Liver CirrhosisPhase 4STOPPITNCT04448028
Stop of Proton-pump Inhibitor Treatment in Patients With Liver Cirrhosis - a Double-blind, Placebo-controlled Trial
A Phase 4 study testing Esomeprazole 20mg in people with Liver Cirrhosis, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
Trial summary
Proton-pump inhibitors (PPI) are commonly prescribed in an uncritical manner to patients with liver cirrhosis without a clear evidence-based indication. Observational studies suggests that PPI use in cirrhotic patients may be a risk factor for the development of infections, especially spontaneous bacterial peritonitis… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Liver Cirrhosis
- What is being tested?
- Esomeprazole 20mg
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 476 participants
- Where
- 1 siteGermany
- Study dates
- 22 Apr 2021to Feb 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
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
- Patients with liver cirrhosis. The diagnosis of liver cirrhosis may be based on histology or a combination of clinical, laboratory and radiological criteria.
- Hospitalization or recent hospitalization (0 to 42 days prior to the baseline visit) with complications of liver cirrhosis.
- Treatment with proton pump inhibitors (PPI) for at least 28 days prior to the screening visit.
- PPI treatment with a single standard dose/day or less for at least 7 days prior to the screening visit.
- Females/males who agree to comply with the applicable contraceptive requirements of the protocol.
- Non-pregnant, non-lactating females.
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- Ability to understand the patient information and to personally sign and date the informed consent to participate in the study, before completing any study related procedures.
- The patient is co-operative and available for the entire study.
- Provided written informed consent.
Who cannot join
- Diagnosis of severe reflux esophagitis (LA grade C or D) by EGD < 2 months prior to the screening visit without PPI-therapy for at least 8 weeks prior to the screening visit.
- Peptic ulcers diagnosed by EGD < 28 days prior to the screening visit.
- History of endoscopic therapy for esophageal varices < 14 days prior to the screening visit.
- Life-expectancy < 1 year (at the discretion of the investigator) due to extrahepatic malignancies, metastasized hepatocellular carcinoma (HCC) or other severe extrahepatic diseases. Importantly, HCC without extrahepatic metastases or a reduced life-expectancy of < 1 year due to liver cirrhosis are not regarded as exclusion criteria.
- Regular intake of non-steroidal anti-inflammatory drugs (NSAID) on a daily basis with the exemption of acetylsalicylic acid (ASS) 100mg/day orally.
- Hypersensitivity or intolerance to esomeprazole, substituted benzimidazoles or other excipients of the IMP.
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- Ongoing therapy with nelfinavir.
- Participation in a clinical trial or use of an IMP within 30 days or five times the half-life of the IMP - whichever is longer - prior to receiving the first dose within this study.
- Positive urine pregnancy test at screening or positive serum pregnancy test before the first treatment or is breast feeding.
- Patient is not willing to use adequate contraceptive precautions during the study and for up to 5 days after the last scheduled dose of IMP.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Germany1 site, 1 recruiting
- Recruiting
University Medical Center Hamburg-Eppendorf
Hamburg, Free and Hanseatic City of Hamburg, 20246
Johannes Kluwe, MD, +4940741059614, j.kluwe@uke.de
Malte H Wehmeyer, MD, +494074100, m.wehmeyer@uke.de
About this study
Proton-pump inhibitors (PPI) are commonly prescribed in an uncritical manner to patients with liver cirrhosis without a clear evidence-based indication. Observational studies suggests that PPI use in cirrhotic patients may be a risk factor for the development of infections, especially spontaneous bacterial peritonitis (SBP). A possible explanation are PPI-associated microbiotic shifts leading to small intestinal bacterial overgrowth with subsequently increased bacterial translocation. Furthermore, PPI therapy in cirrhotic patients may lead to an increased risk for pneumonia and Clostridium difficile-infections.
However, the evidence is ambiguous, as other published studies found no evidence for an association of PPI use with an increased risk for SBP or pneumonia.
