A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, MULTICENTER STUDY TO ASSESS THE EFFICACY AND SAFETY OF RIFAXIMIN SOLUBLE SOLID DISPERSION (SSD) TABLETS FOR THE DELAY OF ENCEPHALOPATHY DECOMPENSATION IN CIRRHOSIS (RED-C)

The primary objective of this study is to evaluate the **efficacy** of rifaximin SSD-40IR compared to placebo in delaying the occurrence of hospitalization related to hepatic encephalopathy (HE) in patients with cirrhosis. This is clinically relevant as it aims to reduce the frequency of hospital admissions, which can significantly impact patient outcomes and healthcare resources.

Secondary objectives include:

• Assessing the effects of treatment with rifaximin SSD-40IR on hospitalization rates, which could provide insights into the broader impact of the treatment on patient health and healthcare utilization.
• Evaluating the safety of rifaximin SSD-40IR following a treatment regimen of 72 weeks, ensuring that the long-term use of the medication is safe for patients.

The clinical trial involves a total of **267 participants** diagnosed with **Hepatic Encephalopathy (OHE)**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including a diagnosis of liver cirrhosis with medically controlled ascites for more than 30 days, a Conn score of less than 2, and a Mini-Mental State Examination score greater than 24 at screening. The trial population is not limited by gender, and both males and females are included. Participants are required to have the ability to independently read, understand, and provide written informed consent. Additionally, females of childbearing potential must have a negative pregnancy test at screening and all participants must agree to use highly effective contraception methods during the study. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, ensuring that ethical considerations are addressed throughout the trial process.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **rifaximin** soluble solid dispersion tablets in delaying encephalopathy decompensation in patients with cirrhosis. The trial will involve participants diagnosed with **hepatic encephalopathy** and will compare the active treatment against a placebo. The study is expected to run until June 2026, with recruitment having commenced in August 2023. Participants will be involved in the study for a maximum treatment period of 72 weeks, during which they will receive either the active drug or placebo orally.

The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor the participants' health and response to treatment, and a final end-of-study visit. The screening visit will ensure that participants meet all inclusion criteria, such as having a diagnosis of liver cirrhosis with controlled ascites and a Conn score of less than 2. Follow-up visits will assess the primary endpoint, which is the time to the first event of overt hepatic encephalopathy requiring hospitalization. Secondary endpoints include the time to a Conn score of 2 or higher, time to all-cause hospitalization, and time to the first event of overt hepatic encephalopathy requiring hospitalization or all-cause death.

Participants are expected to remain in the study for the full duration unless they experience adverse events that necessitate withdrawal, fail to adhere to the study protocol, or choose to withdraw consent. The study will be conducted in accordance with ethical guidelines, and all participants will provide informed consent prior to enrollment. The trial's design ensures that the data collected will be robust and reliable, contributing valuable insights into the management of hepatic encephalopathy in cirrhosis.

The clinical trial involves the administration of **Rifaximin 40 mg Soluble Solid Dispersion Immediate Release Tablets (SSD-40IR)**, an experimental medication developed by Salix Pharmaceuticals Inc. This pharmaceutical product is formulated as a **tablet** and is intended for **oral** administration. The active substance, **rifaximin**, is of chemical origin. The maximum daily dose is 80 mg, with a total maximum dose of 40,320 mg over a treatment period of up to 72 days. The primary objective of this study is to evaluate the efficacy of rifaximin SSD-40IR in delaying the occurrence of hepatic encephalopathy-related hospitalization in patients with cirrhosis. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes a **placebo** as a non-experimental treatment to serve as a comparator. The placebo is designed to match the experimental medication in appearance but does not contain any active pharmaceutical ingredients. It is administered in the same manner as the rifaximin tablets, ensuring the study remains double-blind. The use of a placebo allows for the assessment of the true efficacy and safety profile of the rifaximin SSD-40IR tablets by providing a baseline for comparison. Compliance with the placebo administration will be monitored similarly to the experimental treatment.

The efficacy of Rifaximin 40 mg Soluble Solid Dispersion Immediate Release Tablets (SSD-40IR) in delaying the occurrence of hepatic encephalopathy (HE) decompensation in patients with cirrhosis will be assessed in a randomized, double-blind, placebo-controlled, multicenter study. The primary endpoint for evaluating efficacy is the time to the first event of overt hepatic encephalopathy (OHE) requiring hospitalization. This diagnosis will be confirmed by a trained medical professional using the American Association for the Study of Liver Disease Guidelines and further evaluated by the Clinical Event Adjudication Committee (CEAC) to ensure it meets the endpoint definitions.

Secondary endpoints include the time to the first Conn score of ≥ 2, time to all-cause hospitalization, and time to the first event of OHE requiring hospitalization or all-cause death. These parameters will be measured and collected throughout the study duration, with specific timepoints not explicitly detailed. The study aims to provide a comprehensive assessment of the efficacy of Rifaximin SSD-40IR in the target population, with the trial estimated to conclude by June 2026.