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

Primary Purpose

Septic Shock

Status
Completed
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
placebos
hydrocortisone and fludrocortisone and placebo
recombinant human activated protein C and placebos
recombinant human activated protein C and hydrocortisone and fludrocortisone
Sponsored by
University of Versailles
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Septic Shock focused on measuring septic shock, coagulation, immunomodulation, survival

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Henri Mondor Hospital
  • Raymond Poincaré Hospital
  • Pitié Salpêtrière Hospital
  • Saint Josef Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Active Comparator

Arm Label

1

2

3

4

Arm Description

placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C

Hydrocortisone plus fludrocortisone and a placebo of activated protein C

placebo of hydrocortisone, placebo of fludrocortisone and activated protein C

hydrocortisone plus fludrocortisone plus activated protein C

Outcomes

Primary Outcome Measures

90-day mortality

Secondary Outcome Measures

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

Full Information

First Posted
February 19, 2008
Last Updated
June 10, 2017
Sponsor
University of Versailles
Collaborators
Assistance Publique - Hôpitaux de Paris, Ministry of Health, France
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1. Study Identification

Unique Protocol Identification Number
NCT00625209
Brief Title
Activated Protein C and Corticosteroids for Human Septic Shock
Acronym
APROCCHS
Official Title
Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
March 2008 (undefined)
Primary Completion Date
June 2015 (Actual)
Study Completion Date
July 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Versailles
Collaborators
Assistance Publique - Hôpitaux de Paris, Ministry of Health, France

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Septic Shock
Keywords
septic shock, coagulation, immunomodulation, survival

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1241 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Placebo Comparator
Arm Description
placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C
Arm Title
2
Arm Type
Active Comparator
Arm Description
Hydrocortisone plus fludrocortisone and a placebo of activated protein C
Arm Title
3
Arm Type
Active Comparator
Arm Description
placebo of hydrocortisone, placebo of fludrocortisone and activated protein C
Arm Title
4
Arm Type
Active Comparator
Arm Description
hydrocortisone plus fludrocortisone plus activated protein C
Intervention Type
Drug
Intervention Name(s)
placebos
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
hydrocortisone and fludrocortisone and placebo
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
recombinant human activated protein C and placebos
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
recombinant human activated protein C and hydrocortisone and fludrocortisone
Intervention Description
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
Primary Outcome Measure Information:
Title
90-day mortality
Time Frame
90 day
Secondary Outcome Measure Information:
Title
mortality at 28 day
Time Frame
28-day
Title
mortality at ICU discharge
Time Frame
ICU discharge
Title
mortality at hospital discharge
Time Frame
hospital discharge
Title
mortality at 6 months
Time Frame
6 months
Title
decision to withhold or withdraw active treatments
Time Frame
up to 90 days
Title
Time to wean vasopressor therapy
Time Frame
up to 90 days
Title
number of days alive and free of vasopressor therapy
Time Frame
up to 90 days
Title
time to achieve an SOFA score of less than 6
Time Frame
up to 90 days
Title
number of days alive with a SOFA score < 6 points
Time Frame
up to 90 days
Title
time to wean mechanical ventilation
Time Frame
up to 90 days
Title
number of days alive and free of mechanical ventilation
Time Frame
up to 90 days
Title
Length of intensive care unit and hospital stay
Time Frame
up to hospital discharge
Title
acquisition of new infection
Time Frame
up to 180 days
Title
new episode of sepsis
Time Frame
up to 90 days
Title
new episode of septic shock
Time Frame
up to 90 days
Title
bleeding events
Time Frame
up to 90 days
Title
neurological sequels at intensive care unit and at hospital discharge and at 90 and 180 days
Time Frame
up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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 : 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Benoit Misset, MD
Organizational Affiliation
Unity Health Toronto
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Claude Martin, MD
Organizational Affiliation
Assistance Publique Hopitaux de Marseille, hôpital Nord
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Alain Cariou, MD
Organizational Affiliation
Assistance Publique Hôpitaux de Paris, Hôpital Cochin
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jean Carlet, MD
Organizational Affiliation
Unity Health Toronto
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Christian Brun Buisson, MD
Organizational Affiliation
Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Djillali Annane, MD
Organizational Affiliation
Assistance Publique Hôpitaux de Paris, Hôpital Raymond Poincaré
Official's Role
Principal Investigator
Facility Information:
Facility Name
Henri Mondor Hospital
City
Créteil
ZIP/Postal Code
94
Country
France
Facility Name
Raymond Poincaré Hospital
City
Garches
ZIP/Postal Code
92380
Country
France
Facility Name
Pitié Salpêtrière Hospital
City
Paris
ZIP/Postal Code
75
Country
France
Facility Name
Saint Josef Hospital
City
Paris
ZIP/Postal Code
75
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
27154719
Citation
Annane D, Buisson CB, Cariou A, Martin C, Misset B, Renault A, Lehmann B, Millul V, Maxime V, Bellissant E; APROCCHSS Investigators for the TRIGGERSEP Network. Design and conduct of the activated protein C and corticosteroids for human septic shock (APROCCHSS) trial. Ann Intensive Care. 2016 Dec;6(1):43. doi: 10.1186/s13613-016-0147-3. Epub 2016 May 6. Erratum In: Ann Intensive Care. 2016 Dec;6(1):79.
Results Reference
background
PubMed Identifier
23525934
Citation
Annane D, Timsit JF, Megarbane B, Martin C, Misset B, Mourvillier B, Siami S, Chagnon JL, Constantin JM, Petitpas F, Souweine B, Amathieu R, Forceville X, Charpentier C, Tesniere A, Chastre J, Bohe J, Colin G, Cariou A, Renault A, Brun-Buisson C, Bellissant E; APROCCHSS Trial Investigators. Recombinant human activated protein C for adults with septic shock: a randomized controlled trial. Am J Respir Crit Care Med. 2013 May 15;187(10):1091-7. doi: 10.1164/rccm.201211-2020OC.
Results Reference
result
PubMed Identifier
29490185
Citation
Annane D, Renault A, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Martin C, Timsit JF, Misset B, Ali Benali M, Colin G, Souweine B, Asehnoune K, Mercier E, Chimot L, Charpentier C, Francois B, Boulain T, Petitpas F, Constantin JM, Dhonneur G, Baudin F, Combes A, Bohe J, Loriferne JF, Amathieu R, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Maxime V, Bellissant E; CRICS-TRIGGERSEP Network. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. N Engl J Med. 2018 Mar 1;378(9):809-818. doi: 10.1056/NEJMoa1705716.
Results Reference
derived

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Activated Protein C and Corticosteroids for Human Septic Shock

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