Read more
Moreover, an association between episodes of hepatic encephalopathy and PPI use has been reported.
Infections and hepatic encephalopathy may often lead to a hospitalization of cirrhotic patients and PPI use at discharge has also been associated to early re-hospitalization.
While some studies found an association of PPI and increased mortality in cirrhotic patients, other studies could not observe this association.
Thus, some of the current evidence suggests an unfavourable risk profile of PPIs in patients with liver cirrhosis. However, this patient population is considered to be at a high risk of gastrointestinal haemorrhage from peptic ulcers. Importantly, patients with liver cirrhosis have an increased mortality after peptic ulcer bleeding as compared to patients without cirrhosis. Therefore, generous PPI use may also have a yet unproven preventive effect against upper gastrointestinal bleeding.
The STOPPIT trial is the first prospective, randomized, controlled, double-blind trial investigating the effect of discontinuation of long-term PPI therapy on hospitalized patients with complicated liver cirrhosis with a pre-existing long-term PPI therapy. Importantly, patients with an evidence-based indication for PPI therapy are excluded from the trial. All study participants (n=476) stop their previous PPI treatment and are then randomized (1:1) to receive either placebo (intervention group) or esomeprazole 20mg/day (control group) for 360 days.
The primary hypothesis anticipates a delay of re-hospitalisation and/or death (composite endpoint) in patients who discontinue PPI treatment as compared to patients who continue PPI therapy. Secondary objectives include the assessment of mortality, re-hospitalisation rates, infection rates, rate of acute hepatic decompensation and ACLF, as well as rates of upper and lower gastrointestinal bleeding events in both groups. Impact of prolonged or discontinued PPI therapy on the intestinal microbiota and pharmacoeconomics will be studied as a secondary assessment.
- Conditions
- Liver Cirrhosis
- Being tested
- Placebo, Esomeprazole 20mg
- Keywords
- liver cirrhosis, cirrhosis, fibrosis, complications, drugs, safety, side effects, PPI, proton-pump inhibitors, proton pump inhibitors, pantoprazole, esomeprazole, omeprazole, rabeprazole, lansoprazole
- Medical subject headings
- Liver Cirrhosis, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Patients with a pre-existing PPI therapy discontinue PPI therapy and replace it with placebo over a period of 346 days after a 14 day dose tapering phase.
Esomeprazole 20mgDrug
Also called Proton-pump inhibitor, Proton-pump-inhibitor, Proton pump inhibitor, PPI
Patients with a pre-existing PPI therapy stop their prior PPI medication and have it replaced with esomeprazole 20mg/day for 360 days.
| Study group | Role | What they receive |
|---|---|---|
| Intervention group | Placebo comparator | Patients randomized to the intervention group discontinue their pre-existing PPI treatment and replace it with placebo (day 15 to 360). During the first 14 days (dose tapering phase) patients in the intervention group will receive placebo on day 1, 3, 5, 7, 9, 10, 12, 13 and esomeprazole 20mg on day 2, 4, 6, 8, 11, 14, to minimize the risk for gastric acid rebound symptoms. Receives: Drug: Placebo; Drug: Esomeprazole 20mg |
| Control group | Active comparator | Patients randomized to the control group continue their pre-existing PPI therapy with esomeprazole 20mg/day (day 15 to 360). During the first 14 days (dose tapering phase) patients in the control group receive esomeprazole 20mg/day on day 1 to 14. Receives: Drug: Esomeprazole 20mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Timepoint of first unplanned re-hospitalization or death (whichever occurs first)
Measured: Within 12 months (360 days) after randomization
Secondary outcomes (11)
Timepoint of death
Measured: Within 12 months (360 days) after randomization
Mortality rate
Measured: 360 days after randomization
Timepoint of first unplanned re-hospitalization
Measured: Within 12 months (360 days) after randomization
Rate of unplanned re-hospitalizations
Measured: 360 days after randomization
Overall infection rate
Measured: 360 days after randomization
Infection rates differentiated by site
Infection rates by site of infection (SBP, pneumonia, urinary tract infection, blood stream infection, Clostridium difficile-associated enterocolitis, Norovirus-infection, Sars-CoV-2-infection)
Measured: 360 days after randomization
Rate of acute decompensation of liver cirrhosis
Measured: 360 days after randomization
Rate of acute-on-chronic liver failure (ACLF)
Measured: 360 days after randomization
Rate of upper gastrointestinal bleeding events
Measured: 360 days after randomization
Rate of lower gastrointestinal bleeding events
Measured: 360 days after randomization
Changes of intestinal microbiota between baseline and day 90
The gut microbiota composition will be analyzed by PCR
Measured: 90 days after randomization
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2020
- Study start22 Apr 2021
- Primary completionFeb 2028 (estimated)
- Study completionFeb 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Liver CirrhosisStudies of the same condition, open and under way.
