Liver cirrhosis MedDRA version: 20.0 Level: PT Classification code 10019641 Term: Hepatic cirrhosis System Organ Class: 10019805 - Hepatobiliary disorders MedDRA version: 20.0 Level: LLT Classification code 10024667 Term: Liver cirrhosis System Organ Class: 10019805 - Hepatobiliary disorders MedDRA version: 20.0 Level: PT Classification code 10003445 Term: Ascites System Organ Class: 10017947 - Gastrointestinal disorders MedDRA version: 20.1 Level: LLT Classification code 10051156 Term: Asci
Conditions
Interventions
Trade Name: Nexium mups
Pharmaceutical Form: Capsule
INN or Proposed INN: ESOMEPRAZOLE
CAS Number: 119141-88-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 20-
P
Sponsors
University Medical Center Hamburg-Eppendorf
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female adult (=18 years) patient. 2. Liver cirrhosis (diagnosed either histologically or by a combination of clinical, laboratory and/or radiological signs). 3. Hospitalized or recently hospitalized (up to 42 days before baseline) with complicated liver cirrhosis. 4. PPI treatment for at least 28 days prior to the screening visit. 5. PPI treatment with a single standard dose/day or less for a minimum of 7 days prior to the screening visit. Standard doses of the different PPIs are defined in the protocol. 6. Females/Males who agree to comply with the applicable contraceptive requirements, which are specified in the protocol. 7. Non-pregnant, non-lactating females. 8. 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. 9. The patient is co-operative and available for the entire study. 10. The patient provided written informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 376 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 100
Exclusion criteria
Exclusion criteria: The exclusion criteria of the trial are as follows: 1. Severe esophageal reflux disease (LA grade C or D) diagnosed by esophago-gastro-duodenoscopy (EGD) < 2 months prior to screening without PPI treatment for at least 8 weeks prior to screening. Details on the LA classification-system are provided in the protocol. 2. Peptic ulcers diagnosed by EGD < 28 days prior to screening. 3. Endoscopic therapy for varices < 14 days prior to screening. 4. 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 < 1 year due to liver cirrhosis are not regarded as exclusion criteria. 5. Regular intake of non-steroidal anti-inflammatory drugs (NSAID) on a daily basis with the exemption of acetylsalicylic acid in a dosage of up to 100mg/day. 6. Hypersensitivity or intolerance to esomeprazole, substituted benzimidazoles or other exipients of the IMP (Nexium mups or placebo). 7. Ongoing therapy with nelfinavir. 8. Participating in a clinical trial or use of an investigantional medical product (IMP) within 30 days or five times the half-life of the IMP (whichever is longer) prior to receive the first dose within this study. 9. Positive urine pregnancy test at screening or positive serum pregnancy test before the first treatment or is breast feeding. 10. Patient is not willing to use adequate contraceptive precautions during the study or for up to 5 days after the last scheduled dose of IMP.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the trial is the determination of the time to unplanned re-hospitalization and/or death (composite endpoint) in patients with liver cirrhosis who discontinue long-term proton-pump inhibitor (PPI) therapy (intervention group) as compared to patients who continue PPI therapy (control group) over a period of 12 months (360 days). The PPI in patients of the intervention group is replaced with placebo (taken orally once a day), the PPI in patients of the control group is replaced with esomeprazol 20mg (taken orally once a day).;Secondary Objective: Secondary objectives include a comparison and an assessement of the following events in the two groups (and in subgroups): - Time to death and mortality (overall- and liver related). - Time to and rate of unplanned re-hospitalizations. - Overall infection rates and infection rates differentiated by site of infection (spontaneous bacterial peritonitis, pneumonia, urinary tract infections, blood stream infections, Clostridium difficile-associated enterocolitis, Norovirus infections, Sars-CoV-2 infections). - Rate of acute decompensation of cirrhosis and acute-on-chronic liver failure (ACLF). - Rate and sources of upper and lower gastrointestinal bleeding events. The changes in the intestinal microbiota in both groups and its effect on the primary endpoint will be evaluated. The impact of serum biomarkers on the primary and secondary endpoints will be studied as an exploratory endpoint. Pharmacoeconomic and socioeconomic impact of PPI discontinuation will be assessed.;Timepoint(s) of evaluation of this end point: The evaluation of the primary endpoint for the individual patient will take place as soon as the investigator becomes aware of the event which qualifies as an endpoint criterion (unplanned re-hospitalization or death), since these criteria are also considered a serious adverse event (SAE). The primary endpoint will be analyzed by Cox regression analysis after 184 primary endpoint | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary endpoints of the trial are as follows: 1. Death 2. Unplanned re-hospitalization 3. Any infection and differentiated by site of infection (SBP, pneumonia, urinary tract infection, blood stream infection, Clostridium difficile-associated enterocolitis, Norovirus infection, Sars-CoV-2 infection) 4. Acute hepatic decompensation or acute- on-chronic liver failure (ACLF) 5. Upper or lower gastrointestinal bleeding event Primary and secondary endpoints will be assessed in the following subgroups by a post-hoc analysis: 1. Patients with Child A cirrhosis, Child B cirrhosis and C cirrhosis, respectively, 2. Patients according to their respective etiology of cirrhosis (e.g. alcohol misuse, viral hepatitis B or C, non-alcoholic steatoshepatitis [NASH], or other), 3. Patients with an untreated etiology of cirrhosis (e.g. untreated viral hepatitis or persisting alcohol misuse) compared to patients with a treated etiology of cirrhosis (e.g. sustained virological response after therapy for viral hepatitis or ceased alcohol misuse), 4. Patients with a history of TIPS implantation compared to patients without TIPS. Further experimental endpoints of the trial are: 1. Changes of the intestinal microbiota between baseline and day 90. 2. The impact of different serum biomarkers collected at baseline on the primary and secondary endpoints. The safety endpoints of the trial are as follows: 1. Occurence of any adverse events (AE) during the intervention. 2. Occurence of serious adverse events (SAE) during the intervention. 3. Evidence-based indication for open-label re-therapy with PPIs. Evidence-based indications for PPI-therapy are the following: (a) Peptic ulcer (diagnosed by EGD) (b) Reflux esophagitis LA grade C or D (diagnosed by EGD) (c) Severe hemorrhagic gastritis (diagnosed by EGD and histology) (d) Mallory-Weiss syndrome (diagnosed by EGD);Timepoint(s) of evaluation of this end point: The evaluation of the secondary endpoints takes place | — |
Countries
Germany
Contacts
Public ContactI. Department of Medicine
University Medical Center Hamburg-Eppendorf
Outcome results
None listed