CClinicalTrials.gg
CompletedNCT03452865PPI-SEPSISUpdated Jan 19, 2024

Esomeprazole to Reduce Organ Failure in Sepsis

A Phase 3 interventional study of Esomeprazole and Placebo in Sepsis and Septic Shock, sponsored by Università Vita-Salute San Raffaele. Completed at 17 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-01-19.

Sponsored by Università Vita-Salute San Raffaele · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
300
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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.

02

Conditions studied

  • Sepsis
  • Septic Shock

Keywords

  • proton pump inhibitor
  • esomeprazole
  • sepsis
  • septic shock
  • organ failure
  • SOFA
  • mortality
03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
300 participants (actual)

Study arms

  • Experimental
    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 .

    Drug: Esomeprazole

  • Placebo comparator
    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 .

    Drug: Placebo

Interventions

  • DrugEsomeprazole

    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.

  • DrugPlacebo

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

05

What researchers measure

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).

    Time frame: Days 1-28

Secondary outcomes

  1. Mortality

    Time frame: Day 28, 60 and 90

  2. Antibiotic-free days

    Time frame: Day 28

  3. Adjusted ICU-free days

    Time frame: Day 28

  4. 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).

    Time frame: Days 1-28

06

Study locations

17 sites
  • Policlinico Univeristario Campus Bio-Medico
    Roma, Lazio, Italy
  • IRCCS San Martino Istitute
    Genova, 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, Sardegna, Italy
  • USSL 10 Veneto
    San Dona' Di Piave, Venezia, Italy
  • Ospedale Maggiore di Lodi
    Lodi, Italy
  • Ospedale di Merano
    Merano, Italy
  • Università degli Studi della Campania "Luigi Vanvitelli"
    Napoli, 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, Russian Federation
  • Negovskiy Reanimatology Research Institute
    Moscow, Russian Federation
07

References and documents

Publications

  • 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. PubMed 24335434 ↗
  • 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. PubMed 26903338 ↗
  • Ferner RE, Allison TR. Omeprazole overdose. Hum Exp Toxicol. 1993 Nov;12(6):541-2. doi: 10.1177/096032719301200614. PubMed 7904473 ↗
  • 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. PubMed 11594901 ↗
  • 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. PubMed 17365625 ↗
  • 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. PubMed 23760821 ↗
  • 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. PubMed 24894386 ↗
  • 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. PubMed 23984731 ↗
  • 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. PubMed 19885998 ↗
  • 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. PubMed 27441656 ↗
  • 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. PubMed 24771848 ↗
  • 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. PubMed 26169094 ↗
08

Registry details

Key details

Study ID
NCT03452865
Lead sponsor
Università Vita-Salute San Raffaele
Collaborators
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Responsible party
Giovanni Landoni (MD, Associate Professor, Università Vita-Salute San Raffaele) — Principal investigator
First posted
Mar 2, 2018
Start date
Jan 28, 2020
Primary completion
Aug 21, 2023
Completion
Aug 21, 2023
Last update
Jan 19, 2024

Study contacts

Giacomo Monti, MD
principal investigator · Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute
Giovanni Landoni, MD
study chair · Associate Professor of Anesthesiology and Intensive Care, Vita-Salute San Raffaele University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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