- More trials run by Universitätsklinikum Hamburg-EppendorfThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Study participants are randomized 1:1 to either discontinue their previous PPI therapy and replace it with placebo (intervention group) or continue pre-existing PPI therapy with esomeprazole 20mg/day. Details for the dose tapering phase are described below.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 476 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Universitätsklinikum Hamburg-Eppendorf
- Sponsor type
- University, hospital or other
- Collaborators
- German Federal Ministry of Education and Research, University Hospital Heidelberg
- Responsible party
- Sponsor
- Investigators
- Ansgar W Lohse, MD, Study chair, I. Department of Medicine, University Medical Center Hamburg-EppendorfJohannes Kluwe, MD, Principal investigator, I. Department of Medicine, University Medical Center Hamburg-Eppendorf
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04448028
- Sponsor's protocol ID
- STOPPIT-01
- Other IDs
- 01KG2004, 2019-005008-16, DRKS00021290, 2023-509863-26-00, U1111-1246-0705, 2023, 2019
- Acronym
- STOPPIT
- Status last verified
- Apr 2025
- First submitted
- 23 Jun 2020
- Last updated
- 24 Apr 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: The study protocol is published in the journal "Trials" (open access). After the end of the trial and publication of the primary results, study data may be given to other scientists upon request. A written request accompanied by a reasonable description of the respective project must be given to the STOPPIT project team, which will ultimately decide whether the data will be shared or not.
Publications
Wehmeyer MH, Horvatits T, Buchholz A, Krause L, Walter S, Zapf A, Lohse AW, Kluwe J; STOPPIT-trial group. Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial. Trials. 2022 Apr 12;23(1):302. doi: 10.1186/s13063-022-06232-w.
PubMed 35414106
Study at a glance
From the registry record, last updated by the sponsor on 24 Apr 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Stop of Proton-pump Inhibitor Treatment in Patients With Liver Cirrhosis - a Double-blind, Placebo-controlled Trial
- ClinicalTrials.gov ID
- NCT04448028
- Acronym / sponsor ID
- STOPPIT / STOPPIT-01
- Conditions
- Liver Cirrhosis
- Keywords
- liver cirrhosis, cirrhosis, fibrosis, complications, drugs, safety, side effects, PPI
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 476 participants (estimated)
- Lead sponsor
- Universitätsklinikum Hamburg-EppendorfUniversity, hospital or other
- Collaborators
- German Federal Ministry of Education and Research, University Hospital Heidelberg
- Study start
- 22 Apr 2021 (actual)
- Primary completion
- Feb 2028 (estimated)
- Study completion
- Feb 2028 (estimated)
- First posted
- 25 Jun 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Proton-pump inhibitors (PPI) are commonly prescribed in an uncritical manner to patients with liver cirrhosis without a clear evidence-based indication. Observational studies suggests that PPI use in cirrhotic patients may be a risk factor for the development of infections, especially spontaneous bacterial peritonitis (SBP). A possible explanation are PPI-associated microbiotic shifts leading to small intestinal bacterial overgrowth with subsequently increased bacterial translocation. Furthermore, PPI therapy in cirrhotic patients may lead to an increased risk for pneumonia and Clostridium difficile-infections.
