Combination Therapy for Chronic Hepatitis C Infection
Condition: Hepatitis C, Chronic
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis
Intervention: Sofosbuvir; Ledipasvir; GS-9669; GS-9451
Intervention MeSH terms: Sofosbuvir; Ledipasvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 229.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Interferon Sparing; Directly Acting Antiviral; Ribavarin Sparing

Summary:

      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....
    

Eligibility 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, 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.