Evaluate the Efficacy and Safety of TG-2349 in Subjects With Hepatitis C Infection
Condition: Hepatitis C, Chronic
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis
Intervention: TG-2349; Ribavirin; Interferon Alfa-2a
Intervention description: TG-2349 (Furaprevir) is available as a Swedish orange capsule (size 0) for oral administration. Each capsule contains an equivalent of 100 mg of TG-2349 spray dried solid (SDD) and the following inactive ingredients: microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate, and colloidal silicon oxide.; RBV (Ribavirin or COPEGUS®) is available as a light pink to pink colored, flat, oval-shaped, film-coated tablet for oral administration. Each tablet contains 200 mg of ribavirin and the following inactive ingredients: pregelatinized starch, microcrystalline cellulose, sodium starch glycolate, cornstarch, and magnesium stearate. The coating of the tablet contains Chromatone-P® or Opadry® Pink (made by using hydroxypropyl methyl cellulose, talc, titanium dioxide, synthetic yellow iron oxide, and synthetic red iron oxide), ethyl cellulose (ECD-30), and triacetin.; IFN (Interferon, Peg-interferon alpha-2a or PEGASYS®) is available as a sterile, preservative-free, colorless to light yellow injectable solution administered subcutaneously.
Each prefilled syringe of 180 μg/0.5 mL IFN (expressed as the amount of interferon alfa-2a) also contains acetic acid (0.0231 mg), benzyl alcohol (5 mg), polysorbate 80 (0.025 mg), sodium acetate trihydrate (1.3085 mg), and sodium chloride (4 mg) at pH 6 ± 0.5.
Intervention MeSH terms: Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No

Summary:

      A Phase 2, Multicenter, Randomized, Open-label, Dose-ranging Study to Evaluate the Efficacy
      and Safety of TG-2349 in Combination with Peg-interferon and Ribavirin in Treatment Naïve
      East Asian Subjects with Chronic Hepatitis C Virus Genotype 1b Infection.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Willing and able to provide written informed consent.

          2. East Asian subjects, male or female, and age between 18 (or legal adult age) and 70
             years, inclusive, at Baseline/Day 1.

          3. Body mass index (BMI) in the range of 18.0 to 35.0 kg/m2 (inclusive) and body weight ≥
             40 kg.

          4. Presence of chronic hepatitis C (CHC) as documented below:

        (1) A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test
        at least 6 months prior to the Baseline/Day 1 visit or (2) A liver biopsy or FibroTest
        performed prior to the Baseline/Day 1 visit with evidence of chronic HCV infection, such as
        the presence of fibrosis and/or inflammation.

        5. Positive for anti-HCV antibody at Screening. 6. Presence of an HCV RNA level ≥ 1 x 10000
        IU/mL at Screening as determined by the Central Laboratory.

        7. Presence of genotype 1b HCV-infection at Screening as determined by the Central
        Laboratory. Any non-definitive results will exclude the subject from study participation.

        8. HCV treatment naïve defined as no prior therapy with any interferon (IFN), ribavirin
        (RBV), or other approved or investigational HCV-specific agent.

        9. Absence of cirrhosis

        Cirrhosis as defined as any one of the following:

          1. Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5).

          2. FibroScan showing cirrhosis or results > 12.5 kPa.

          3. FibroTest fibrosis score of > 0.58 and APRI (AST: platelet ratio index) of > 2 during
             Screening.

        If no definitive diagnosis of cirrhosis by the above criteria, a liver biopsy is required;
        liver biopsy results will supersede non-invasive testing results and be considered
        definitive.

        10. Screening ECG without clinically significant abnormalities. 11. Subjects must have the
        following laboratory parameters at Screening:

          1. ALT ≤ 10 × the upper limit of normal (ULN)

          2. AST ≤ 10 × ULN

          3. Total bilirubin ≤ 1.5 × ULN except history of Gilbert's syndrome. If Gilbert's
             syndrome is the proposed etiology, the total bilirubin must ≤ 2 × ULN.

          4. Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

          5. Platelet count ≥ 90,000 cells/mm3

          6. HbA1c ≤ 8.5%

          7. Thyroid stimulating hormone (TSH) and free T4 ≤ ULN

          8. Creatinine clearance (CLcr) ≥ 60 mL /min, as calculated by the Cockcroft-Gault
             equation

          9. Serum creatinine ≤ 1.5 × ULN

         10. Hemoglobin ≥ 11 g/dL for female subjects; ≥ 12 g/dL for male subjects

         11. Albumin ≥ 3.5 g/dL

         12. INR (International Normalized Ratio for Prothrombin Time) ≤ 1.5 x ULN unless subject
             is stable on an anticoagulant regimen affecting INR

         13. Anti-nuclear antibodies (ANA) ≤ 1:320. 12. Subject must be of generally good health,
             with the exception of chronic HCV infection, as determined by Investigator.

        13. 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.

        14. A female subject is eligible to enter the study if it is confirmed that she is:

        (1) Not pregnant or nursing. (2) Of non-childbearing potential (i.e., women who have had a
        hysterectomy, have both ovaries removed or medically documented ovarian failure, or are
        postmenopausal - women > 50 years of age with cessation (for ≥12 months) of previously
        occurring menses), or (3) Of childbearing potential (i.e., women who have not had a
        hysterectomy, have not had both ovaries removed, and have not had medically documented
        ovarian failure).

        Women ≤ 50 years of age with amenorrhea will be considered to be of childbearing potential.
        These women must have a negative serum pregnancy test at Screening and a negative urine
        pregnancy test at the Baseline/Day 1 visit prior to randomization. They must also agree to
        one of the following from Screening until 6 months after the last dose of study drug(s):

        - Complete abstinence from intercourse. Periodic abstinence from intercourse (e.g.,
        calendar, ovulation, symptothermal, post-ovulation methods) is not permitted.

        Or - Consistent and correct use of 1 of the following methods of birth control listed
        below, in addition to a male partner who correctly uses a condom, from Screening until 6
        months after the last dose of study drug(s):

          1. intrauterine device (IUD) with a failure rate of < 1% per year

          2. female barrier method: cervical cap or diaphragm with spermicidal agent

          3. tubal sterilization

          4. vasectomy in male partner

          5. hormone-containing contraceptive:

        i. implants of levonorgestrel ii. injectable progesterone iii. oral contraceptives (either
        combined or progesterone only) iv. contraceptive vaginal ring v. transdermal contraceptive
        patch. 15. Male subjects must agree to consistently and correctly use a condom, while their
        female partner agrees to use 1 of the methods of birth control listed above, from Screening
        until 6 months after the last dose of study drug(s).

        16. Male subjects must agree to refrain from sperm donation from Screening until at least 6
        months after the last dose of study drug(s).

        Exclusion Criteria:

          1. Presence of cirrhosis.

          2. Positive serological test for IgM anti-HAV (hepatitis A virus) antibody or HBsAg at
             Screening.

          3. Positive ELISA test for HIV-1 or HIV-2 at Screening.

          4. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson disease,
             alfa-1 antitrypsin deficiency, cholangitis).

          5. Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1.

          6. Clinically-relevant drug abuse within 12 months of Screening. A positive drug screen
             will exclude subjects unless it can be explained by a prescribed medication; the
             diagnosis and prescription must be approved by Investigator.

          7. Alcohol misuse as defined by an AUDIT score of ≥ 8.

          8. Contraindications to RBV or IFN therapy, including hemoglobinopathies (e.g.,
             thalassemia major or sickle-cell anemia), autoimmune thyroiditis or other autoimmune
             disorders including autoimmune hepatitis.

          9. Pregnant or nursing female or male with pregnant female partner.

         10. Use of any prohibited medications within 30 days of the Baseline/Day 1 visit:

        (1) Hematologic stimulating agents (e.g., erythropoiesis-stimulating agents [ESAs],
        granulocyte colony stimulating factor [G-CSF], and thrombopoietin [TPO] mimetics) (2)
        Chronic use of systemic immunosuppressants including, but not limited to, corticosteroids
        (prednisone equivalent of > 10 mg/day for > 2 weeks), azathioprine, or monoclonal
        antibodies (eg, infliximab) (3) Investigational agents or devices for any indication (4)
        Drugs disallowed per prescribing information of RBV or IFN (5) Any prohibited medications
        listed in Table 6-2. 11. Known hypersensitivity to RBV, IFN, TG-2349, sulfa drugs, or
        formulation excipients.

        12. Current or prior history of any of the following:

          1. 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.

          2. Gastrointestinal disorder or post operative condition that could interfere with the
             absorption of the study drugs.

          3. Difficulty with blood collection and/or poor venous access for the purposes of
             phlebotomy.

          4. Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal
             hemorrhage).

          5. Central nervous system (CNS) trauma, seizure disorder, stroke or transient ischemic
             attack.

          6. Solid organ transplantation.

          7. Significant cardiac disease (including but not limited to the myocardial infarction
             based on ECG and/or clinical history).

          8. Significant pulmonary disease or porphyria.

          9. Clinically significant retinal disease

         10. Psychiatric hospitalization, suicide attempt, and/or a period of disability as a
             result of their psychiatric illness within the last 5 years. Subjects with psychiatric
             illness (without the prior mentioned conditions) that is well-controlled on a stable
             treatment regimen for at least 12 months prior to Baseline/Day 1 or has not required
             medication in the last 12 months may be included.

         11. Malignancy within 5 years prior to Screening, with the exception of specific cancers
             that are entirely cured by surgical resection (basal cell skin cancer, etc). Subjects
             under evaluation for possible malignancy are not eligible.

         12. Significant drug allergy (such as anaphylaxis or hepatotoxicity).