Randomized Controlled Trial to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension
Condition: Liver Cirrhosis; Portal Hypertension
MeSH terms: Liver Cirrhosis; Hypertension, Portal; Hypertension; Fibrosis
Study type: Interventional
Phase: Phase 2/Phase 3

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).
    

Intervention name(s): sapropterin
Intervention type(s): Drug
Intervention description(s): two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment