Clinical trial NCT06473493: The Safety and Efficacy of Alverine in the Treatment of Cirrhotic Portal Hypertension
Official title: The Safety and Efficacy of Compound Alverine Citrate Soft Capsules in the Treatment of Portal Hypertension in Patients With Liver Cirrhosis: a Multicentre, Single-arm, Exploratory Trial s: a Multicentre, Single-arm, Exploratory Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Hypertension, Portal
Keywords: Portal hypertension
Alverine
Pharmacological therapy
Lead sponsor: Shanghai Changzheng Hospital
Sponsor class: OTHER
Collaborators: name: Shanghai East Hospital
name: Daping Hospital, Army Medical Center of PLA
First posted: 2024-06-25
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Study Overall Design: This trial is a prospective, multi-center, single-arm, exploratory clinical study. Subjects who meet the inclusion criteria and do not meet the exclusion criteria will receive Compound Alverine Citrate Capsules (Lejiansu; specification: each capsule contains 60 mg of Alverine Citrate and 300 mg of Simethicone; produced by Laboratoires Mayoly Spindler, France) after signing the informed consent form. The dosage is 180 mg/day (1 capsule orally three times a day) for a treatment period of 24 weeks. Apart from the baseline period, efficacy will be evaluated at the end of the 24-week treatment period. Safety assessments will be conducted throughout the trial. The safety evaluation will be performed 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

Intervention: 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.

Study Objectives: To evaluate the safety and efficacy of Compound Alverine Citrate Capsules in treating portal hypertension in patients with cirrhosis.

Study Endpoints Primary Endpoints

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

Secondary Endpoints

1. HVPG Changes: The absolute value and percentage change in HVPG from baseline after 24 weeks of treatment.
2. Decompensation Events: Incidence of cirrhosis decompensation events during treatment, including esophageal/gastric variceal bleeding and re-bleeding, new or worsening ascites, spontaneous bacterial peritonitis, overt hepatic encephalopathy, and acute kidney injury/hepatorenal syndrome.
3. 12-Week Response Rate: The treatment response rate at 12 weeks.
4. Mortality and Transplantation: Rates of death, liver transplantation, and liver disease-related mortality during the treatment period.

Exploratory Endpoints

1. Cardiac Function: Changes in cardiac function from baseline after 24 weeks of treatment.
2. Liver and Spleen Stiffness: Changes in liver and spleen stiffness from baseline after 24 weeks of treatment.
3. Esophageal Varices: Status of esophageal varices after 24 weeks of treatment.

Sample Size Calculation: This trial is a single-arm, exploratory clinical study, and plans to enroll 30 subjects.


Eligibility criteria: Inclusion Criteria:

* Age between 18 and 80 years (inclusive), regardless of gender.
* Patients diagnosed with cirrhosis through clinical evaluation, laboratory tests, imaging studies, and/or liver biopsy.
* Hepatic venous pressure gradient (HVPG) ≥ 12 mmHg.
* Willingness to participate and sign the informed consent form.

Exclusion Criteria:

* Use of non-selective β-blockers (e.g., carvedilol, propranolol) or alverine, papaverine, and its derivatives (e.g., papaverine hydrochloride, drotaverine hydrochloride) within 4 weeks prior to enrollment.
* Previous transjugular intrahepatic portosystemic shunt (TIPS) or other interventional treatments affecting portal pressure (including splenic embolization, microwave treatment of the spleen).
* Previous liver transplantation.
* Occurrence of overt hepatic encephalopathy or esophageal/gastric variceal bleeding within 2 weeks prior to enrollment; endoscopic treatment of esophageal/gastric varices within 1 week prior to enrollment or planned endoscopic treatment.
* Use of somatostatin and its analogs, vasopressin, terlipressin, dopamine, norepinephrine, and other vasoactive drugs within 1 week prior to enrollment.
* History of alcoholism within 12 weeks prior to enrollment and inability to stop drinking during the study (equivalent ethanol intake ≥ 30 g/day for males, ≥ 20 g/day for females).
* Serum total bilirubin level ≥ 3×ULN (for autoimmune liver disease patients, ≥ 5×ULN), serum sodium level \< 125 mmol/L, white blood cell count \< 1×10\^9/L, platelet count \< 50×10\^9/L, INR \> 1.8, or serum creatinine ≥ 1.2×ULN.
* Presence of thrombosis in the portal venous system (including the portal vein, splenic vein, superior mesenteric vein, etc.) or cavernous transformation of the portal vein; previous portal venous system thrombosis if no definite thrombosis detected in the portal venous system within 2 weeks.
* HBV DNA or HCV RNA above the lower limit of detection; patients undergoing active antiviral treatment for hepatitis C; antiviral treatment for hepatitis B \< 24 weeks.
* Uncontrollable active infections (e.g., pulmonary infection, abdominal infection, HIV) within 2 weeks prior to enrollment.
* Uncontrolled hypertension, diabetes, or other severe heart/lung diseases.
* Diagnosis or suspicion of malignant tumors, including liver cancer.
* Known allergy to alverine or papaverine and its derivatives (e.g., papaverine hydrochloride, drotaverine hydrochloride) or simethicone.
* Presence of psychiatric symptoms.
* Pregnant or breastfeeding women, or women who may be pregnant.
* Participation in other drug trials within 4 weeks prior to enrollment.
* Any other reasons deemed by the researchers as unsuitable for participation.

Primary outcomes:
measure: Safety assessment: the incidence of adverse events, serious adverse events, and adverse events leading to treatment discontinuation after treatment.
timeFrame: 24 weeks
measure: 24-week response rate
timeFrame: 24 weeks
Secondary outcomes:
measure: HVPG changes: the absolute value change in HVPG from baseline after 24 weeks of treatment
timeFrame: 24 weeks
measure: HVPG changes: the percentage change in HVPG from baseline after 24 weeks of treatment
timeFrame: 24 weeks
measure: The incidence of decompensation events
timeFrame: 24 weeks
measure: 12-week response rate
timeFrame: 12 weeks
measure: Mortality rate
timeFrame: 24 weeks
measure: Transplantation rate
timeFrame: 24 weeks
Other outcomes:
measure: Cardiac function changes
timeFrame: 24 weeks
measure: Liver stiffness changes
timeFrame: 24 weeks
measure: Spleen stiffness changes
timeFrame: 24 weeks
measure: Esophageal varices changes
timeFrame: 24 weeks
Locations:
Study officials:
affiliation: Shanghai Changzheng Hospital
name: Wei-Fen Xie, M.D.
role: PRINCIPAL_INVESTIGATOR
References: