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NCT Number: NCT04448028

Stop of Proton-pump Inhibitor Treatment in Patients With Liver Cirrhosis - a Double-blind, Placebo-controlled Trial

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.

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Key information

Conditions

Liver Cirrhosis Digestive System Diseases Fibrosis Liver Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

University Medical Center Hamburg-Eppendorf

Hamburg, Free and Hanseatic City of Hamburg, 20246, Germany

Location status: Recruiting

Location contact

Ansgar W Lohse, MD

PRINCIPAL_INVESTIGATOR

Johannes Kluwe, MD

CONTACT

[email protected]

+4940741059614

Johannes Kluwe, MD

SUB_INVESTIGATOR

Malte H Wehmeyer, MD

CONTACT

[email protected]

+494074100

Malte H Wehmeyer, MD

SUB_INVESTIGATOR

Thomas Horvatits, MD

SUB_INVESTIGATOR

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.
  • 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.

Exclusion criteria

  • 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.
  • 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.

Treatment and study plan

Placebo

Drug

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 20mg

Drug

Patients with a pre-existing PPI therapy stop their prior PPI medication and have it replaced with esomeprazole 20mg/day for 360 days.

Other names: Proton-pump inhibitor, Proton-pump-inhibitor, Proton pump inhibitor, PPI

Primary outcomes

  1. Timepoint of first unplanned re-hospitalization or death (whichever occurs first)

    Time frame: Within 12 months (360 days) after randomization

Secondary outcomes

  1. Timepoint of death

    Time frame: Within 12 months (360 days) after randomization

  2. Mortality rate

    Time frame: 360 days after randomization

  3. Timepoint of first unplanned re-hospitalization

    Time frame: Within 12 months (360 days) after randomization

  4. Rate of unplanned re-hospitalizations

    Time frame: 360 days after randomization

  5. Overall infection rate

    Time frame: 360 days after randomization

  6. Infection rates differentiated by site

    Time frame: 360 days after randomization

    Infection rates by site of infection (SBP, pneumonia, urinary tract infection, blood stream infection, Clostridium difficile-associated enterocolitis, Norovirus-infection, Sars-CoV-2-infection)

  7. Rate of acute decompensation of liver cirrhosis

    Time frame: 360 days after randomization

  8. Rate of acute-on-chronic liver failure (ACLF)

    Time frame: 360 days after randomization

  9. Rate of upper gastrointestinal bleeding events

    Time frame: 360 days after randomization

  10. Rate of lower gastrointestinal bleeding events

    Time frame: 360 days after randomization

  11. Changes of intestinal microbiota between baseline and day 90

    Time frame: 90 days after randomization

    The gut microbiota composition will be analyzed by PCR

Other outcomes

  1. Rate of occurence of the safety endpoint (evidence-based indication for open-label re-therapy with PPIs)

    Time frame: 360 days after randomization

  2. Rate of any (serious) adverse events

    Time frame: 360 days after randomization

Study contacts

Contact information is provided by the study sponsor or research team.

Malte H Wehmeyer, MD

CONTACT

[email protected]

+494074100

STOPPIT Project Team

CONTACT

[email protected]

+494074100

Sponsors and collaborators

Lead sponsor

Universitätsklinikum Hamburg-Eppendorf

Other

Collaborators

  • German Federal Ministry of Education and Research
  • University Hospital Heidelberg

Registry information

Acronym: STOPPIT

Important dates

Study start
2021
Primary completion
2028
Study completion
2028
First posted
Jun 25, 2020
Registry last updated
Apr 24, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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