Septic ShockPhase 3APROCCHSNCT00625209

Activated Protein C and Corticosteroids for Human Septic Shock

A Phase 3 study testing recombinant human activated protein C and hydrocortisone and fludrocortisone in people with Septic Shock, run by University of Versailles at 4 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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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 Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Septic Shock
What is being tested?: recombinant human activated protein C and hydrocortisone and fludrocortisone
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 1,241 participants
Where: 4 sitesFrance
Study dates: Mar 2008to Jul 2016
Phase: Phase 3
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Show all 29Show fewer

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.

Trial locations and contacts

4 sites in 1 country.

France4 sites

Henri Mondor Hospital
Créteil, 94
Raymond Poincaré Hospital
Garches, 92380
Pitié Salpêtrière Hospital
Paris, 75
Saint Josef Hospital
Paris, 75

Other trials in France

About this study

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

Read the 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
Being tested: placebos, hydrocortisone and fludrocortisone and placebo, recombinant human activated protein C and placebos, recombinant human activated protein C and hydrocortisone and fludrocortisone
Keywords: septic shock, coagulation, immunomodulation, survival
Medical subject headings: Shock, Septic, Thrombosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

placebosDrug
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 placeboDrug
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 placebosDrug
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 fludrocortisoneDrug
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

Study groups in NCT00625209
Study group	Role	What they receive
1	Placebo comparator	placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C Receives: Drug: placebos
2	Active comparator	Hydrocortisone plus fludrocortisone and a placebo of activated protein C Receives: Drug: hydrocortisone and fludrocortisone and placebo
3	Active comparator	placebo of hydrocortisone, placebo of fludrocortisone and activated protein C Receives: Drug: recombinant human activated protein C and placebos
4	Active comparator	hydrocortisone plus fludrocortisone plus activated protein C Receives: Drug: recombinant human activated protein C and hydrocortisone and fludrocortisone

What is being measured

The primary outcome is the main question the study is designed to answer.

90-day mortality
Measured: 90 day

Secondary outcomes (17)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Mar 2008Jul 2016

First posted28 Feb 2008 (estimated)
Study startMar 2008
Primary completionJun 2015
Study completionJul 2016

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (4)Papers the sponsor has linked to this study.
Other trials for Septic ShockStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 1,241 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00625209
Sponsor's protocol ID: P070128
Acronym: APROCCHS
Status last verified: Jun 2017
First submitted: 19 Feb 2008
Last updated: 14 Jun 2017
Results posted: No
Data monitoring committee: Yes

Publications

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.
PubMed 27154719
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.
PubMed 23525934
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.
PubMed 38310918
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.
PubMed 29490185

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Septic Shock trials

Study at a glance

From the registry record, last updated by the sponsor on 14 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase III of Recombinant Human Activated Protein C and Low Dose of Hydrocortisone and Fludrocortisone in Adult Septic Shock
ClinicalTrials.gov ID: NCT00625209
Acronym / sponsor ID: APROCCHS / P070128
Conditions: Septic Shock
Keywords: septic shock, coagulation, immunomodulation, survival
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,241 participants (actual)
Lead sponsor: University of VersaillesUniversity, hospital or other
Collaborators: Assistance Publique - Hôpitaux de Paris, Ministry of Health, France
Study start: Mar 2008
Primary completion: Jun 2015 (actual)
Study completion: Jul 2016 (actual)
First posted: 28 Feb 2008 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

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.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
1	Placebo comparator	Drug: placebosplacebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C
2	Active comparator	Drug: hydrocortisone and fludrocortisone and placeboHydrocortisone plus fludrocortisone and a placebo of activated protein C
3	Active comparator	Drug: recombinant human activated protein C and placebosplacebo of hydrocortisone, placebo of fludrocortisone and activated protein C
4	Active comparator	Drug: recombinant human activated protein C and hydrocortisone and fludrocortisonehydrocortisone plus fludrocortisone plus activated protein C

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (6 listed)

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

Key exclusion criteria (29 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
placebosplacebo 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	Drug	1
hydrocortisone and fludrocortisone and placebohydrocortisone 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	Drug	2
recombinant human activated protein C and placebosactivated 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	Drug	3
recombinant human activated protein C and hydrocortisone and fludrocortisone96 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	Drug	4

Primary outcome

90-day mortality
Time frame: 90 day

17 secondary outcomes

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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 14 Jun 2017.
Background: PubMed 27154719Annane 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.
Results publication: PubMed 23525934Annane 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.
Derived from this study: PubMed 38310918Heming 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.
Derived from this study: PubMed 29490185Annane 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.

Related trials for Septic Shock

Active, not recruitingPhase 4
Thymosin Alpha 1 and IgM Levels in Sepsis
Sepsis, Septic Shock
Not yet recruiting
Vitamin C for Acute Kidney Injury in ACLF With Septic Shock: A Randomized Controlled Trial
Acute-on-Chronic Liver Failure (ACLF)
Not yet recruiting
ICU-SUCCEED for Survivors of Acute Respiratory Failure and Their Caregivers
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Not yet recruitingObservational study
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RecruitingObservational study
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Sepsis

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Benoit Misset, MD principal investigator

Unity Health Toronto

Claude Martin, MD principal investigator

Assistance Publique Hopitaux de Marseille, hôpital Nord

Alain Cariou, MD principal investigator

Assistance Publique Hôpitaux de Paris, Hôpital Cochin

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing recombinant human activated protein C and hydrocortisone and fludrocortisone in people with Septic Shock, run by University of Versailles at 4 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

90-day mortality (time frame: 90 day). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00625209, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2017.