The Efficacy and Safety of Alverine in the Treatment of Portal Hypertension in Patients With Liver Cirrhosis
NCT Number: NCT06470386
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2|PHASE3
Conditions: Hypertension, Portal
Interventions: DRUG: Alverine|DRUG: Carvedilol
Sponsor: Shanghai Changzheng Hospital
Collaborators: Shandong Provincial Hospital|Shanghai East Hospital|Shanghai Zhongshan Hospital|Affiliated Drum Tower Hospital of Nanjing University Medical School|The First Affiliated Hospital of Nanchang University|Shanghai Public Health Clinical Center|Daping Hospital, Army Medical Center of PLA
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 178
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: NONE|Primary Purpose: TREATMENT
Start Date: 2024-06
Completion Date: 2025-11

Summary:
Study Overall Design:

This trial is a prospective, open-label, multicenter, randomized controlled clinical trial. Subjects who meet the inclusion criteria and do not meet the exclusion criteria will be randomly assigned to either the Alverine treatment group or the Carvedilol treatment group in a 1:1 ratio after signing the informed consent form. After randomization, participants will enter a 24-week medication period. Apart from the baseline period, the efficacy of the treatment will be evaluated 24 weeks post-treatment. The safety evaluation will be conducted according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 by the National Cancer Institute.

Study Population:

Patients with cirrhotic portal hypertension.

Interventions:

Alverine Group: Compound Alverine Citrate Capsules (Lejiansu; each capsule contains 60 mg of Alverine Citrate and 300 mg of Simethicone; manufactured by the French company UCB Pharma), 180 mg/day (1 capsule orally, 3 times a day), taken continuously for 24 weeks.

Carvedilol Group: Jinluo (Carvedilol Tablets; 6.25 mg; manufactured by Qilu Pharmaceutical Co., Ltd.), taken orally, starting dose of 6.25 mg once a day, gradually adjusted according to heart rate to 6.25 mg twice a day, 12.5 mg in the morning and 6.25 mg in the evening, 12.5 mg twice a day, or adjusted to the maximum tolerated dose (heart rate greater than 55 beats/min and systolic blood pressure greater than 90 mmHg), taken continuously for 24 weeks.

Study Objectives:

1. Primary Study Objective Evaluate the efficacy and safety of Compound Alverine Citrate Capsules in the treatment of cirrhotic portal hypertension.
2. Secondary Study Objectives Evaluate the effect of Compound Alverine Citrate Capsules on the incidence of esophagogastric variceal bleeding and other cirrhotic decompensation events.
3. Exploratory Study Objectives Evaluate the efficacy of Compound Alverine Citrate Capsules in the treatment of cirrhotic portal hypertension using other non-invasive detection methods. Observe the effects of Compound Alverine Citrate Capsules on the multi-omics characteristics of cirrhosis, reversal of portal hypertension, recompensation of decompensated cirrhosis, and prevention of the progression of cirrhosis to liver cancer.

Study Endpoints:

(1) Primary Study Endpoints

1. The treatment response rate, defined as a reduction in HVPG of ≥10% from baseline or a reduction to below 12 mmHg after 24 weeks of treatment.
2. The incidence, events, and severity of adverse events, serious adverse events, and adverse events leading to treatment discontinuation after treatment (evaluated according to CTCAE version 5.0).

(2) Secondary Study Endpoints

1. Incidence of esophagogastric variceal bleeding during treatment.
2. Incidence of other cirrhotic decompensation events (new onset or progression of ascites, spontaneous bacterial peritonitis, overt hepatic encephalopathy, acute kidney injury/hepatorenal syndrome, primary liver cancer, etc.) during treatment.
3. Reduction in HVPG from baseline after 24 weeks of treatment.
4. Mortality/liver transplantation rate during treatment.
5. Overall survival time of subjects.
6. Reduction in mean arterial pressure (MAP) and heart rate from baseline after 24 weeks of treatment.

(3) Exploratory Study Endpoints

1. Changes in liver stiffness and spleen stiffness from baseline after 24 weeks of treatment.
2. Improvement in liver function (Child-Pugh score, MELD score) after 24 weeks of treatment.
3. Changes in cardiac function (left ventricular ejection fraction) from baseline after 24 weeks of treatment.
4. Changes in imaging characteristics, blood/stool metabolomics characteristics, portal hypertension reversal biomarkers, cirrhosis recompensation biomarkers, and cirrhosis progression to liver cancer biomarkers after 24 weeks of treatment.

Sample Size Calculation:

In animal experiments, it was confirmed that there was no statistically significant difference in the effect of Alverine and Carvedilol in treating portal hypertension. Literature reports indicate that the treatment response rate of Carvedilol for cirrhotic portal hypertension is approximately 60%. Based on the sample size calculation method for non-inferiority trials with two samples, with a non-inferiority margin δ=0.20, a one-sided α=0.025, and β=0.2, the calculated sample size for each group is 74 cases, totaling 148 cases. Considering a 20% dropout rate, a total of 178 cases are needed.

Primary Outcome Measures: The response rate., The response rate to treatment, defined as the percentage of patients with a decrease in HVPG of ≥10% from baseline or a decrease to below 12 mmHg after 24 weeks of treatment., 24 weeks|Safety assessment., The incidence of adverse events, serious adverse events, and adverse events leading to treatment discontinuation after treatment The incidence of adverse events, serious adverse events, and adverse events leading to treatment discontinuation after treatment., 24 weeks
Secondary Outcome Measures: Incidence of esophageal and gastric variceal bleeding during treatment., 24 weeks|Incidence of other cirrhosis decompensation events during treatment., other cirrhosis decompensation events: new-onset ascites/progression of ascites, spontaneous bacterial peritonitis, overt hepatic encephalopathy, acute kidney injury/hepatorenal syndrome, primary liver cancer, etc., 24 weeks|Degree of decrease in HVPG compared to baseline HVPG after 24 weeks of treatment., 24 weeks|Mortality/liver transplantation rate during treatment., 24 weeks|Overall survival time of the subjects., 24 weeks|Degree of decrease in mean arterial pressure (MAP) compared to baseline values after treatment., 24 weeks|Degree of decrease in heart rate compared to baseline values after treatment., 24 weeks
Other Outcome Measures: Changes in liver stiffness and spleen stiffness compared to baseline levels after 24 weeks of treatment. Changes in liver stiffness and spleen stiffness compared to baseline levels after 24 weeks of treatment., 24 weeks|Improvement in liver function (Child-Pugh score) after 24 weeks of treatment., 24 weeks|Improvement in liver function (MELD score) after 24 weeks of treatment., 24 weeks|Changes in cardiac function (left ventricular ejection fraction) compared to baseline values after 24 weeks of treatment. Changes in cardiac function (left ventricular ejection fraction) compared to baseline values after 24 weeks of treatment., 24 weeks