However, the evidence is ambiguous, as other published studies found no evidence for an association of PPI use with an increased risk for SBP or pneumonia.
Moreover, an association between episodes of hepatic encephalopathy and PPI use has been reported.
Infections and hepatic encephalopathy may often lead to a hospitalization of cirrhotic patients and PPI use at discharge has also been associated to early re-hospitalization.
While some studies found an association of PPI and increased mortality in cirrhotic patients, other studies could not observe this association.
Thus, some of the current evidence suggests an unfavourable risk profile of PPIs in patients with liver cirrhosis. However, this patient population is considered to be at a high risk of gastrointestinal haemorrhage from peptic ulcers. Importantly, patients with liver cirrhosis have an increased mortality after peptic ulcer bleeding as compared to patients without cirrhosis. Therefore, generous PPI use may also have a yet unproven preventive effect against upper gastrointestinal bleeding.
The STOPPIT trial is the first prospective, randomized, controlled, double-blind trial investigating the effect of discontinuation of long-term PPI therapy on hospitalized patients with complicated liver cirrhosis with a pre-existing long-term PPI therapy. Importantly, patients with an evidence-based indication for PPI therapy are excluded from the trial. All study participants (n=476) stop their previous PPI treatment and are then randomized (1:1) to receive either placebo (intervention group) or esomeprazole 20mg/day (control group) for 360 days.
The primary hypothesis anticipates a delay of re-hospitalisation and/or death (composite endpoint) in patients who discontinue PPI treatment as compared to patients who continue PPI therapy. Secondary objectives include the assessment of mortality, re-hospitalisation rates, infection rates, rate of acute hepatic decompensation and ACLF, as well as rates of upper and lower gastrointestinal bleeding events in both groups. Impact of prolonged or discontinued PPI therapy on the intestinal microbiota and pharmacoeconomics will be studied as a secondary assessment.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Study participants are randomized 1:1 to either discontinue their previous PPI therapy and replace it with placebo (intervention group) or continue pre-existing PPI therapy with esomeprazole 20mg/day. Details for the dose tapering phase are described below.
| Arm | Type | Receives |
|---|---|---|
| Intervention group | Placebo comparator | Drug: Placebo, Drug: Esomeprazole 20mgPatients randomized to the intervention group discontinue their pre-existing PPI treatment and replace it with placebo (day 15 to 360). During the first 14 days (dose tapering phase) patients in the intervention group will receive placebo on day 1, 3, 5, 7, 9, 10, 12, 13 and esomeprazole 20mg on day 2, 4, 6, 8, 11, 14, to minimize the risk for gastric acid rebound symptoms. |
| Control group | Active comparator | Drug: Esomeprazole 20mgPatients randomized to the control group continue their pre-existing PPI therapy with esomeprazole 20mg/day (day 15 to 360). During the first 14 days (dose tapering phase) patients in the control group receive esomeprazole 20mg/day on day 1 to 14. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Patients with liver cirrhosis. The diagnosis of liver cirrhosis may be based on histology or a combination of clinical, laboratory and radiological criteria.
- Hospitalization or recent hospitalization (0 to 42 days prior to the baseline visit) with complications of liver cirrhosis.
- Treatment with proton pump inhibitors (PPI) for at least 28 days prior to the screening visit.
- PPI treatment with a single standard dose/day or less for at least 7 days prior to the screening visit.
- Females/males who agree to comply with the applicable contraceptive requirements of the protocol.
