Abstract
BACKGROUND: Pakistan has a high prevalence of HCV and HBV, causing cirrhosis, leading to hepatic encephalopathy in approximately 30-45% of cirrhotic patients. Overt hepatic encephalopathy (OHE) is a serious type of hepatic encephalopathy that refers to brain dysfunction resulting from acute or chronic liver disease. Patients present flapping tremors and mental alterations leading to a coma, which disrupts daily activities and patient health-related quality of life. OHE can be treated by lactulose, rifaximin, probiotics, and L-ornithine L-aspartate (LOLA). Lactulose (controlled drug for trial) is the main treatment for OHE, even though its effectiveness in clinical trials has remained varied. Rifaximin (interventional drug), probiotics (interventional drug), and LOLA (interventional drug) all showed a significant effect in reducing the grade of hepatic encephalopathy, lowering blood ammonia levels, and enhancing psychomotor function in OHE patients. Our trial aims to determine the most effective treatment combination, as despite the availability of multiple treatment options, the efficacy is still uncertain. Limited studies have compared individual treatments, but no research has been conducted to assess all four treatment groups together, i.e., Group A (lactulose) as the control group, Group B (rifaximin + lactulose), Group C (probiotics + lactulose), and Group D (LOLA + lactulose). METHODS: This trial is a single-center, parallel, multi-arm, randomized, unblinded, lactulose-controlled clinical trial. A total of 252 patients (both male and female aged 18-80 years), 63 in each treatment group, will be recruited in the study from the time of participation in the trial until the end of treatment (days 1-5). Primary outcome is to assess grade reversal of OHE on day 5 of trial participation. The secondary outcome is to determine the length of hospital stay and recovery time (days), monitoring of adverse drug reactions and death by cause in OHE patients. DISCUSSION: This randomized controlled trial protocol will compare the efficacy of four proposed groups of medications to fill the gap in current knowledge. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2300075925, registered on 19 September 2023; ClinicalTrials.gov NCT07037394, registered on 24 June 2025. Released to the public on 26 June 2025.