Activated Protein C and Corticosteroids for Human Septic Shock

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

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

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.

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 :

1. any surgery in the past 12 hours, or any surgery associated with high risk of bleeding;
2. chronic liver disease with a Child score C;
3. recent trauma;
4. any intracranial mass, or stroke or head injury in the past 3 months;
5. severe thrombocytopenia (< 30.000 /mm3, before platelet transfusion);
6. formal indication for anticoagulation, or any other condition associated with increased risk of bleeding, as appreciated by the patient's physician.