Official Title: “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

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2010

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.

Intervention(s) in this Clinical Trial

• Drug: placebos
  • 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
• Drug: hydrocortisone and fludrocortisone and placebo
  • 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
• Drug: recombinant human activated protein C and placebos
  • 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
• Drug: recombinant human activated protein C and hydrocortisone and fludrocortisone
  • 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

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: 1
  • placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C
• Active Comparator: 2
  • Hydrocortisone plus fludrocortisone and a placebo of activated protein C
• Active Comparator: 3
  • placebo of hydrocortisone, placebo of fludrocortisone and activated protein C
• Active Comparator: 4
  • hydrocortisone plus fludrocortisone plus activated protein C

Primary Measures

• 90-day mortality
  • Time Frame: 90 day
    Safety Issue?: Yes

Secondary Measures

• mortality at 28 day
  • Time Frame: 28-day
    Safety Issue?: Yes
• mortality at hospital discharge
  • Time Frame: hospital discharge
    Safety Issue?: Yes
• mortality at 6 months
  • Time Frame: 6 months
    Safety Issue?: Yes
• decision to withhold or withdraw active treatments
  • Time Frame: up to 90 days
    Safety Issue?: No
• Time to wean vasopressor therapy
  • Time Frame: up to 90 days
    Safety Issue?: No
• time to achieve an SOFA score of less than 6
  • Time Frame: up to 90 days
    Safety Issue?: No
• Length of intensive care unit and hospital stay
  • Time Frame: up to hospital discharge
    Safety Issue?: Yes
• acquisition of new infection
  • Time Frame: up to 180 days
    Safety Issue?: Yes
• bleeding events
  • Time Frame: up to 90 days
    Safety Issue?: Yes
• neurological sequels at intensive care unit discharge and at 90 and 180 days
  • Time Frame: up to 6 months
    Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Versailles

Overall Clinical Trial Officials and Contacts

Benoit Misset, MD Principal Investigator St. Joseph Hospital  

Overall Contact: Djillali Annane, MD 33147107786 djillali.annane@rpc.aphp.fr

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00625209

Study ID Number: P070128

ClinicalTrials.gov Identifier: NCT00625209

Health Authority: France: Afssaps - French Health Products Safety Agency