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

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ClinicalTrials.gov Identifier: NCT03520660
Recruitment Status : Recruiting
First Posted : May 10, 2018
Last Update Posted : October 24, 2018
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 clinic stay 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 screening tests at 3 visits in those 12 weeks, then 4 visits in the next 24 weeks.

Phase 1 participants who test negative for hepatitis C and all other 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

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
Diabetes Mellitus Hepatitis C, Chronic Cardiovascular Diseases

Detailed Description:
We intend to observe up to 350 patients with chronic HCV infection who have successfully eradiated HCV following therapy with direct acting antiviral agents and describe the clinical, virological, laboratory, histological and immunological outcomes following eradication of HCV. Subjects will be recruited from two sources: 1) subjects who have already achieved SVR with a DAA only regimen and who have undergone a liver biopsy within five years prior to therapy and no history of hepatic decompensation or hepatocellular carcinoma and 2) 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. Subjects yet to achieve SVR with evidence of clinical cirrhosis will undergo a transjugular liver biopsy with measurement of portal pressures in lieu of the percutaneous liver biopsy. Subjects yet to achieve an SVR will receive 12 weeks of therapy with sofosbuvir/velapatasvir fixed dose combination. Subjects who have attained a SVR (or upon achieving an SVR) will undergo a thorough medical evaluation, laboratory testing, transient elastography and 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. Transient elastography will be performed annually in all subjects. For subjects with cirrhosis, esophagogastroduodenoscopy will be performed annually and imaging every 24 weeks. At the end of 240 weeks, all subjects will be admitted to undergo 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 pressure measurements. The primary goal of the study will be to describe the natural history 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 : Observational
Estimated Enrollment : 450 participants
Observational Model: Cohort
Time Perspective: Prospective
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

Group/Cohort
1
patients with chronic HCV infection



Primary Outcome Measures :
  1. Liver-related outcomes [ Time Frame: 5 and 10 years ]

Secondary Outcome Measures :
  1. Non-liver related outcomes [ Time Frame: 5-10 years ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
patients with chronic HCV infection
Criteria
  • Phase I

Inclusion Criteria for Subjects Who Have Not Achieved a SVR (Phase I)

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:

  • Male or female, age greater than or equal to 18 years.
  • Either treatment na(SqrRoot) ve 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:

    1. A positive HCV RNA or positive HCV genotyping test at least 6 months prior to the Baseline/Day 1 visit, or
    2. A liver biopsy performed prior to screening visit showing evidence of chronic hepatitis.

      5) Subjects must have the following laboratory parameters at screening:

  • ALT less than or equal to 10 (SqrRoot) the upper limit of normal (ULN)
  • AST less than or equal 10 (SqrRoot) ULN
  • Total bilirubin <2.5 mg/dL, Direct bilirubin less than or equal 1.5 ULN
  • Platelets more than or equal 50,000 K/mm3
  • HbA1c less than or equal 8.5%
  • eGFR more than or equal 60 mL /min, as calculated by the CKD-EPI equation.
  • Hemoglobin more than or equal 10g/dL.
  • Albumin more than or equal 3g/dL
  • INR less than or equal 1.5 unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.
  • HCV RNA positive at screening

    6) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments, including all required post-treatment visits.

    7) Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator.

Exclusion Criteria for Subjects Who Have Not Achieved a SVR

Subjects who meet any of the following exclusion criteria will not to be enrolled in this arm of the study:

  1. Pregnancy, active breast-feeding, or inability to practice adequate contraception, in women of childbearing potential. Adequate contraception is defined as vasectomy in men, tubal ligation in women, or use of two methods such as condoms and spermicide combination, birth control pills, an intrauterine device, Depo-Provera, or Norplant until 12 weeks post therapy.
  2. 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 more than or equal to 2.5 mg/dL (with direct bilirubin more than or equal to 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.
  3. 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).
  4. Chronic liver disease of a non-HCV etiology with the exception of steatosis (e.g., chronic hepatitis B, NASH, hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis).
  5. Evidence of harmful or hazardous drinking as defined as a score more than or equal to 8 on the AUDIT questionnaire.
  6. Co-infection with HIV defined as the presence of anti-HIV in serum.
  7. Clinically-relevant drug abuse based on patient history within 12 months of screening.
  8. Use of any prohibited concomitant medications as described in concomitant medications and Table 1 within 21 days of the Baseline/Day 1 visit; this washout period does not apply to PPIs, which can be taken up to 7 days before baseline Day 1.
  9. Use of antiviral medications within the last 30 days.
  10. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent more than or equal to 10 mg/day).
  11. Known hypersensitivity to sofosbuvir and velpatasvir, or formulation excipients.
  12. Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver that is suggestive of hepatocellular carcinoma, or an alphafetoprotein level of greater than 500 ng/mL.
  13. 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.
  14. 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.
  15. Inability to provide consent.

Phase II

Inclusion Criteria for Phase II (follow-up after SVR24):

  1. Age greater than or equal to 18 years and older, male or female
  2. SVR following therapy with a direct acting antiviral agent regimen and available liver biopsy performed prior to treatment and up to 5 years prior to enrollment (2 unstained slides or a hematoxylin and eosin and Mason trichrome stained slides must be available)
  3. Subject must be of generally good health as determined by the Investigator.
  4. Willing and able to provide written informed consent.

Exclusion Criteria for Phase II (follow-up after SVR24):

  1. 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 greater than or equal to 2.5 mg/dL (with direct bilirubin greater than or equal to 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.
  2. 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).
  3. Chronic liver disease with the exception of steatosis (e.g., chronic hepatitis B, NASH, hemochromatosis, Wilson s disease, alfa-1 antitrypsin deficiency, cholangitis).
  4. Evidence of harmful or hazardous drinking as defined as a score greater than or equal to 8 on the AUDIT questionnaire.
  5. Co-infection with HIV defined as the presence of anti-HIV in serum.
  6. Clinically-relevant drug abuse based on patient history within 12 months of screening.
  7. Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent greater than or equal to 10 mg/day).
  8. Hepatocellular carcinoma, or the presence of a mass on imaging studies of the liver that is suggestive of hepatocellular carcinoma, or an alphafetoprotein level of greater than 500 ng/mL.
  9. 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.
  10. 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: Marc G Ghany, M.D. (301) 402-5115 mg228m@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     History of Changes
Other Study ID Numbers: 180091
18-DK-0091
First Posted: May 10, 2018    Key Record Dates
Last Update Posted: October 24, 2018
Last Verified: October 16, 2018

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Studies a U.S. FDA-regulated Drug Product: No
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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Diabetes Mellitus
Hepatitis
Hepatitis C
Cardiovascular Diseases
Hepatitis C, Chronic
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Antiviral Agents
Anti-Infective Agents