Esomeprazole to Reduce Organ Failure in Sepsis

NCT ID: NCT03452865

Last Updated: 2024-01-19

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

300 participants

Study Classification

INTERVENTIONAL

Study Start Date

2020-01-28

Study Completion Date

2023-08-21

Brief Summary

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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.

Detailed Description

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Conditions

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Sepsis Septic Shock

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Esomeprazole

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 .

Group Type EXPERIMENTAL

Esomeprazole

Intervention Type 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.

Placebo

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 .

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

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

Interventions

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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.

Intervention Type DRUG

Placebo

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

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

OTHER

Sponsor Role collaborator

Università Vita-Salute San Raffaele

OTHER

Sponsor Role lead

Responsible Party

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Giovanni Landoni

MD, Associate Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Giacomo Monti, MD

Role: PRINCIPAL_INVESTIGATOR

Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute

Giovanni Landoni, MD

Role: STUDY_CHAIR

Associate Professor of Anesthesiology and Intensive Care, Vita-Salute San Raffaele University

Locations

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Policlinico Univeristario Campus Bio-Medico

Rome, Lazio, Italy

Site Status

IRCCS San Martino Istitute

Genoa, Liguria, Italy

Site Status

Humanitas Clinical Institute

Rozzano, Lombardy, Italy

Site Status

IRCCS San Raffaele Scientific Institute

Milan, MI, Italy

Site Status

A.O.U. Mater Domini

Catanzaro, Reggio Calabria, Italy

Site Status

Azienda Ospedaliera Universitaria

Cagliari, Sardinia, Italy

Site Status

USSL 10 Veneto

San Donà di Piave, Venezia, Italy

Site Status

Ospedale Maggiore di Lodi

Lodi, , Italy

Site Status

Ospedale di Merano

Merano, , Italy

Site Status

Università degli Studi della Campania "Luigi Vanvitelli"

Napoli, , Italy

Site Status

AOU Pisana

Pisa, , Italy

Site Status

A.O.R San Carlo

Potenza, , Italy

Site Status

Azienda Ospedaliera San Giovanni Battista Molinette di Torino

Torino, , Italy

Site Status

Ospedale Santa Maria della Misericordia

Udine, , Italy

Site Status

Astana Medical University

Kazakhstan, , Kazakhstan

Site Status

Federal Clinical & Research Center for Reanimatology and Rehabilitation

Moscow, , Russia

Site Status

Negovskiy Reanimatology Research Institute

Moscow, , Russia

Site Status

Countries

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Italy Kazakhstan Russia

References

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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.

Reference Type BACKGROUND
PMID: 24335434 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26903338 (View on PubMed)

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

Reference Type BACKGROUND
PMID: 7904473 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 11594901 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 17365625 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23760821 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24894386 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 23984731 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 19885998 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 27441656 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 24771848 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26169094 (View on PubMed)

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.

Reference Type DERIVED
PMID: 40439536 (View on PubMed)

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.

Reference Type DERIVED
PMID: 37625587 (View on PubMed)

Other Identifiers

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2018-000488-98

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PPI-SEPSIS

Identifier Type: -

Identifier Source: org_study_id

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