Activated Protein C and Corticosteroids for Human Septic Shock

Septic Shock Clinical Trial

— APROCCHS  

Official title:

Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00625209
• Other study ID #: P070128
• Status: Completed
• Phase: Phase 3
• First received: February 19, 2008
• Last updated: June 10, 2017
• Start date: March 2008
• Est. completion date: July 2016

Study information

• Verified date: June 2017
• Source: University of Versailles
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1241
• Est. completion date: July 2016
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Septic Shock
• Shock
• Shock, Septic

Intervention

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
• 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
• 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
• 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

Locations

Country	Name	City	State
France	Henri Mondor Hospital	Créteil
France	Raymond Poincaré Hospital	Garches
France	Pitié Salpêtrière Hospital	Paris
France	Saint Josef Hospital	Paris

Sponsors (3)

Lead Sponsor	Collaborator
University of Versailles	Assistance Publique - Hôpitaux de Paris, Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (2)

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. — View 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, Tesnière A, Chastre J, Bohe J, Colin G, Cariou A, Renault A, Brun-Buisson C, Bellissa — View Citation

Outcome

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