GR270773 In The Treatment Of Suspected Or Confirmed Gram-Negative Severe Sepsis In Adults

Study Overview
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Brief Summary
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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.

Official Title
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A Prospective, Randomized, Double-blind, Placebo Controlled, Dose Ranging, Multi-Center Study of the Safety and Efficacy of Three Days Continuous Intravenous Infusion of GR270773 in the Treatment of Suspected or Confirmed Gram-negative Severe Sepsis in Adults

Conditions
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Sepsis

Intervention / Treatment
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* Drug: Intravenous GR270773- Phospholipid Emulsion
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Intravenous GR270773- Phospholipid Emulsion|nan|
|Other: Placebo|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 (post-infusion) up to Day 28 Follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline (Day 1, pre-infusion) up to Day 28 Follow-up | 
| 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. | Baseline (Day 1, pre-infusion) up to Day 28 Follow up | 
| 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. | Day 1 (pre-infusion) up to Day 28 Follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe sepsis, septic shock, Gram-negative infection, phospholipid emulsion