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Combination Therapy for Chronic Hepatitis C Infection

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT01805882
First received: March 5, 2013
Last updated: September 27, 2014
Last verified: August 2014
  Purpose

Background:

- GS-7977, GS-5885, GS-9669, and GS-9451 are new drugs for treating hepatitis C virus (HCV) infection. GS-7977 may help treat the infection when used with other treatments like interferon therapy. GS-5885, and GS-9669, and GS-9451 also lower the amount of HCV in the body. Researchers want to see whether GS-7977 can be combined with any of the other three drugs to treat HCV infection. Some participants will take GS-7977 and GS-5885. Others will take GS-7977, GS-5885 and GS-9669 or GS-7977, GS-5885 and GS-9451.

Objectives:

- To see whether GS-7977 with GS-5885 alone or in combination with either GS-9669 or 9451 can be used to treat HCV infection.

Eligibility:

Individuals at least 18 years of age who have chronic HCV infection and have never been treated for it.

Individuals at least 18 years of age who have chronic HCV infection and have not responded to interferon therapy.

Individuals at least 18 years of age who have chronic HCV infection with advanced liver disease and have never been treated for HCV

Design:

Participants will be screened with a physical exam and medical history. Blood samples will be collected. A liver biopsy may also be performed.

Some participants will take the two study drugs and some will take three study drugs. Those who take GS-7977 and GS-5885 will have one daily tablet named fixed dose combination or FDC. Those who take GS-7977 and CS-9669 will have three daily tablets taken once daily. Those who take GS-7977 and GS-5885 and GS-9451 will take 2 pills once a day. GS-7977 and GS-5885 will be combined in one pill and GS-9451 will be in another pill.

Treatment will be monitored with frequent blood tests. These tests will check liver function and the level of HCV infection. Participants may have other blood tests as needed for treatment.

Participants will have 6, 8, or 12 weeks of treatment depending on which study drugs are scheduled to take. After they complete their schedule, they will stop treatment with the study drugs. They may also have another liver biopsy.

Participants will have regular follow-up visits over the next 48 weeks. They will have physical exams and provide blood samples....


Condition Intervention Phase
Hepatitis C, Chronic
Drug: Fixed Dose GS-7977/GS-5885
Drug: FDC with GS-9451
Drug: FDC with GS-9669
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study to Evaluate the Safety and Efficacy of Multiple Anti-HCV Combination Therapy in Chronically Infected Hepatitis C Patients

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The incidence and severity of adverse events (AEs) during and following treatment with GS-7977 in combination with GS-5885, GS-9669 or GS-9451 and the proportion of subjects who achieve SVR12. [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Correlation and comparison of early viral kinetics with response to treatment; host and viral factors influencing response, comparison of HCV viral kinetics and pharmacodynamics in HCV treatment naive vs. null responders. [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 325
Study Start Date: January 2013
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
12 weeks of GS-7977and GS-5885 (FDC) in HCV genotype 1 (GT-1) treatment naive subjects
Drug: Fixed Dose GS-7977/GS-5885
N/A
Experimental: Group B
6 weeks of FDC with GS-9669 in HCV GT-1 treatment naive subjects
Drug: FDC with GS-9669
N/A
Experimental: Group C
6 weeks of FDC with GS-9451 in HCV GT-1 treatment naive subjects
Drug: FDC with GS-9451
N/A
Experimental: Group D
24 weeks with or without RBV
Drug: Fixed Dose GS-7977/GS-5885
N/A
Experimental: Group E
12 weeks of FDC in HCV GT- 4 treatment naive subjects
Drug: Fixed Dose GS-7977/GS-5885
N/A
Experimental: Group F
8 weeks of FDC with GS-9669 in HCV GT-1 treatment naive subjects with advanced liver disease (N=20)
Drug: FDC with GS-9669
N/A
Experimental: Group G
8 weeks of FDC with GS-9451 in HCV GT-1 treatment naive subjects with advanced liver disease (N=20)
Drug: FDC with GS-9451
N/A
Experimental: Group H
8 weeks of FDC with GS-9669 in HCV GT-1 treatment experienced subjects (N=20)
Drug: FDC with GS-9669
N/A
Experimental: Group I
8 weeks of FDC with GS-9451 in HCV GT-1 treatment experienced subjects (N=20)
Drug: FDC with GS-9451
N/A

Detailed Description:

Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated 180 million people infected worldwide. In the United States an estimated 4.1 million people are infected, and HCV is the principal cause of death from liver disease and leading indication for liver transplantation. While treatment with ribavirin (RBV) and pegylated interferon (PEG) in combination with boceprevir/telaprevir is the currently recommended therapy for chronic HCV infection and has superior cure rates compared to PEG+RBV alone in HCV monoinfected patients, treatment is still associated with a high incidence of adverse events (AEs), discontinuations, and poor cure rates in several populations. Recent studies have demonstrated that the use of a combination of antivirals which target HCV without interferon (IFN) can cure HCV without additional toxicities. However, the determinants of response to IFN-free regimens has not been established.