Key exclusion criteria (10 listed)
- Diagnosis of severe reflux esophagitis (LA grade C or D) by EGD < 2 months prior to the screening visit without PPI-therapy for at least 8 weeks prior to the screening visit.
- Peptic ulcers diagnosed by EGD < 28 days prior to the screening visit.
- History of endoscopic therapy for esophageal varices < 14 days prior to the screening visit.
- Life-expectancy < 1 year (at the discretion of the investigator) due to extrahepatic malignancies, metastasized hepatocellular carcinoma (HCC) or other severe extrahepatic diseases. Importantly, HCC without extrahepatic metastases or a reduced life-expectancy of < 1 year due to liver cirrhosis are not regarded as exclusion criteria.
- Regular intake of non-steroidal anti-inflammatory drugs (NSAID) on a daily basis with the exemption of acetylsalicylic acid (ASS) 100mg/day orally.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPatients with a pre-existing PPI therapy discontinue PPI therapy and replace it with placebo over a period of 346 days after a 14 day dose tapering phase. | Drug | Intervention group |
| Esomeprazole 20mgAlso: Proton-pump inhibitor, Proton-pump-inhibitor, Proton pump inhibitor, PPIPatients with a pre-existing PPI therapy stop their prior PPI medication and have it replaced with esomeprazole 20mg/day for 360 days. | Drug | Control group, Intervention group |
Primary outcome
Timepoint of first unplanned re-hospitalization or death (whichever occurs first)
Time frame: Within 12 months (360 days) after randomization
11 secondary outcomes
Timepoint of death
Time frame: Within 12 months (360 days) after randomization
Mortality rate
Time frame: 360 days after randomization
Timepoint of first unplanned re-hospitalization
Time frame: Within 12 months (360 days) after randomization
Rate of unplanned re-hospitalizations
Time frame: 360 days after randomization
Overall infection rate
Time frame: 360 days after randomization
Infection rates differentiated by site
Time frame: 360 days after randomization
Rate of acute decompensation of liver cirrhosis
Time frame: 360 days after randomization
Rate of acute-on-chronic liver failure (ACLF)
Time frame: 360 days after randomization
Rate of upper gastrointestinal bleeding events
Time frame: 360 days after randomization
Rate of lower gastrointestinal bleeding events
Time frame: 360 days after randomization
Changes of intestinal microbiota between baseline and day 90
Time frame: 90 days after randomization
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Apr 2025.
- Background: PubMed 35414106Wehmeyer MH, Horvatits T, Buchholz A, Krause L, Walter S, Zapf A, Lohse AW, Kluwe J; STOPPIT-trial group. Stop of proton-pump inhibitor treatment in patients with liver cirrhosis (STOPPIT): study protocol for a prospective, multicentre, controlled, randomized, double-blind trial. Trials. 2022 Apr 12;23(1):302. doi: 10.1186/s13063-022-06232-w.
- Individual participant dataSharing planned: Yes. The study protocol is published in the journal "Trials" (open access). After the end of the trial and publication of the primary results, study data may be given to other scientists upon request. A written request accompanied by a reasonable description of the respective project must be given to the STOPPIT project team, which will ultimately decide whether the data will be shared or not.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Ansgar W Lohse, MD study chair
I. Department of Medicine, University Medical Center Hamburg-Eppendorf
Johannes Kluwe, MD principal investigator
I. Department of Medicine, University Medical Center Hamburg-Eppendorf
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Esomeprazole 20mg in people with Liver Cirrhosis, run by Universitätsklinikum Hamburg-Eppendorf at 1 site in Germany.
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 9 inclusion and 10 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: looking for participants now, as of the sponsor's last update on 24 Apr 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact STOPPIT Project Team (+494074100, STOPPIT@uke.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Timepoint of first unplanned re-hospitalization or death (whichever occurs first) (time frame: Within 12 months (360 days) after randomization). 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 NCT04448028, which also lists 1 linked publication.
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 24 Apr 2025.