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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03520660
Recruitment Status : Recruiting
First Posted : May 11, 2018
Last Update Posted : January 5, 2022
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) )

Brief 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.


Condition or disease Intervention/treatment Phase
Diabetes Mellitus Hepatitis C, Chronic Cardiovascular Diseases Drug: Epclusa Phase 4

Detailed 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Long-Term Follow-Up Of Subjects With CHC Who Achieved A Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents
Actual Study Start Date : October 19, 2018
Estimated Primary Completion Date : December 31, 2032
Estimated Study Completion Date : December 31, 2032

Arm Intervention/treatment
Experimental: Phase I
Phase I treatment
Drug: Epclusa
sofosbuvir/velapatasvir combination (Epclusa)

No Intervention: Phase II after Phase I
Participants who achieved SVR12 in Phase I
No Intervention: Phase II without Phase I
Participants who achieved SVR 24 previously



Primary Outcome Measures :
  1. Phase II: Liver-related clinical outcome, HCC, or liver-related mortality [ Time Frame: 480 Weeks ]
    Composite of ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal hemorrhage, hepatocellular carcinoma, liver-related mortality

  2. Phase I - SVR 12 [ Time Frame: 24 weeks ]
    SVR at 12 weeks after completion of 12 weeks of treatment


Secondary Outcome Measures :
  1. Phase II: all-cause mortality [ Time Frame: 480 weeks ]
  2. Phase II: HCC [ Time Frame: 480 weeks ]
  3. Phase II: Change in Ishak fibrosis score [ Time Frame: 480 weeks ]
  4. Phase II: Change in Fibroscan [ Time Frame: 480 weeks ]


Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Phase I Treatment

  • Male or female, >= 18 years of age
  • 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.
  • Subject must be of generally good health as determined by the Investigator.

EXCLUSION CRITERIA:

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
  • Current or prior history of any of the following:

    • 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
    • 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 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.
  • 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.
  • 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
  • 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 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
    • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03520660


Contacts
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Contact: Steffan L Cooper (301) 451-6984 steffan.cooper@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Marc G Ghany, M.D. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional Information:
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Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier: NCT03520660    
Other Study ID Numbers: 180091
18-DK-0091
First Posted: May 11, 2018    Key Record Dates
Last Update Posted: January 5, 2022
Last Verified: November 23, 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ):
Natural History
Hepatitis C Virus
Hepatocellular Carcinoma
Fibrosis
Immune Response
Additional relevant MeSH terms:
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Hepatitis C
Hepatitis C, Chronic
Hepatitis
Cardiovascular Diseases
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Infections
RNA Virus Infections
Blood-Borne Infections
Communicable Diseases
Flaviviridae Infections
Hepatitis, Chronic
Sofosbuvir-velpatasvir drug combination
Antiviral Agents
Anti-Infective Agents