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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sara Varea, Fundacion Clinic per a la Recerca Biomédica
ClinicalTrials.gov Identifier:
NCT01456286
First received: October 17, 2011
Last updated: October 1, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Liver Cirrhosis
Portal Hypertension
Drug: sapropterin
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Trial, Masked, and Placebo Controlled to Assess the Effects of Sapropterin on Hepatic and Systemic Hemodynamics in Patients With Liver Cirrhosis and Portal Hypertension

Resource links provided by NLM:


Further study details as provided by Fundacion Clinic per a la Recerca Biomédica:

Primary Outcome Measures:
  • Changes in Hepatic Venous Pressure Gradient [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    Changes in portal pressure gradient as measured by hepatic vein catheterization, induced by 2 week treatment with sapropterin/placebo


Enrollment: 42
Study Start Date: October 2011
Study Completion Date: October 2013
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sapropterin
5 mg/kg daily first week; 10 mg/kg daily second week of treatment
Drug: sapropterin
two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week
Placebo Comparator: placebo Drug: sapropterin
two weeks of treatment: 5 mg/kg per day during first week 10 mg/kg per day during second week

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).

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  • Concomitant beginning of non-selective beta-blockers (propranolol, nadolol) during the administration of sapropterin. Beta-blockers are not exclusion criteria if they are on stable doses in the previous 6 weeks.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01456286

Locations
Spain
Hospital Ramón y Cajal
Madrid, Madrid Community, Spain, 28034
Hospital Clínic de Barcelona
Barcelona, Spain, 08036
Sponsors and Collaborators
Fundacion Clinic per a la Recerca Biomédica
Investigators
Principal Investigator: Juan C García-Pagán, MD phD Hospital Clínic of Barcelona
  More Information

No publications provided

Responsible Party: Sara Varea, Clinical Research Manager, Fundacion Clinic per a la Recerca Biomédica
ClinicalTrials.gov Identifier: NCT01456286     History of Changes
Other Study ID Numbers: TEHYLIC
Study First Received: October 17, 2011
Last Updated: October 1, 2013
Health Authority: Spain: Spanish Agency of Medicines

Additional relevant MeSH terms:
Hypertension
Hypertension, Portal
Liver Cirrhosis
Fibrosis
Vascular Diseases
Cardiovascular Diseases
Liver Diseases
Digestive System Diseases
Pathologic Processes
Verapamil
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014