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| Name | Class |
|---|---|
| Assistance Publique - Hôpitaux de Paris | OTHER |
| Ministry of Health, France | OTHER_GOV |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 1 | Placebo Comparator | placebo of hydrocortisone, placebo of fludrocortisone and placebo of activated protein C |
|
| 2 | Active Comparator | Hydrocortisone plus fludrocortisone and a placebo of activated protein C |
|
| 3 | Active Comparator | placebo of hydrocortisone, placebo of fludrocortisone and activated protein C |
|
| 4 | Active Comparator | hydrocortisone plus fludrocortisone plus activated protein C |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| 90-day mortality | 90 day |
| Measure | Description | Time Frame |
|---|---|---|
| mortality at 28 day | 28-day | |
| mortality at ICU discharge | ICU discharge | |
| mortality at hospital discharge |
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Inclusion Criteria:
Exclusion Criteria:
Amendments to eligibility criteria were:
On 27/03/2008: Changes in following exclusion criteria :
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 :
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Henri Mondor Hospital | Créteil | 94 | France | |||
| Raymond Poincaré Hospital |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27154719 | Background | 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. | |
| 23525934 |
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| 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 |
|
| 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 |
|
| 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 |
|
| hospital discharge |
| mortality at 6 months | 6 months |
| decision to withhold or withdraw active treatments | up to 90 days |
| Time to wean vasopressor therapy | up to 90 days |
| number of days alive and free of vasopressor therapy | up to 90 days |
| time to achieve an SOFA score of less than 6 | up to 90 days |
| number of days alive with a SOFA score < 6 points | up to 90 days |
| time to wean mechanical ventilation | up to 90 days |
| number of days alive and free of mechanical ventilation | up to 90 days |
| Length of intensive care unit and hospital stay | up to hospital discharge |
| acquisition of new infection | up to 180 days |
| new episode of sepsis | up to 90 days |
| new episode of septic shock | up to 90 days |
| bleeding events | up to 90 days |
| neurological sequels at intensive care unit and at hospital discharge and at 90 and 180 days | up to 6 months |
| Garches |
| 92380 |
| France |
| Pitié Salpêtrière Hospital | Paris | 75 | France |
| Saint Josef Hospital | Paris | 75 | France |
| 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. |
| 38310918 | Derived | 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. |
| 29490185 | 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. |
| ID | Term |
|---|---|
| D012772 | Shock, Septic |
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D018805 | Sepsis |
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
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| ID | Term |
|---|---|
| D006854 | Hydrocortisone |
| D005438 | Fludrocortisone |
| C421124 | drotrecogin alfa activated |
| ID | Term |
|---|---|
| D011282 | Pregnenediones |
| D011283 | Pregnenes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D015062 | 11-Hydroxycorticosteroids |
| D006889 | Hydroxycorticosteroids |
| D000305 | Adrenal Cortex Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D015065 | 17-Hydroxycorticosteroids |
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