This is an open label study to assess the safety, tolerability, and efficacy of treatment with GS-7977 with GS-5885, alone or in combination with GS-9669 and/or GS-9451 (selective HCV nucleotide NS5B, NS5A, nonnucleotide NS5B and NS3 inhibitors, respectively) in HCV infected treatment na(SqrRoot) ve and treatment experienced patients with early and advanced liver disease. The findings from this study will aid in our understanding of determinants of response to an IFN-free regimen in HCV infected patients for both patients with early and advanced liver disease as well as in patients who are treatment na(SqrRoot) ve and those who have been treated before for HCV.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Eighteen years of age or older at screening.
    2. Female study participants with childbearing potential (as defined below) and all males must be willing to practice either:

      • Abstinence from sexual intercourse or
      • One or more forms of effective barrier contraception throughout dosing and for 30 days following the last dose. This cannot include hormonal contraception for female subjects.

      Effective forms of barrier contraception include:

      • a male condom with spermicide
      • use by female sexual partner of a female condom with spermicide

      Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) includes any female who:

      • Has had a hysterectomy or
      • Has had a bilateral oophorectomy (ovariectomy) or
      • Is post-menopausal (a demonstration of a total cessation of menses for greater than or equal to1 year)
      • Has had a bilateral tubal ligation or fallopian tube inserts
    3. Chronic HCV GT-1 or GT-4 infection as documented by greater than or equal to 1 measurement of serum HCV RNA greater than or equal to 2,000 international units per milliliter during screening and at least one of the following:

      • A positive anti-HCV antibody, HCV RNA
      • HCV genotype test result greater than or equal to 12 months prior to the baseline (day 0) visit together with current positive HCV RNA and anti-HCV antibody test results
      • Positive HCV RNA test and anti-HCV antibody test results together with a liver biopsy consistent with chronic HCV infection or a liver biopsy performed before enrollment with evidence of chronic hepatitis C infection disease, such as the presence of fibrosis.
    4. Group A may include up to 20% of subjects with compensated cirrhosis.

      Group B and C may only include subjects with absence of cirrhosis.

      Group D & E may include subjects with compensated cirrhosis.

      Group F may only include patients with advanced liver disease (historic Metavir or HAI Stage 3 or 4 or ISHAK Stage 4, 5 or 6 or cirrhosis as defined below)

      Group G and H may only include those with absence of cirrhosis and HAI Stage 0-2 or FibroTest as below.

      Cirrhosis is defined as any one of the following:

      1. Any biopsy showing cirrhosis.
      2. A FibroTest score of greater than or equal to 0.75 AND an AST: platelet ratio (APRI) of > 2 performed within 12 months of screening.

      Liver imaging within 6 months of Day 0 to exclude hepatocellular carcinoma (HCC) is required in patients with cirrhosis.

      Absence of cirrhosis is defined as one of the following:

      1. A liver biopsy performed within 36 calendar months of screening showing absence of cirrhosis.
      2. A FibroTest score of < 0.48 AND APRI of < 1 performed within 6 months of screening. This would also qualify a subject for Group G and H as having Stage 0-2 disease in the absence of a liver biopsy.

      In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required (for Groups B, C, G and H).

    5. Ability to communicate effectively with the study investigator and other key personnel.
    6. Willing to give written informed consent and comply with the study restrictions and requirements.
    7. Opioid-dependent individuals must be participating in a supervised treatment program.
    8. Subjects must have an external primary care doctor (outside of the CC and the NIH) for their medical management.

