Clinical trial NCT00625209: Activated Protein C and Corticosteroids for Human Septic Shock
Official title: Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Septic Shock
Keywords: septic shock
coagulation
immunomodulation
survival
Lead sponsor: University of Versailles
Sponsor class: OTHER
Collaborators: name: Assistance Publique - Hôpitaux de Paris
name: Ministry of Health, France
First posted: 2008-02-28
Enrollment: 1241
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

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.

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 :

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.

Primary outcomes:
measure: 90-day mortality
timeFrame: 90 day
Secondary outcomes:
measure: mortality at 28 day
timeFrame: 28-day
measure: mortality at ICU discharge
timeFrame: ICU discharge
measure: mortality at hospital discharge
timeFrame: hospital discharge
measure: mortality at 6 months
timeFrame: 6 months
measure: decision to withhold or withdraw active treatments
timeFrame: up to 90 days
measure: Time to wean vasopressor therapy
timeFrame: up to 90 days
measure: number of days alive and free of vasopressor therapy
timeFrame: up to 90 days
measure: time to achieve an SOFA score of less than 6
timeFrame: up to 90 days
measure: number of days alive with a SOFA score < 6 points
timeFrame: up to 90 days
measure: time to wean mechanical ventilation
timeFrame: up to 90 days
measure: number of days alive and free of mechanical ventilation
timeFrame: up to 90 days
measure: Length of intensive care unit and hospital stay
timeFrame: up to hospital discharge
measure: acquisition of new infection
timeFrame: up to 180 days
measure: new episode of sepsis
timeFrame: up to 90 days
measure: new episode of septic shock
timeFrame: up to 90 days
measure: bleeding events
timeFrame: up to 90 days
measure: neurological sequels at intensive care unit and at hospital discharge and at 90 and 180 days
timeFrame: up to 6 months
Other outcomes:
Locations:
city: Créteil
country: France
facility: Henri Mondor Hospital
city: Garches
country: France
facility: Raymond Poincaré Hospital
city: Paris
country: France
facility: Pitié Salpêtrière Hospital
city: Paris
country: France
facility: Saint Josef Hospital
Study officials:
affiliation: Unity Health Toronto
name: Benoit Misset, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique Hopitaux de Marseille, hôpital Nord
name: Claude Martin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Cochin
name: Alain Cariou, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Unity Health Toronto
name: Jean Carlet, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor
name: Christian Brun Buisson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Raymond Poincaré
name: Djillali Annane, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.