Esomeprazole to Reduce Organ Failure in Sepsis

Sepsis Clinical Trial

— PPI-SEPSIS  

Official title:

Proton Pump Inhibitors (PPI) as a New Strategy for Therapy in Sepsis: Clinical Trial to Reduce Severity of Organ Failure and in Vitro Experiments to Search Specific Hallmarks in Monocytes From Septic Patients and to Characterize the Mechanism of Action of PPI

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03452865
• Other study ID #: PPI-SEPSIS
• Secondary ID: 2018-000488-98
• Status: Completed
• Phase: Phase 3
• Start date: January 28, 2020
• Est. completion date: August 21, 2023

Study information

• Verified date: January 2024
• Source: Università Vita-Salute San Raffaele
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: August 21, 2023
• Est. primary completion date: August 21, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age = 18 years old

• Admitted to intensive care unit or emergency department

• Sepsis or septic shock

• Able to express informed consent. For unconscious patients, current laws will be applied as requested by Ethical Committee.

Exclusion Criteria

• Able to express informed consent and deny it

• Known allergy or intolerance to study drug

• Little chance of survival, as defined by a SAPS II score more than 65 point

• Concomitant acquired immunodeficiency syndrome

• On immunosuppressant or long-term corticosteroid therapy

• Receiving lifesaving drugs known to have a strong interference with esomeprazole

• Sepsis or septic shock since over 36 hours

• Severe hepatic dysfunction

• Pregnant or breastfeeding

Related Conditions & MeSH terms

• Sepsis
• Septic Shock
• Shock, Septic
• Toxemia

Intervention

Drug:
• Esomeprazole
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.
• Placebo
0.9% sodium chloride (same ml of the study drug)

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera Universitaria	Cagliari	Sardegna
Italy	A.O.U. Mater Domini	Catanzaro	Reggio Calabria
Italy	IRCCS San Martino Istitute	Genova	Liguria
Italy	Ospedale Maggiore di Lodi	Lodi
Italy	Ospedale di Merano	Merano
Italy	IRCCS San Raffaele Scientific Institute	Milan	MI
Italy	Università degli Studi della Campania "Luigi Vanvitelli"	Napoli
Italy	AOU Pisana	Pisa
Italy	A.O.R San Carlo	Potenza
Italy	Policlinico Univeristario Campus Bio-Medico	Roma	Lazio
Italy	Humanitas Clinical Institute	Rozzano	Lombardy
Italy	USSL 10 Veneto	San Dona' Di Piave	Venezia
Italy	Azienda Ospedaliera San Giovanni Battista Molinette di Torino	Torino
Italy	Ospedale Santa Maria della Misericordia	Udine
Kazakhstan	Astana Medical University	Kazakhstan
Russian Federation	Federal Clinical & Research Center for Reanimatology and Rehabilitation	Moscow
Russian Federation	Negovskiy Reanimatology Research Institute	Moscow

Sponsors (2)

Lead Sponsor	Collaborator
Università Vita-Salute San Raffaele	IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

Countries where clinical trial is conducted

Italy,  Kazakhstan,  Russian Federation, 

References & Publications (12)

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. Erratum In: N Engl J Med. 2013 Nov 21;369(21):2069. — View Citation

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. — View Citation

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. — View Citation

Ferner RE, Allison TR. Omeprazole overdose. Hum Exp Toxicol. 1993 Nov;12(6):541-2. doi: 10.1177/096032719301200614. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Secondary	Mortality		Day 28, 60 and 90
Secondary	Antibiotic-free days		Day 28
Secondary	Adjusted ICU-free days		Day 28
Secondary	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