Activated Protein C and Corticosteroids for Human Septic Shock

Study Overview
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Brief Summary
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This study aims at comparing the efficacy and safety of recombinant human activated protein C to that of low dose of corticosteroids and at investigating the interaction between these drugs in the management of septic shock

Detailed Description
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Septic shock still places a burden in the healthcare system round around the world. In the early 20ties, clinical trials suggested potential benefits from activated protein C in severe sepsis and of corticosteroids when given to adults with refractory shock. More recent studies suggested that patients with moderate sepsis or septic shock may not benefit from either activated protein C or corticosteroids. Therefore, current international guidelines suggest that physicians may consider using these drugs in the more severe cases of sepsis. The main risk associated with the use of activated protein C is bleeding and the main risk associated with the use of steroids is superinfection. It is paramount that a new adequately powered trial explores the benefit/risk ratio of these two drugs and of their combination in a population of adult patients with septic shock. After the withdrawal of Xigris in October 2011, the study was suspended and restarted in June 2012 to investigate the benefit to risk ratio of corticosteroids.

Official Title
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Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock

Conditions
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Septic Shock

Intervention / Treatment
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* Drug: placebos
* Drug: hydrocortisone and fludrocortisone and placebo
* Drug: recombinant human activated protein C and placebos
* Drug: recombinant human activated protein C and hydrocortisone and fludrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: hospitalized in intensive care unit for less than 7 days septic shock for less than 24 hours at least one proven site of infection at least 2 organ dysfunction as defined by a SOFA score =or> to 3 for at least 6 consecutive hours need for vasopressor (dopamine =or>15µg/kg/min or epinephrine/norepinephrine at =or>0,25 µg/kg/min for at least 6 consecutive hours, to maintain systolic arterial pressure at 90 mmHg or more OR mean arterial pressure at 6( mmHg or more informed consent Exclusion Criteria: pregnancy or breath feeding decision not to resuscitate underlying disease with an estimated life expectancy of less than 1 month formal indication for corticosteroids recent surgery (ie within the past 72 hours) or a surgery at high risk of bleeding gastro-intestinal bleeding within the past 6 weeks chronic liver disease (Child C) recent trauma (ie within the past 72 hours) intracranial process history of stroke, CNS bleeding or traumatic brain injury within the past 3 months platelet counts of less than 30000 per cubic millimeter formal indication for curative anticoagulant; prophylactic use of heparin is allowed any condition of high risk of bleeding as per patient's primary physicians hypersensitivity of activated drotrecogin alpha or any other component of the drug no affiliation to a social security Amendments to eligibility criteria were: On 27/03/2008: Changes in following exclusion criteria : surgical procedure in the past 7 days was changed for surgical procedure within 72 hours, or any surgery associated with high risk of bleeding, or a planned surgery within 24 h. chronic liver disease was clarified as chronic liver disease with Child score C. severe thrombopenia was clarified as severe thrombopenia (<30,000/mm3, before transfusion). On 25/08/2009: The exclusion criteria: surgical procedure within 72 hours, or any surgery associated with high risk of bleeding, or a planned surgery within 24 h was changed for surgical procedure within 12 hours, or any surgery associated with high risk of bleeding On 11/06/2010: the inclusion criteria: admitted to the ICU for < 7 days was removed; and a new exclusion criteria was added: patients who had a previous episode of sepsis during the same hospital stay On 18/04/2012: following the withdrawal of DAA from the market: the following exclusion criteria (only related to DAA) were removed : any surgery in the past 12 hours, or any surgery associated with high risk of bleeding; chronic liver disease with a Child score C; recent trauma; any intracranial mass, or stroke or head injury in the past 3 months; severe thrombocytopenia (< 30.000 /mm3, before platelet transfusion); formal indication for anticoagulation, or any other condition associated with increased risk of bleeding, as appreciated by the patient's physician.

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: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 1<br>placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C | Drug: placebos<br>* placebo of hydrocortisone as an iv bolus every 6 hours for seven days plus placebo of fludrocortisone given through the nasogastric tube once a day for seven days plus placebo of activated protein C given as a continuous infusion for 96 hours<br>|
| Active Comparator: 2<br>Hydrocortisone plus fludrocortisone and a placebo of activated protein C | Drug: hydrocortisone and fludrocortisone and placebo<br>* hydrocortisone will be given as 50mg iv bolus every 6 hours for seven days and a tablet of 50µg of fludrocortisone will be given once a day via the nasogastric tube for seven days and a placebo of activated protein C will be given as a continuous infusion for 96 hours<br>|
| Active Comparator: 3<br>placebo of hydrocortisone, placebo of fludrocortisone and activated protein C | Drug: recombinant human activated protein C and placebos<br>* activated protein C will be given as a continuous infusion at a dose of 24 µg/kg/h four 96 hours and hydrocortisone placebo as an iv bolus every 6 hours and fludrocortisone placebo once a day through the gastric tube will be given for seven days<br>|
| Active Comparator: 4<br>hydrocortisone plus fludrocortisone plus activated protein C | Drug: recombinant human activated protein C and hydrocortisone and fludrocortisone<br>* 96 hours continuous infusion of 24µg/kg/h of activated protein C plus seven day treatment with 50mg iv bolus of hydrocortisone every 6 hours and 50µg of fludrocortisone via the nasogastric tube once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day mortality |  | 90 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mortality at 28 day |  | 28-day | 
| mortality at ICU discharge |  | ICU discharge | 
| mortality at hospital discharge |  | hospital discharge | 
| mortality at 6 months |  | 6 months | 
| decision to withhold or withdraw active treatments |  | up to 90 days | 
| Time to wean vasopressor therapy |  | up to 90 days | 
| number of days alive and free of vasopressor therapy |  | up to 90 days | 
| time to achieve an SOFA score of less than 6 |  | up to 90 days | 
| number of days alive with a SOFA score < 6 points |  | up to 90 days | 
| time to wean mechanical ventilation |  | up to 90 days | 
| number of days alive and free of mechanical ventilation |  | up to 90 days | 
| Length of intensive care unit and hospital stay |  | up to hospital discharge | 
| acquisition of new infection |  | up to 180 days | 
| new episode of sepsis |  | up to 90 days | 
| new episode of septic shock |  | up to 90 days | 
| bleeding events |  | up to 90 days | 
| neurological sequels at intensive care unit and at hospital discharge and at 90 and 180 days |  | up to 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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septic shock, coagulation, immunomodulation, survival