment
The new onset organ failure was defined as first time each of the following criteria were met after start of study medication up to Day 28. Respiratory failure: defined by requiring mechanical ventilation not less than 24 hours due to surgery. Renal failure: defined by requiring the initiation of hemodialysis or hemofiltration. Coagulopathy: defined by disseminated intravascular coagulation (DIC) requiring transfusion with platelets or fresh frozen plasma or anticoagulant therapy. Cardiovascular failure: defined by sustained hypotension requiring vasopressor support of dopamine \>5 microgram per kilogram per minute (µg/kg/min), epinephrine, norepinephrine, phenylephrine or vasopressin at any dose if used to increase blood pressure for \>=6 continuous h. Analysis was done treating the death as a new onset organ failure (counted in both the numerator and denominator).
Time frame: Baseline (Day 1, pre-infusion) up to Day 28 Follow-up
Population: ITT Population. Organ failure occurring during the 28 days post-enrollment that was not in failure at enrollment. Subjects who die prior to observing a new organ failure are counted as a failure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With New Onset Organ Failure, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrolment | 122 Participants |
| Low GR270773 | Number of Participants With New Onset Organ Failure, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrolment | 157 Participants |
| High GR270773 | Number of Participants With New Onset Organ Failure, Regardless of Cause, Occurring During the 28 Days Post Enrollment in an Organ Not in Failure at Enrolment | 57 Participants |