Combination Therapy for Chronic Hepatitis C Infection
Combination Therapy for Chronic Hepatitis C Infection
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 4, 6 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....
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 have 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 naive 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 naive and those who have been treated before
 for HCV.
-  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, or 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 or

 -  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, D-ReTx & 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(r) 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(r) 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).

 -  Any malignancy or its treatment that in the opinion of the PI may cause ongoing
 interference with host immunity; 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 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-9451 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):

 -  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).

 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.