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| ID | Type | Description | Link |
|---|---|---|---|
| 2018-000488-98 | EudraCT Number |
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| Name | Class |
|---|---|
| IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy | OTHER |
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Sepsis is a severe disease with a high mortality rate and lack of efficacious therapies. Proton pump inhibitors (PPI) are drugs widely used to inhibit acid secretion by gastric cells and with a high safety profile. Carta and Rubartelli (IRCCS San Martino - Genova) have recently reported that PPI, such as esomeprazole, inhibit TNF-alfa and IL-1ß secretion. Moreover, they showed that a single administration of PPI protects mice from endotoxic shock with no adverse effects. PPI-SEPSIS is a randomized, double blind, controlled against placebo clinical trial to test if high-doses esomeprazole in septic patients reduces the severity of organs failure.
In parallel, the investigators will evaluate ex vivo in monocytes from septic patients: redox state and response to inflammatory stimuli; ATP release; metabolic changes and pH; cytokine production; the effects of PPI on these parameters.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Esomeprazole | Experimental | Patients randomized to Esomeprazole Group will receive a bolus of 160 mg of esomeprazole (diluted in 100 ml of 0.9% sodium chloride for intravenous use and administered over 60 minutes) and an intravenous infusion of 12 mg/hr (diluted in 0.9% sodium chloride at a concentration of 8 mg/ml will be injected at a rate of 1.5 ml/hr) for 72 hours . |
|
| Placebo | Placebo Comparator | Patients randomized to Placebo Group will receive a bolus of 100 ml of 0.9% sodium chloride for intravenous use administered over 60 minutes with no active principle and an intravenous infusion of 0.9% sodium chloride at a rate of 1.5 ml/hr with no active principle for 72 hours . |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Esomeprazole | Drug | 160 mg of esomeprazole will be diluted in 100 ml of 0.9% sodium chloride for intravenous use for bolus. For continuous intravenous infusion, 40 mg of esomeprazole will be reconstituted by adding 5 ml of 0.9% sodium chloride for intravenous use at a concentration of 8 mg/ml. |
| Measure | Description | Time Frame |
|---|---|---|
| SOFA score reduction | SOFA (sequential organ failure assessment) score is used to track a person's status during the stay in an intensive care unit to determine the extent of a person's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (better outcome) to 24 points (worse outcome). | Days 1-28 |
| Measure | Description | Time Frame |
|---|---|---|
| Mortality | Day 28, 60 and 90 | |
| Antibiotic-free days | Day 28 | |
| Adjusted ICU-free days |
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Inclusion Criteria:
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Giacomo Monti, MD | Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute | Principal Investigator |
| Giovanni Landoni, MD | Associate Professor of Anesthesiology and Intensive Care, Vita-Salute San Raffaele University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Policlinico Univeristario Campus Bio-Medico | Rome | Lazio | Italy | |||
| IRCCS San Martino Istitute |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24335434 | Background | Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014 Jan 1;5(1):4-11. doi: 10.4161/viru.27372. Epub 2013 Dec 11. | |
| 26903338 | Background | Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287. |
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| ID | Term |
|---|---|
| D018805 | Sepsis |
| D012772 | Shock, Septic |
| ID | Term |
|---|---|
| D007239 | Infections |
| D018746 | Systemic Inflammatory Response Syndrome |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
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| ID | Term |
|---|---|
| D064098 | Esomeprazole |
| ID | Term |
|---|---|
| D009853 | Omeprazole |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
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|
| Placebo | Drug | 0.9% sodium chloride (same ml of the study drug) |
|
| Day 28 |
| Single organ failure severity | Highest mean difference in each different category of SOFA score. SOFA (sequential organ failure assessment) score is used to track a person's status during the stay in an intensive care unit to determine the extent of a person's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems which are added up. Each score ranges from 0 to 4. SOFA score ranges from 0 (better outcome) to 24 points (worse outcome). | Days 1-28 |
| Genoa |
| Liguria |
| Italy |
| Humanitas Clinical Institute | Rozzano | Lombardy | 20100 | Italy |
