Esomeprazole to Reduce Organ Failure in Sepsis (PPI-SEPSIS)

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

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.

Study Overview

• Status: Completed
• Conditions: Sepsis; Septic Shock
• Intervention / Treatment: Drug: Esomeprazole; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Giacomo Monti, MD; Phone Number: +39 0226432222; Email: monti.giacomo@hsr.it

Study Locations

• Italy
  • Lodi, Italy
    • Ospedale Maggiore di Lodi
  • Merano, Italy
    • Ospedale di Merano
  • Napoli, Italy
    • Università degli Studi della Campania "Luigi Vanvitelli"
  • Pisa, Italy
    • AOU Pisana
  • Potenza, Italy
    • A.O.R San Carlo
  • Torino, Italy
    • Azienda Ospedaliera San Giovanni Battista Molinette di Torino
  • Udine, Italy
    • Ospedale Santa Maria della Misericordia
  • Lazio
    • Roma, Lazio, Italy
      • Policlinico Univeristario Campus Bio-Medico
  • Liguria
    • Genova, Liguria, Italy
      • IRCCS San Martino Istitute
  • Lombardy
    • Rozzano, Lombardy, Italy, 20100
      • Humanitas Clinical Institute
  • MI
    • Milan, MI, Italy, 20132
      • IRCCS San Raffaele Scientific Institute
  • Reggio Calabria
    • Catanzaro, Reggio Calabria, Italy
      • A.O.U. Mater Domini
  • Sardegna
    • Cagliari, Sardegna, Italy
      • Azienda Ospedaliera Universitaria
  • Venezia
    • San Dona' Di Piave, Venezia, Italy
      • USSL 10 Veneto
• Kazakhstan
  • Kazakhstan, Kazakhstan
    • Astana Medical University
• Russian Federation
  • Moscow, Russian Federation
    • Federal Clinical & Research Center for Reanimatology and Rehabilitation
  • Moscow, Russian Federation
    • Negovskiy Reanimatology Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; 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 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; 0.9% sodium chloride (same ml of the study drug)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality		Day 28, 60 and 90
Antibiotic-free days		Day 28
Adjusted ICU-free days		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

Collaborators and Investigators

• Sponsor: Università Vita-Salute San Raffaele
• Collaborators: IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
• Investigators: Principal Investigator: Giacomo Monti, MD, Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute; Study Chair: Giovanni Landoni, MD, Associate Professor of Anesthesiology and Intensive Care, Vita-Salute San Raffaele University

Publications and helpful links

General Publications

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

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2020
• Primary Completion (Actual): August 21, 2023
• Study Completion (Actual): August 21, 2023

Study Registration Dates

• First Submitted: February 26, 2018
• First Submitted That Met QC Criteria: February 26, 2018
• First Posted (Actual): March 2, 2018

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: septic shock; sepsis; mortality; proton pump inhibitor; esomeprazole; SOFA; organ failure
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Shock; Sepsis; Toxemia; Shock, Septic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Esomeprazole
• Other Study ID Numbers: PPI-SEPSIS; 2018-000488-98 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No