Discontinuation of Esomeprazole Magnesium Trihydrate in Patients with Liver Cirrhosis: A Double-Blind, Placebo-Controlled Clinical Trial

The primary objective of this study is to determine the **time to first unplanned re-hospitalization or death** (composite endpoint) in patients with **liver cirrhosis** who discontinue long-term proton-pump inhibitor (PPI) therapy compared to those who continue PPI therapy over a period of 12 months. This is clinically relevant as it evaluates the potential impact of PPI discontinuation on patient outcomes, which could influence treatment guidelines for individuals with liver cirrhosis.

Secondary objectives include:

• Comparing and assessing endpoints such as time to death, mortality (overall and liver-related), time to and rate of unplanned re-hospitalizations, overall infection rates, and infection rates by site, including spontaneous bacterial peritonitis, pneumonia, urinary tract infections, bloodstream infections, Clostridium difficile-associated enterocolitis, Norovirus infections, and Sars-CoV-2 infections. Additionally, the rate of acute decompensation of cirrhosis, acute-on-chronic liver failure, and sources of gastrointestinal bleeding events will be evaluated.
• Assessing changes in the intestinal microbiota in both groups and evaluating its effect on the primary endpoint.
• Assessing the potential pharmacoeconomic and socioeconomic impact of PPI discontinuation.

The clinical trial involves participants diagnosed with **liver cirrhosis**, a condition confirmed either histologically or through a combination of clinical, laboratory, and radiological signs. The study population includes both male and female adults aged 18 years and older. Participants are required to have been hospitalized or recently hospitalized within 42 days prior to the baseline with complicated liver cirrhosis and must have been on proton-pump inhibitor (PPI) treatment for at least 28 days before screening. The trial includes individuals who have been on a single standard dose of PPI per day or less for a minimum of 7 days prior to screening. Both genders are represented, and the study includes a vulnerable population. Participants must be non-pregnant, non-lactating females or males and must agree to comply with contraceptive requirements as per the protocol. They should be able to understand the patient information and provide written informed consent. The sponsor has not provided the total number of participants involved in the trial.

The clinical trial is designed to evaluate the effects of discontinuing long-term **proton-pump inhibitor** (PPI) therapy in patients with **liver cirrhosis**. This is a randomized, double-blind, placebo-controlled trial with a duration of 12 months (360 days). Participants will be randomly assigned to either the intervention group, which will discontinue PPI therapy, or the control group, which will continue PPI therapy. The primary endpoint is the time to first unplanned re-hospitalization or death within 12 months after randomization. Secondary endpoints include all-cause and liver-related death, unplanned re-hospitalization, infection rates, acute hepatic decompensation, and changes in intestinal microbiota.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, diagnosis of liver cirrhosis, and prior PPI treatment. Participants must provide written informed consent and demonstrate the ability to comply with study requirements. Follow-up visits will occur at regular intervals to assess health status, adherence to the protocol, and any adverse events. The end-of-study visit will evaluate the final outcomes and collect data on the primary and secondary endpoints.

Participant involvement is expected to last for the entire 12-month period unless early termination is warranted. Conditions for early termination include withdrawal of consent, non-compliance with study procedures, or any adverse event that poses a risk to the participant's health. The trial is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **Nexium mups 20 mg** gastro-resistant tablets, which contain the active substance **esomeprazole magnesium trihydrate**. This medication is provided in a pharmaceutical form designed to resist gastric acid, ensuring the active ingredient is released in the intestine. The maximum daily dose is 20 mg, with a total maximum dose of 7200 mg over the treatment period. The tablets are administered orally. For the trial, the tablets are removed from their original blister packaging, over-encapsulated with a filler medium (Mannitol/Aerosil), and placed into a blinded, labeled blister or bottle. This process ensures stability and maintains the blind nature of the study. The treatment period for this medication is up to 360 days.

The study also includes a **placebo** control, provided as **P-Tabletten weiß 7 mm Lichtenstein**. These tablets are chemically inert and serve as a comparator to the active treatment. The placebo is also administered orally and is designed to match the active treatment in appearance to maintain blinding. The placebo tablets have no active pharmacological effect and are used to assess the efficacy of the active treatment by comparison. The maximum treatment period for the placebo is also 360 days, aligning with the active treatment schedule.

Efficacy in the clinical trial titled "Stop of proton-pump inhibitor treatment in patients with liver cirrhosis – a double-blind, placebo-controlled trial (STOPPIT)" will be assessed using a composite primary endpoint. This endpoint is defined as the time to first unplanned re-hospitalization or death within 12 months after randomization. The trial aims to compare patients with liver cirrhosis who discontinue long-term proton-pump inhibitor (PPI) therapy (intervention group) to those who continue PPI therapy (control group).

Secondary endpoints include all-cause and liver-related death, unplanned re-hospitalization, any infection differentiated by site (such as spontaneous bacterial peritonitis, pneumonia, urinary tract infection, bloodstream infection, Clostridium difficile-associated enterocolitis, Norovirus infection, and Sars-CoV-2 infection), acute hepatic decompensation and acute-on-chronic liver failure (ACLF), and upper and lower gastrointestinal bleeding events. Additionally, an experimental endpoint will assess changes in intestinal microbiota between baseline and day 90.