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

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 Overview

• Status: Recruiting
• Conditions: Liver Cirrhosis
• Intervention / Treatment: Drug: Placebo; Drug: Esomeprazole 20mg

• Study Type: Interventional
• Enrollment (Anticipated): 476
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: STOPPIT Project Team; Phone Number: +494074100; Email: STOPPIT@uke.de
• Study Contact Backup: Name: Malte H Wehmeyer, MD; Phone Number: +494074100; Email: m.wehmeyer@uke.de

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Recruiting
    • University Medical Center Hamburg-Eppendorf
    • Contact: Malte H Wehmeyer, MD; Phone Number: +494074100; Email: m.wehmeyer@uke.de
    • Contact: Johannes Kluwe, MD; Phone Number: +4940741059614; Email: j.kluwe@uke.de
    • Principal Investigator: Ansgar W Lohse, MD
    • Sub-Investigator: Johannes Kluwe, MD
    • Sub-Investigator: Malte H Wehmeyer, MD
    • Sub-Investigator: Thomas Horvatits, MD

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Intervention group; 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.	Drug: Placebo; 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.; Drug: Esomeprazole 20mg; 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: PPI; Proton pump inhibitor; Proton-pump inhibitor; Proton-pump-inhibitor
Active Comparator: Control group; 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.	Drug: Esomeprazole 20mg; 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: PPI; Proton pump inhibitor; Proton-pump inhibitor; Proton-pump-inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Timepoint of first unplanned re-hospitalization or death (whichever occurs first)	Within 12 months (360 days) after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Timepoint of death		Within 12 months (360 days) after randomization
Mortality rate		360 days after randomization
Timepoint of first unplanned re-hospitalization		Within 12 months (360 days) after randomization
Rate of unplanned re-hospitalizations		360 days after randomization
Overall infection rate		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)	360 days after randomization
Rate of acute decompensation of liver cirrhosis		360 days after randomization
Rate of acute-on-chronic liver failure (ACLF)		360 days after randomization
Rate of upper gastrointestinal bleeding events		360 days after randomization
Rate of lower gastrointestinal bleeding events		360 days after randomization
Changes of intestinal microbiota between baseline and day 90	The gut microbiota composition will be analyzed by PCR	90 days after randomization

Other Outcome Measures

Outcome Measure	Time Frame
Rate of occurence of the safety endpoint (evidence-based indication for open-label re-therapy with PPIs)	360 days after randomization
Rate of any (serious) adverse events	360 days after randomization

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: German Federal Ministry of Education and Research; University Hospital Heidelberg
• Investigators: Study Chair: Ansgar W Lohse, MD, I. Department of Medicine, University Medical Center Hamburg-Eppendorf; Principal Investigator: Johannes Kluwe, MD, I. Department of Medicine, University Medical Center Hamburg-Eppendorf

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2021
• Primary Completion (Anticipated): March 1, 2025
• Study Completion (Anticipated): March 1, 2025

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 24, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: safety; complications; cirrhosis; PPI; fibrosis; esomeprazole; omeprazole; liver cirrhosis; lansoprazole; side effects; rabeprazole; drugs; pantoprazole; proton pump inhibitors; proton-pump inhibitors
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Esomeprazole; Proton Pump Inhibitors
• Other Study ID Numbers: STOPPIT-01; 2019-005008-16 (EudraCT Number); DRKS00021290 (Registry Identifier: DRKS - German Clinical Trials Register); U1111-1246-0705 (Other Identifier: World Health Organization); 01KG2004 (Other Grant/Funding Number: German Federal Ministry of Education and Research)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

The study protocol will be published in an appropriate scientific journal (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.

IPD Sharing Time Frame

The protocol will be published in an appropriate open access journal after approval of the protocol by the responsible ethic board and competent authority.

Patient data will be made accessible upon reasonable request after the publication of the primary results (anticipated 6 months after the end of the trial). There are no planes for limiting the time the data is available on reasonable request.

• IPD Sharing Access Criteria: Protocol publication will be open access in an appropriate journal. Anonymized individual patient data will be available upon reasonable request. However, for each respective request, the STOPPIT project team will decide whether the data will be shared or not.
• IPD Sharing Supporting Information Type: Study Protocol

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