Randomized Controlled Trial to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension

NCT ID: NCT01456286

Last Updated: 2013-10-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-10-31
• Study Completion Date: 2013-10-31

Brief Summary

The purpose of this study is to determine whether sapropterin (an oral analogue of tetrahydrobiopterin) could have a role in the treatment of portal hypertension secondary to liver cirrhosis. Sapropterin or placebo will be given for two weeks in patients with liver cirrhosis and clinically significant portal hypertension. Systemic and hepatic hemodynamics studies will be performed at baseline and after the intervention to assess the effect of sapropterin.

Detailed Description

Portal hypertension and its complications (variceal bleeding, encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome) are the main cause of death and liver transplantation in patients with cirrhosis. Diminishing portal hypertension by drugs (beta-blockers) is associated with a protection in the development of complications from portal hypertension. For this reason it is important to investigate and develop drugs that can reduce the portal pressure in liver cirrhosis. Tetrahydrobiopterin has been shown to decrease portal pressure in animal models of cirrhosis by improving intrahepatic resistance and by increasing nitric oxide bioavailability (eNOS co-factor). These effects were not associated to deleterious effects on systemic hemodynamics.

This study aims to test if sapropterin (an oral analogue of tetrahydrobiopterin) can play a role in the management of portal hypertension. For this, patients with liver cirrhosis and clinically significant portal hypertension will be randomized to receive sapropterin or placebo for two weeks. Patients will undergo an hepatic vein catheterization to asses the hepatic venous pressure gradient (HVPG), and those having and HVPG of 10 mmHg or higher will be randomized to receive sapropterin or placebo. Swan-Ganz catheterization, systemic measurements, and hepatic blood flow by indocyanine green method will also be performed. Patients will receive sapropterin or placebo for two weeks at a dosage of 5 mg/kg/d in the first week, increasing to 10 mg/kg/d in the second week if there are no adverse events or intolerance. A second systemic and hepatic hemodynamic study will be performed after 2 weeks of treatment to assess changes.

Changes in laboratory tests, liver function (Child-Pugh and MELD scores), endothelial dysfunction and oxidative stress markers (Von Willebrand Factor, Malondialdehyde) will be monitored during the study. As sapropterin has been never evaluated in cirrhotic patients, tolerance and adverse effects related to the medication will be registered.

The study will be stratified according to previous beta-blocker therapy (receiving or not receiving beta-blockers).

Conditions

Liver Cirrhosis; Portal Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Sapropterin

5 mg/kg daily first week; 10 mg/kg daily second week of treatment

Group Type: EXPERIMENTAL

sapropterin

Intervention Type: DRUG

two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week

placebo

Group Type: PLACEBO_COMPARATOR

sapropterin

Intervention Type: DRUG

two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week

Interventions

sapropterin

two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Liver cirrhosis of any etiology diagnosed by biopsy or by clinical-imaging data
• Male or female patients between 18-75 years old in whom hepatic vein catheterization is indicated.
• Clinically significant portal hypertension defined by a HVPG ≥ 10 mmHg.
• Signed informed consent.

Exclusion Criteria

• End-stage liver failure defined by one of the following: Prothrombin activity < 40% and/or Bilirubin > 5 mg/dl.
• Pregnancy or breastfeeding.
• Treatment with carvedilol or nitrates.
• Previous TIPS or derivative shunt.
• Hepatocellular carcinoma exceeding Milan criteria.
• Spontaneous bacterial peritonitis or any active infection when entering in the study.
• Portal vein thrombosis or cavernomatosis at ultrasound.
• Chronic heart failure, respiratory failure or chronic renal failure (Creatinine >2 mg/dl).
• Previous convulsions or epilepsy.
• Hypersensibility to sapropterin or any of its excipients.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fundacion Clinic per a la Recerca Biomédica

OTHER

Sponsor Role: lead

Responsible Party

Sara Varea

Clinical Research Manager

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Juan C García-Pagán, MD phD

Role: PRINCIPAL_INVESTIGATOR

Hospital Clínic of Barcelona

Locations

Hospital Clínic de Barcelona

Barcelona, Barcelona, Spain

Hospital Ramón y Cajal

Madrid, Madrid Community, Spain

Countries

Spain

Other Identifiers

TEHYLIC

Identifier Type: -

Identifier Source: org_study_id