EXCLUSION CRITERIA:

  1. 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.
    • Poor venous access interfering with required study blood collection.
    • Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
    • Solid organ transplantation.
    • Significant pulmonary disease, significant cardiac disease or porphyria.
    • Unstable psychiatric disease (Subjects with psychiatric illness that is well-controlled on a stable treatment regimen or currently not requiring medication may be included).
    • Malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screening); subjects under evaluation for malignancy are not eligible.
    • Significant drug allergy (such as anaphylaxis or hepatotoxicity).
    • Substance abuse, which in the opinion of the investigator is likely to interfere with medication adherence or study compliance.
    • Lactose allergy, patients with lactose intolerance will be evaluated on a case-by-case basis.
  2. Positive test results at screening for hepatitis B virus (HBV) surface antigen (HBsAg), HBV DNA (if medically indicated) or anti-HIV antibody (unless previously treated on 13-I-0159).
  3. Prior exposure to any direct-acting antivirals for HCV infection, except for patients who were previously treated studies 11-I-0258, 13-I-1059 or this study enrolling in Group D.
  4. History of clinically significant chronic liver disease due to other etiology (e.g., hemochromatosis, autoimmune hepatitis, Wilson s disease, alpha 1-antitrypsin deficiency, alcoholic liver disease, moderate non-alcoholic steatohepatitis and toxin exposures).
  5. Use of herbal/natural remedies for potential benefit to the liver within 21 Days of Day 0.
  6. History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease.
  7. Screening or baseline ECG with clinically significant ECG findings, or a personal/first degree relative history of Torsade de pointes.
  8. Abnormal hematological and biochemical parameters at screening, including:

    • Neutrophil count less than 750 cells per cubic millimeter.
    • Hemoglobin level < 9 g/dL. If Hgb < 11g/dL in women

    and < 12 g/dL in men other causes of anemia should be excluded as medically indicated.

    • Platelet count less than or equal to 50,000 cells per cubic millimeter.
    • Estimated glomerular filtration rate less than 50 milliliter/min/1.73m(2).
    • ALT or AST level greater than or equal to 10 times upper limit of normal (ULN).
    • Serum lipase level greater than or equal to greater than or equal to 1. 5 times upper limit of normal (ULN)at screening or during the screening period in a patient with symptoms consistent with pancreatitis.
    • Total bilirubin level greater than or equal to 2.0 times upper limit of normal (ULN), except in subjects with Gilbert s syndrome.
    • Albumin level less than or equal to 3.0 grams per deciliter in patients without cirrhosis, albumin less than or equal to 2.8 g/dL in cirrhotic patients.
  9. Poorly controlled diabetes mellitus indicated by hemoglobin A1C greater than 9% at screening.
  10. Donation or loss of blood of greater than 400 milliliter within 8 weeks prior to the first dose of the study drugs.
  11. Known hypersensitivity to GS-5885, GS-7977, GS-9669, GS-9541 or formulation excipients.
  12. Pregnant/Breastfeeding women.
  13. Need for use of the following medications from 21 days prior to the start of study drugs through the end of treatment (unless otherwise specified in Table 7-9):

    • Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs); granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics).
    • Chronic systemic immunosuppressants including, but not limited to, corticosteroids (prednisone equivalent of greater than 10 milligrams per day for greater than 2 weeks), azathioprine, or monoclonal antibodies (e.g., infliximab).
    • Investigational agents or devices for any indication.
    • Medications for disease conditions excluded from the protocol (e.g., active cancer, transplantation) are not listed under this Concomitant Medication section and are disallowed in the study.
    • Concomitant use of certain medications or herbal/natural supplements per PI discretion expected to result in pharmacokinetic interactions resulting in increases or decreases in exposure of study drug(s) as listed in Table Table 7-9 of this protocol.
  14. Co-enrollment Guidelines: Co-enrollment in other clinical trials is restricted, other than enrollment in observational studies. Study staff should be notified of co-enrollment status, as it may require prior approval of the investigator.
  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: NCT01805882

Contacts
Contact: Mary McLaughlin, R.N. (301) 435-8001 mmclaughlin@niaid.nih.gov
Contact: Henry Masur, M.D. (301) 496-9320 hmasur@cc.nih.gov

Locations
United States, District of Columbia
Family Medical and Conseling Services Recruiting
Washington, DC, District of Columbia, United States, 20020
Unity Health Care, Inc./DC General Recruiting
Washington, DC, District of Columbia, United States, 20002
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Henry Masur, M.D. National Institutes of Health Clinical Center (CC)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT01805882     History of Changes
Other Study ID Numbers: 130066, 13-I-0066
Study First Received: March 5, 2013
Last Updated: September 27, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Interferon Sparing
Directly Acting Antiviral
Ribavarin Sparing

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Hepatitis, Chronic
Hepatitis, Viral, Human
Digestive System Diseases
Enterovirus Infections
Flaviviridae Infections
Liver Diseases
Picornaviridae Infections
RNA Virus Infections
Virus Diseases

ClinicalTrials.gov processed this record on October 29, 2014