People With CHC Who Achieved a Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents

Cardiovascular Diseases Clinical Trial

Official title: Long-Term Follow-Up Of Subjects With CHC Who Achieved A Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents

Status Active, not recruiting

Clinical Trial Summary

Background:

Chronic hepatitis C infects the liver. It may scar the liver. This is called cirrhosis and may lead to liver cancer or death. Current chronic hepatitis C treatments cure most people. But some keep getting complications even after it is cured. Researchers want to study why.

Objective:

To study the course and complications of liver disease after cure of hepatitis C infection.

Eligibility:

Adults 18 years and older infected with chronic hepatitis C virus who were never treated or were treated and not cured and those who were cured

Design:

Participants will be screened with:

Blood and urine tests

Questionnaires

Liver ultrasound

Fibroscan. A probe vibrates the liver, testing stiffness.

In Phase 1, people with chronic hepatitis C will:

Have a 3-day hospital admission to repeat some screening tests and have a liver biopsy. A small piece of liver is removed by needle passed through the skin.

Take 1 tablet containing 2 hepatitis C drugs once a day for 12 weeks.

Repeat some blood tests at 3 visits in those 12 weeks while on treatment, then 4 additional visits in the next 24 weeks with more blood work collected.

Phase 1 participants who test negative for hepatitis C and all other eligible participants will enter Phase 2.

Phase 2 participants will have a visit every 24 weeks for 10 years. These may include:

Repeats of screening tests

Questionnaires

Scans

Stool tests

Chest x-ray

Heart function test

Endoscopy. A tube guides a camera into the upper digestive system.

At about 5 years, participants will have another liver biopsy.

Some participants will give separate consent for genetic testing and a special blood procedure.

Clinical Trial Description

Study Description:<TAB>

We intend to enroll up to 350 subjects with chronic hepatitis C virus (HCV) infection. Subjects will be recruited from two sources:

1. Phase I: treatment na(SqrRoot) ve or experienced who have failed a prior treatment (including DAA-experienced) who are willing to undergo a pre-treatment liver biopsy.

1. Subjects yet to achieve an SVR will receive 12 weeks of therapy with sofosbuvir/velapatasvir (Epclusa(R)) fixed dose combination

2. Subjects yet to achieve SVR with evidence of clinical cirrhosis will undergo a transjugular liver biopsy with hepatic venous portal gradient (HVPG) pressure measurements in lieu of the percutaneous liver biopsy

2. Phase II: subjects who have already achieved sustained virologic response (SVR) with oral direct-acting antiviral agent (DAA) only regimen and who have undergone a liver biopsy prior to therapy and no history of hepatic decompensation or hepatocellular carcinoma.

Subjects who have attained an SVR prior to enrollment (or upon achieving an SVR12 and SVR24 in Phase I) will undergo a thorough medical evaluation:

• laboratory testing

• Fibroscan(R)

• hepatic ultrasound

Thereafter, subjects will be followed prospectively every 24 weeks for liver decompensation (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage), hepatocellular carcinoma, liver-related mortality, and all-cause mortality. During each study visit, subjects will be questioned on the development of these adverse outcomes. In addition, blood will be drawn for the assessment of routine blood tests, quantitative viral biomarker levels, serological response markers and immune cell functional status. Blood, urine, and stool will be collected and stored for exploratory biomarker development. Fibroscan(R) will be performed annually in all subjects. For subjects with cirrhosis, esophagogastroduodenoscopy (EGD) will be performed annually and imaging every 24 weeks. At the end of 240 weeks, all subjects will be admitted for a liver biopsy to assess the stage of liver fibrosis. In subjects with cirrhosis at study entry, the liver biopsy will be performed by the transjugular route with hepatic venous portal gradient (HVPG) pressure measurements.

The primary goal of the study will be to describe the outcome of viral eradication following treatment with direct acting antiviral agents, to identify predictors of adverse outcomes after sustained viral eradication and regression of fibrosis/cirrhosis.

Objectives:

Primary Objective:

• Phase 1: SVR12 and SVR24

• Phase II: The rate of clinical outcomes (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage), hepatocellular carcinoma, liver-related mortality, and all-cause mortality

Secondary Objectives:

• Phase II: The proportion and rates of fibrosis regression in subjects

• Phase II: The agreement between Fibroscan and Ishak fibrosis score

• Phase II: The comparison of change in Fibroscan and change in Ishak fibrosis as predictors of the primary outcome.

• Phase II: To assess regression of portal hypertension in subjects with pre-existing portal hypertension either confirmed by direct portal pressure measurement, indirectly by hepatic venous pressure gradient or clinical evidence of portal hypertension such as presence of esophageal or gastric varices of portal hypertensive gastropathy and all-cause mortality.

Exploratory Objective:

• To develop novel biomarkers and genetic predictors of liver-related complications including hepatocellular carcinoma.

• To assess outcome of HCV-related immune dysfunction following sustained eradication of HCV.

• To assess changes in antibody titer and breadth, B cell activation, and T cell memory after sustained HCV eradication.

• To prospectively assess the rate of non-hepatic outcomes (diabetes, cardiovascular and renal disease, malignancy including lymphoma, and health related quality of life) following SVR with DAA agents.

• To characterize the changes in serum lipids and lipoproteins during and after therapy with direct acting antiviral agents and assess cardiovascular risk following eradication of HCV based on serum/plasma LDL particle number.

Endpoints:

Primary Endpoint:

• SVR at 12 weeks after completion of 12 weeks of treatment.

• Composite of ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, liver-related mortality, and all-cause mortality at 480 weeks.

Secondary Endpoints:

• Improvement in semi-quantitative Ishak fibrosis score after HCV clearance.

• Correlation between Fibroscan (transient elastography) with Ishak fibrosis score after HCV clearance.

• Does change improvement in Fibroscan and change in Ishak fibrosis correlate with clinical outcome.

• Change in portal pressure after SVR12. ;

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Diabetes Mellitus
• Hepatitis
• Hepatitis C
• Hepatitis C, Chronic

• NCT number: NCT03520660
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: October 19, 2018
• Completion date: December 31, 2032