Esomeprazole to Reduce Organ Failure in Sepsis

NCT03452865 | Completed Phase 3 DMC

• 2 other identifiers: PPI-SEPSIS2018-000488-98
• Study Type: interventional
• Target: 300
• Locations: 3 countries
• Sites: 17

Brief 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.

Conditions

Sepsis; Septic Shock

Keywords

proton pump inhibitor; esomeprazole; sepsis; septic shock; organ failure; SOFA; mortality

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Mortality

  Day 28, 60 and 90

• Antibiotic-free days

  Day 28

• Adjusted ICU-free days

  Day 28

• Single organ failure severity

  Days 1-28

Study Arms (2)

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 .

Drug: Esomeprazole

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 .

Drug: Placebo

Interventions

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.

Esomeprazole

Placebo DRUG

0.9% sodium chloride (same ml of the study drug)

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Università Vita-Salute San Raffaele: lead
• IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy: collaborator

Study Sites (17)

Policlinico Univeristario Campus Bio-Medico

Rome, Lazio, Italy

Location

IRCCS San Martino Istitute

Genoa, Liguria, Italy

Location

Humanitas Clinical Institute

Rozzano, Lombardy, 20100, Italy

Location

IRCCS San Raffaele Scientific Institute

Milan, MI, 20132, Italy

Location

A.O.U. Mater Domini

Catanzaro, Reggio Calabria, Italy

Location

Azienda Ospedaliera Universitaria

Cagliari, Sardinia, Italy

Location

USSL 10 Veneto

San Donà di Piave, Venezia, Italy

Location

Ospedale Maggiore di Lodi

Lodi, Italy

Location

Ospedale di Merano

Merano, Italy

Location

Università degli Studi della Campania "Luigi Vanvitelli"

Napoli, Italy

Location

AOU Pisana

Pisa, Italy

Location

A.O.R San Carlo

Potenza, Italy

Location

Azienda Ospedaliera San Giovanni Battista Molinette di Torino

Torino, Italy

Location

Ospedale Santa Maria della Misericordia

Udine, Italy

Location

Astana Medical University

Kazakhstan, Kazakhstan

Location

Federal Clinical & Research Center for Reanimatology and Rehabilitation

Moscow, Russia

Location

Negovskiy Reanimatology Research Institute

Moscow, Russia

Location

Related Publications (14)

• 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.

  PMID: 24335434 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.

  PMID: 26903338 BACKGROUND

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

  PMID: 7904473 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.

  PMID: 11594901 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.

  PMID: 17365625 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.

  PMID: 23760821 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.

  PMID: 24894386 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.

  PMID: 23984731 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.

  PMID: 19885998 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.

  PMID: 27441656 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.

  PMID: 24771848 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.

  PMID: 26169094 BACKGROUND

• 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.

  PMID: 40439536 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.

  PMID: 37625587 DERIVED

MeSH Terms

Conditions

Sepsis; Shock, Septic

Interventions

Esomeprazole

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Intervention Hierarchy (Ancestors)

Omeprazole; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• 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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, Associate Professor

Study Record Dates

• First Submitted: February 26, 2018
• First Posted: March 2, 2018
• Study Start: January 28, 2020
• Primary Completion: August 21, 2023
• Study Completion: August 21, 2023
• Last Updated: January 19, 2024

Record last verified: 2024-01

Locations

IT (14); RU (2); KA (1)