Activated Protein C and Corticosteroids for Human Septic Shock

NCT00625209 | Completed Phase 3 DMC

• 1 other identifier: P070128
• Study Type: interventional
• Target: 1,241
• Locations: 1 country
• Sites: 4

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

Conditions

Septic Shock

Keywords

septic shock; coagulation; immunomodulation; survival

Outcome Measures

Primary Outcomes (1)

• 90-day mortality

  90 day

Secondary Outcomes (17)

• mortality at 28 day

  28-day

• mortality at ICU discharge

  ICU discharge

• mortality at hospital discharge

  hospital discharge

• mortality at 6 months

  6 months

• decision to withhold or withdraw active treatments

  up to 90 days

Study Arms (4)

1

PLACEBO COMPARATOR

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

Drug: placebos

2

ACTIVE COMPARATOR

Hydrocortisone plus fludrocortisone and a placebo of activated protein C

Drug: hydrocortisone and fludrocortisone and placebo

3

ACTIVE COMPARATOR

placebo of hydrocortisone, placebo of fludrocortisone and activated protein C

Drug: recombinant human activated protein C and placebos

4

ACTIVE COMPARATOR

hydrocortisone plus fludrocortisone plus activated protein C

Drug: recombinant human activated protein C and hydrocortisone and fludrocortisone

Interventions

placebos 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

1

hydrocortisone and fludrocortisone and placebo 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

2

recombinant human activated protein C and placebos 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

3

recombinant human activated protein C and hydrocortisone and fludrocortisone 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

4

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Versailles: lead
• Assistance Publique - Hôpitaux de Paris: collaborator
• Ministry of Health, France: collaborator

Study Sites (4)

Henri Mondor Hospital

Créteil, 94, France

Location

Raymond Poincaré Hospital

Garches, 92380, France

Location

Pitié Salpêtrière Hospital

Paris, 75, France

Location

Saint Josef Hospital

Paris, 75, France

Location

Related Publications (4)

• 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.

  PMID: 27154719 BACKGROUND

• 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.

  PMID: 23525934 RESULT

• 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.

  PMID: 38310918 DERIVED

• 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.

  PMID: 29490185 DERIVED

MeSH Terms

Conditions

Shock, Septic; Thrombosis

Interventions

Hydrocortisone; Fludrocortisone; drotrecogin alfa activated

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Study Officials

• Benoit Misset, MD

  Unity Health Toronto

  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

  Unity Health Toronto

  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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor in medicine

Study Record Dates

• First Submitted: February 19, 2008
• First Posted: February 28, 2008
• Study Start: March 1, 2008
• Primary Completion: June 1, 2015
• Study Completion: July 1, 2016
• Last Updated: June 14, 2017

Record last verified: 2017-06

Locations

FR (4)