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

Primary Purpose

Sepsis, Septic Shock

Status
Recruiting
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Esomeprazole
Placebo
Sponsored by
UniversitΓ  Vita-Salute San Raffaele
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis focused on measuring proton pump inhibitor, esomeprazole, sepsis, septic shock, organ failure, SOFA, mortality

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age β‰₯ 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

Sites / Locations

  • Policlinico Univeristario Campus Bio-MedicoRecruiting
  • IRCCS San Martino Istitute
  • Humanitas Clinical InstituteRecruiting
  • IRCCS San Raffaele Scientific InstituteRecruiting
  • A.O.U. Mater DominiRecruiting
  • Azienda Ospedaliera UniversitariaRecruiting
  • USSL 10 VenetoRecruiting
  • Ospedale Maggiore di LodiRecruiting
  • Ospedale di MeranoRecruiting
  • UniversitΓ  degli Studi della Campania "Luigi Vanvitelli"Recruiting
  • AOU PisanaRecruiting
  • AOU PisanaRecruiting
  • A.O.R San CarloRecruiting
  • Azienda Ospedaliera San Giovanni Battista Molinette di Torino
  • Ospedale Santa Maria della MisericordiaRecruiting
  • Astana Medical UniversityRecruiting
  • Federal Clinical & Research Center for Reanimatology and RehabilitationRecruiting
  • Negovskiy Reanimatology Research InstituteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Esomeprazole

Placebo

Arm Description

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 .

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 .

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Mortality
Antibiotic-free days
Adjusted ICU-free days
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).

Full Information

First Posted
February 26, 2018
Last Updated
August 30, 2023
Sponsor
UniversitΓ  Vita-Salute San Raffaele
Collaborators
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
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1. Study Identification

Unique Protocol Identification Number
NCT03452865
Brief Title
Esomeprazole to Reduce Organ Failure in Sepsis
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 28, 2020 (Actual)
Primary Completion Date
August 2023 (Anticipated)
Study Completion Date
August 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
UniversitΓ  Vita-Salute San Raffaele
Collaborators
IRCCS Azienda Ospedaliera Universitaria San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sepsis, Septic Shock
Keywords
proton pump inhibitor, esomeprazole, sepsis, septic shock, organ failure, SOFA, mortality

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Esomeprazole
Arm Type
Experimental
Arm Description
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 .
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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 .
Intervention Type
Drug
Intervention Name(s)
Esomeprazole
Intervention Description
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
Intervention Name(s)
Placebo
Intervention Description
0.9% sodium chloride (same ml of the study drug)
Primary Outcome Measure Information:
Title
SOFA score reduction
Description
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 Outcome Measure Information:
Title
Mortality
Time Frame
Day 28, 60 and 90
Title
Antibiotic-free days
Time Frame
Day 28
Title
Adjusted ICU-free days
Time Frame
Day 28
Title
Single organ failure severity
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age β‰₯ 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Giacomo Monti, MD
Phone
+39 0226432222
Email
monti.giacomo@hsr.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Giacomo Monti, MD
Organizational Affiliation
Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Giovanni Landoni, MD
Organizational Affiliation
Associate Professor of Anesthesiology and Intensive Care, Vita-Salute San Raffaele University
Official's Role
Study Chair
Facility Information:
Facility Name
Policlinico Univeristario Campus Bio-Medico
City
Roma
State/Province
Lazio
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Felice E AgrΓ², Prof
Email
f.agro@unicampus.it
Facility Name
IRCCS San Martino Istitute
City
Genova
State/Province
Liguria
Country
Italy
Individual Site Status
Active, not recruiting
Facility Name
Humanitas Clinical Institute
City
Rozzano
State/Province
Lombardy
ZIP/Postal Code
20100
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Massimiliano Greco, MD
Facility Name
IRCCS San Raffaele Scientific Institute
City
Milan
State/Province
MI
ZIP/Postal Code
20132
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Giacomo Monti, MD
Phone
+39 022643 2222
Email
monti.giacomo@hsr.it
Facility Name
A.O.U. Mater Domini
City
Catanzaro
State/Province
Reggio Calabria
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Federico Longhini, MD
Email
longhini.federico@gmail.com
Facility Name
Azienda Ospedaliera Universitaria
City
Cagliari
State/Province
Sardegna
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gabriele Finco, MD
Facility Name
USSL 10 Veneto
City
San Dona' Di Piave
State/Province
Venezia
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fabio Toffoletto, MD
Email
fabio.toffoletto@ulss10.veneto.it
Facility Name
Ospedale Maggiore di Lodi
City
Lodi
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Carmine D Votta
Facility Name
Ospedale di Merano
City
Merano
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Simon Rauch, MD
Email
simon.rauch@sabes.it
Facility Name
UniversitΓ  degli Studi della Campania "Luigi Vanvitelli"
City
Napoli
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Caterina M Pace
Facility Name
AOU Pisana
City
Pisa
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francesco Corradi, MD
Facility Name
AOU Pisana
City
Pisa
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Fabio Guarracino, MD
Email
f.guarracino@ao-pisa.toscana.it
Facility Name
A.O.R San Carlo
City
Potenza
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gianluca Paternoster, MD
Email
paternostergianluca@gmail.com
Facility Name
Azienda Ospedaliera San Giovanni Battista Molinette di Torino
City
Torino
Country
Italy
Individual Site Status
Completed
Facility Name
Ospedale Santa Maria della Misericordia
City
Udine
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tiziana Bove, Prof
Facility Name
Astana Medical University
City
Kazakhstan
Country
Kazakhstan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Aidos Konkayev, MD
Facility Name
Federal Clinical & Research Center for Reanimatology and Rehabilitation
City
Moscow
Country
Russian Federation
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ivan Redkin, MD
Email
redkin70@mail.ru
Facility Name
Negovskiy Reanimatology Research Institute
City
Moscow
Country
Russian Federation
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristina Kadanceva, MD

12. IPD Sharing Statement

Citations:
PubMed Identifier
24335434
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.
Results Reference
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PubMed Identifier
26903338
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.
Results Reference
background
PubMed Identifier
7904473
Citation
Ferner RE, Allison TR. Omeprazole overdose. Hum Exp Toxicol. 1993 Nov;12(6):541-2. doi: 10.1177/096032719301200614.
Results Reference
background
PubMed Identifier
11594901
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.
Results Reference
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PubMed Identifier
17365625
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.
Results Reference
background
PubMed Identifier
23760821
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.
Results Reference
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PubMed Identifier
24894386
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.
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PubMed Identifier
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Citation
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.
Results Reference
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PubMed Identifier
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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.
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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.
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Esomeprazole to Reduce Organ Failure in Sepsis

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