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SepsisPhase 3PPI-SEPSISNCT03452865

Esomeprazole to Reduce Organ Failure in Sepsis

A Phase 3 study testing Esomeprazole in people with Sepsis and Septic Shock, run by Università Vita-Salute San Raffaele at 17 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Sepsis, Septic Shock
What is being tested?
Esomeprazole
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
300 participants
Where
17 sitesin 3 countries
Study dates
28 Jan 2020to 21 Aug 2023
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 9Show fewer
  • Sepsis or septic shock since over 36 hours
  • Severe hepatic dysfunction
  • Pregnant or breastfeeding

Trial locations and contacts

17 sites in 3 countries.

17 sites in 3 countries

Italy14 sites

  • Azienda Ospedaliera Universitaria

    Cagliari, Sardinia

  • A.O.U. Mater Domini

    Catanzaro, Reggio Calabria

  • IRCCS San Martino Istitute

    Genoa, Liguria

  • Ospedale Maggiore di Lodi

    Lodi

  • Ospedale di Merano

    Merano

  • IRCCS San Raffaele Scientific Institute

    Milan, MI, 20132

  • Università degli Studi della Campania "Luigi Vanvitelli"

    Naples

  • AOU Pisana

    Pisa

  • A.O.R San Carlo

    Potenza

  • Policlinico Univeristario Campus Bio-Medico

    Rome, Lazio

  • Humanitas Clinical Institute

    Rozzano, Lombardy, 20100

  • USSL 10 Veneto

    San Donà di Piave, Venezia

  • Azienda Ospedaliera San Giovanni Battista Molinette di Torino

    Torino

  • Ospedale Santa Maria della Misericordia

    Udine

Other trials in Italy

Russia2 sites

  • Federal Clinical & Research Center for Reanimatology and Rehabilitation

    Moscow

  • Negovskiy Reanimatology Research Institute

    Moscow

Other trials in Russia

Kazakhstan1 site

  • Astana Medical University

    Kazakhstan

Other trials in Kazakhstan

About this study

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

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
Being tested
Esomeprazole, Placebo
Keywords
proton pump inhibitor, esomeprazole, sepsis, septic shock, organ failure, SOFA, mortality
Medical subject headings
Sepsis, Shock, Septic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • EsomeprazoleDrug

    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.

  • PlaceboDrug

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

Study groups in NCT03452865
Study groupRoleWhat they receive
EsomeprazoleExperimentalPatients 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 .
Receives: Drug: Esomeprazole
PlaceboPlacebo comparatorPatients 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 .
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: Days 1-28

Secondary outcomes (4)

  1. Mortality

    Measured: Day 28, 60 and 90

  2. Antibiotic-free days

    Measured: Day 28

  3. Adjusted ICU-free days

    Measured: 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).

    Measured: Days 1-28

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Mar 2018
  2. Study start28 Jan 2020
  3. Primary completion21 Aug 2023
  4. Study completion21 Aug 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
300 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03452865
Sponsor's protocol ID
PPI-SEPSIS
Other IDs
2018-000488-98, 2018
Acronym
PPI-SEPSIS
Status last verified
Jan 2024
First submitted
26 Feb 2018
Last updated
19 Jan 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

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.

    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

  • 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.

    PubMed 40439536

  • 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.

    PubMed 37625587

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Esomeprazole in people with Sepsis and Septic Shock, run by Università Vita-Salute San Raffaele at 17 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Jan 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Italy, Russia, Kazakhstan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

SOFA score reduction (time frame: Days 1-28). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03452865, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jan 2024.

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