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Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHS)

This study has been completed.
Sponsor:
Collaborators:
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
Information provided by (Responsible Party):
Djillali Annane, University of Versailles
ClinicalTrials.gov Identifier:
NCT00625209
First received: February 19, 2008
Last updated: June 10, 2017
Last verified: June 2017
  Purpose
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

Condition Intervention Phase
Septic Shock 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 Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock

Resource links provided by NLM:


Further study details as provided by Djillali Annane, University of Versailles:

Primary Outcome Measures:
  • 90-day mortality [ Time Frame: 90 day ]

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

Enrollment: 1241
Study Start Date: March 2008
Study Completion Date: July 2016
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C
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
Active Comparator: 2
Hydrocortisone plus fludrocortisone and a placebo of activated protein C
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
Active Comparator: 3
placebo of hydrocortisone, placebo of fludrocortisone and activated protein C
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
Active Comparator: 4
hydrocortisone plus fludrocortisone plus activated protein C
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00625209

Locations
France
Henri Mondor Hospital
Créteil, France, 94
Raymond Poincaré Hospital
Garches, France, 92380
Pitié Salpêtrière Hospital
Paris, France, 75
Saint Josef Hospital
Paris, France, 75
Sponsors and Collaborators
University of Versailles
Assistance Publique - Hôpitaux de Paris
Ministry of Health, France
Investigators
Principal Investigator: Benoit Misset, MD St. Joseph Hospital Health Center
Principal Investigator: Claude Martin, MD Assistance Publique Hopitaux de Marseille, hôpital Nord
Principal Investigator: Alain Cariou, MD Assistance Publique Hôpitaux de Paris, Hôpital Cochin
Principal Investigator: Jean Carlet, MD St. Joseph Hospital Health Center
Principal Investigator: Christian Brun Buisson, MD Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor
Principal Investigator: Djillali Annane, MD Assistance Publique Hôpitaux de Paris, Hôpital Raymond Poincaré
  More Information

Publications:
Responsible Party: Djillali Annane, Professor in medicine, University of Versailles
ClinicalTrials.gov Identifier: NCT00625209     History of Changes
Other Study ID Numbers: P070128
Study First Received: February 19, 2008
Last Updated: June 10, 2017

Keywords provided by Djillali Annane, University of Versailles:
septic shock
coagulation
immunomodulation
survival

Additional relevant MeSH terms:
Shock
Shock, Septic
Pathologic Processes
Sepsis
Infection
Systemic Inflammatory Response Syndrome
Inflammation
Hydrocortisone 17-butyrate 21-propionate
Cortisol succinate
Hydrocortisone acetate
Hydrocortisone
Fludrocortisone
Protein C
Drotrecogin alfa activated
Anti-Inflammatory Agents
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 21, 2017