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

  • STATUS
    Recruiting
  • End date
    Dec 31, 2032
  • participants needed
    450
  • sponsor
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Updated on 22 September 2021
liver cancer
cancer
interferon
ribavirin
liver disease
cirrhosis
hemoglobin a1c
glycosylated hemoglobin
fibroscan
antiviral drugs
chronic hepatitis
hemophilia
hcv genotype

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.

Description

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

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

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

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

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 SVR24 in Phase I) will undergo a thorough medical evaluation:

laboratory testing

Fibroscan

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 will be performed annually in all subjects. For subjects with cirrhosis, esophagogastroduodenoscopy (EDG) 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.

Details
Condition Diabetes Mellitus, Chronic viral hepatitis C, Cardiovascular Disease, Diabetes Prevention, Diabetes Mellitus Types I and II, Diabetes (Pediatric), diabetes mellitus (dm), cardiovascular diseases, cardiovascular disease (cvd), cardiovascular system diseases, cardiovascular disorders
Treatment Epclusa
Clinical Study IdentifierNCT03520660
SponsorNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Last Modified on22 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Phase I Treatment
Male or female, >= 18 years of age
Subject must be of generally good health as determined by the Investigator
Either treatment naive or experienced defined as failure of a prior course of interferon-based and ribavirin, DAA plus interferon and DAA only (except for NS5a failures)
Confirmation of chronic HCV infection documented by either
A positive HCV RNA or positive HCV genotyping test at least 6-months prior to the Baseline/Day 1 visit, or
A liver biopsy performed prior to screening visit showing evidence of chronic hepatitis
Subjects must have the following laboratory parameters at screening
ALT <= 10 x the upper limit of normal (ULN)
AST <= 10 x ULN
Total bilirubin <2.5 mg/dL, Direct bilirubin <= 1.5 ULN
Platelets >= 50,000 K/mm3
HbA1c <= 8.5%
Hemoglobin >= 10g/dL
Albumin >= 3g/dL
INR <= 1.5 unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
HCV RNA positive at screening
Subjects must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator
Phase II Follow-up
Male or female >= 18 years of age
SVR24 following therapy with a direct acting antiviral agent regimen and available liver biopsy performed prior to treatment

Exclusion Criteria

Current or prior history of any of the following
Solid organ transplantation
History of malignancy or treatment for a malignancy within the past 3 years that is associated with a life expectancy <5 years (except adequately treated carcinoma in situ or basal cell carcinoma of the skin)
Co-infection with HIV defined as the presence of anti-HIV in serum
Active psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, or personality disorder that, in the investigator s opinion, might interfere with participation in the study
Presence of conditions that, in the opinion of the investigators, would not allow the patient to be followed in the current study for at least 1 year
An individual who meets any of the following criteria will be excluded from
participation in this study
Phase I Treatment
Pregnancy or lactation
Inability to practice one form of adequate contraction for females of childbearing potential
Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded
Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug
Decompensated liver disease as defined by serum bilirubin >= 2.5 mg/dL (with direct bilirubin >= 1.5 mg/dL), INR >1.5 a serum albumin of less than 3 g/dL, or a history of ascites, hepatorenal syndrome, variceal bleeding, or hepatic encephalopathy
Significant pulmonary disease, significant cardiac disease, or porphyria
Chronic liver disease of a non-HCV etiology with the exception of steatosis (e.g., chronic hepatitis B, hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis)
Evidence of harmful or hazardous drinking as defined as a score >= 8 on the AUDIT questionnaire
Clinically relevant drug abuse based on patient history within 12 months of screening
Use of any prohibited concomitant medications within 21 days of the Baseline/Day 1 visit; this washout period does not apply to proton pump inhibitors, which can be taken up to 7 days before baseline Day 1 for the following
Acid reducing Agents
Antiarrhythmics
Anticancer
Antimycobacterial
HIV antivirals
Herbal supplements
HMG-CoA Reductase Inhibitors
Use of antiviral medications within the last 30 days
Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent >= 10 mg/day)
Known hypersensitivity to sofosbuvir and velpatasvir, or formulation excipients
Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver that is suggestive of hepatocellular carcinoma, or an alpha-fetoprotein level of greater than 500 mg/mL
Presence of conditions that, in the opinion of the investigators, would not allow the subject to n the current study for at least 1 year
Phase II Follow-up
Pregnancy
Current or prior history of any of the following
Clinically significant illness (other than resolved HCV) or any other major medical disorder that may interfere with subject treatment, assessment, or compliance with the protocol; subjects currently under evaluation for a potentially clinically significant illness
(other than HCV) are also excluded
\--Decompensated liver disease as defined by serum bilirubin >= 2.5 mg/dL
(with direct
bilirubin >= 1.5 mg/dL), INR >1.5 a serum albumin of less than 3 g/dL, or a
history of ascites, hepatorenal syndrome, variceal bleeding, or hepatic
encephalopathy
Solid organ transplantation
Significant pulmonary disease, significant cardiac disease, or porphyria
History of malignancy or treatment for a malignancy within the past 3 years that is associated with a life expectancy <5 years (except adequately treated carcinoma in situ or basal cell carcinoma of the skin)
Chronic liver disease with the exception of steatosis (e.g., chronic hepatitis B, hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis)
Evidence of harmful or hazardous drinking as defined as a score >= 8 on the AUDIT questionnaire
Co-infection with HIV defined as the presence of anti-HIV in serum
Clinically relevant drug abuse based on patient history within 12 months of screening
Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent >= 10 mg/day)
Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver that is suggestive of hepatocellular carcinoma, or an alpha-fetoprotein level of greater than 500 mg/mL
Active psychiatric problems such as major depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe anxiety, or personality disorder that, in the investigator s opinion, might interfere with participation in the study
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