| IRCCS San Raffaele Scientific Institute | Milan | MI | 20132 | Italy |
| A.O.U. Mater Domini | Catanzaro | Reggio Calabria | Italy |
| Azienda Ospedaliera Universitaria | Cagliari | Sardinia | Italy |
| USSL 10 Veneto | San Donà di Piave | Venezia | Italy |
| Ospedale Maggiore di Lodi | Lodi | Italy |
| Ospedale di Merano | Merano | Italy |
| Università degli Studi della Campania "Luigi Vanvitelli" | Naples | Italy |
| AOU Pisana | Pisa | Italy |
| A.O.R San Carlo | Potenza | Italy |
| Azienda Ospedaliera San Giovanni Battista Molinette di Torino | Torino | Italy |
| Ospedale Santa Maria della Misericordia | Udine | Italy |
| Astana Medical University | Kazakhstan | Kazakhstan |
| Federal Clinical & Research Center for Reanimatology and Rehabilitation | Moscow | Russia |
| Negovskiy Reanimatology Research Institute | Moscow | Russia |
| 7904473 | Background | Ferner RE, Allison TR. Omeprazole overdose. Hum Exp Toxicol. 1993 Nov;12(6):541-2. doi: 10.1177/096032719301200614. |
| 11594901 | Background | Ferreira FL, Bota DP, Bross A, Melot C, Vincent JL. Serial evaluation of the SOFA score to predict outcome in critically ill patients. JAMA. 2001 Oct 10;286(14):1754-8. doi: 10.1001/jama.286.14.1754. |
| 17365625 | Background | Forrester MB. Pattern of proton pump inhibitor calls to Texas poison centers, 1998-2004. J Toxicol Environ Health A. 2007 Apr 15;70(8):705-14. doi: 10.1080/15287390601188045. |
| 23760821 | Background | Neumann I, Letelier LM, Rada G, Claro JC, Martin J, Howden CW, Yuan Y, Leontiadis GI. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013 Jun 12;2013(6):CD007999. doi: 10.1002/14651858.CD007999.pub2. |
| 24894386 | Background | Orme RM, Perkins GD, McAuley DF, Liu KD, Mason AJ, Morelli A, Singer M, Ashby D, Gordon AC. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial. Trials. 2014 Jun 2;15:199. doi: 10.1186/1745-6215-15-199. |
| 23984731 | Background | Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51. doi: 10.1056/NEJMra1208623. No abstract available. |
| 19885998 | Background | Noritomi DT, Soriano FG, Kellum JA, Cappi SB, Biselli PJ, Liborio AB, Park M. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009 Oct;37(10):2733-9. doi: 10.1097/ccm.0b013e3181a59165. |
| 27441656 | Background | Balza E, Piccioli P, Carta S, Lavieri R, Gattorno M, Semino C, Castellani P, Rubartelli A. Proton pump inhibitors protect mice from acute systemic inflammation and induce long-term cross-tolerance. Cell Death Dis. 2016 Jul 21;7(7):e2304. doi: 10.1038/cddis.2016.218. |
| 24771848 | Background | Lavieri R, Piccioli P, Carta S, Delfino L, Castellani P, Rubartelli A. TLR costimulation causes oxidative stress with unbalance of proinflammatory and anti-inflammatory cytokine production. J Immunol. 2014 Jun 1;192(11):5373-81. doi: 10.4049/jimmunol.1303480. Epub 2014 Apr 25. |
| 26169094 | Background | Cui LH, Li C, Wang XH, Yan ZH, He X, Gong SD. The therapeutic effect of high-dose esomeprazole on stress ulcer bleeding in trauma patients. Chin J Traumatol. 2015;18(1):41-3. doi: 10.1016/j.cjtee.2014.06.001. |
| 40439536 | Derived | Monti G, Carta S, Kotani Y, Bruni A, Konkayeva M, Guarracino F, Yakovlev A, Cucciolini G, Shemetova M, Scapol S, Momesso E, Garofalo E, Brizzi G, Baldassarri R, Ajello S, Isirdi A, Meroi F, Baiardo Redaelli M, Boffa N, Votta CD, Borghi G, Montrucchio G, Rauch S, D'Amico F, Pace MC, Paternoster G, Vitale F, Giardina G, Labanca R, Lembo R, Marmiere M, Marzaroli M, Nakhnoukh C, Plumari V, Scandroglio AM, Scquizzato T, Sordoni S, Valsecchi D, Agro FE, Finco G, Bove T, Corradi F, Likhvantsev V, Longhini F, Konkayev A, Landoni G, Bellomo R, Zangrillo A; PPI-SEPSIS Study Group. A Multinational Randomized Trial of Mega-Dose Esomeprazole as Anti-Inflammatory Agent in Sepsis. Crit Care Med. 2025 Aug 1;53(8):e1554-e1566. doi: 10.1097/CCM.0000000000006720. Epub 2025 May 29. |
| 37625587 | Derived | Monti G, Konkayev A, Carta S, Bradic N, Bruni A, Kotani Y, Guarracino F, Redkin I, Biondi-Zoccai G, Benedetto U, D'Ascenzo F, Garofalo E, Baiardo Redaelli M, Brizzi G, Forfori F, Borghi G, Scapol S, Momesso E, Cuffaro R, Boffa N, Rauch S, D'Amico F, Montrucchio G, Pace MC, Galbiati C, Bosso S, Savelli F, Giardina G, Silvetti S, Tripodi VF, Labanca R, Lembo R, Marmiere M, Marzaroli M, Nakhnoukh C, Valsecchi D, Finco G, Agro FE, Bove T, Corradi F, Longhini F, Landoni G, Bellomo R, Zangrillo A; Collaborators. High dose esomeprazole as an anti-inflammatory agent in sepsis: Protocol for a randomized controlled trial. Contemp Clin Trials. 2023 Oct;133:107319. doi: 10.1016/j.cct.2023.107319. Epub 2023 Aug 23. |
| D013568 |
| Pathological Conditions, Signs and Symptoms |
| D012769 | Shock |
| D009930 |
| Organic Chemicals |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |