Activated Protein C and Corticosteroids for Human Septic Shock

NCT ID: NCT00625209

Last Updated: 2017-06-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 1241 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-03-31
• Study Completion Date: 2016-07-31

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.

Conditions

Septic Shock

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

1

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

Group Type: PLACEBO_COMPARATOR

placebos

Intervention Type: DRUG

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

2

Hydrocortisone plus fludrocortisone and a placebo of activated protein C

Group Type: ACTIVE_COMPARATOR

hydrocortisone and fludrocortisone and placebo

Intervention Type: DRUG

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

3

placebo of hydrocortisone, placebo of fludrocortisone and activated protein C

Group Type: ACTIVE_COMPARATOR

recombinant human activated protein C and placebos

Intervention Type: DRUG

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

4

hydrocortisone plus fludrocortisone plus activated protein C

Group Type: ACTIVE_COMPARATOR

recombinant human activated protein C and hydrocortisone and fludrocortisone

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: 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

Intervention Type: 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

Intervention Type: DRUG

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:

• "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).

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: collaborator

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

University of Versailles

OTHER

Sponsor Role: lead

Responsible Party

Djillali Annane

Professor in medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Benoit Misset, MD

Role: PRINCIPAL_INVESTIGATOR

Unity Health Toronto

Claude Martin, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique Hopitaux de Marseille, hôpital Nord

Alain Cariou, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique Hôpitaux de Paris, Hôpital Cochin

Jean Carlet, MD

Role: PRINCIPAL_INVESTIGATOR

Unity Health Toronto

Christian Brun Buisson, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor

Djillali Annane, MD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique Hôpitaux de Paris, Hôpital Raymond Poincaré

Locations

Henri Mondor Hospital

Créteil, , France

Raymond Poincaré Hospital

Garches, , France

Pitié Salpêtrière Hospital

Paris, , France

Saint Josef Hospital

Paris, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 27154719 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23525934 (View on PubMed)

Heming N, Renault A, Kuperminc E, Brun-Buisson C, Megarbane B, Quenot JP, Siami S, Cariou A, Forceville X, Schwebel C, Leone M, Timsit JF, Misset B, Benali MA, 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, Cook F, Slama M, Leroy O, Capellier G, Dargent A, Hissem T, Bounab R, Maxime V, Moine P, Bellissant E, Annane D; APROCCHSS investigators; CRICS-TRIGGERSEP network. Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial. Lancet Respir Med. 2024 May;12(5):366-374. doi: 10.1016/S2213-2600(23)00430-7. Epub 2024 Feb 1.

Reference Type: DERIVED

PMID: 38310918 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29490185 (View on PubMed)

Other Identifiers

P070128

Identifier Type: -

Identifier Source: org_study_id