A Study to Evaluate the Efficacy and Safety of TG-2349 in Combination With Peg-interferon and Ribavirin in Subjects With Chronic Hepatitis C Virus Genotype 1b Infection
A Study to Evaluate the Efficacy and Safety of TG-2349 in Combination With Peg-interferon and Ribavirin in Subjects With Chronic Hepatitis C Virus Genotype 1b Infection
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.
It is a multicenter, randomized, open-label study to evaluate the safety, tolerability, and
 antiviral efficacy of two different doses of TG-2349 combined with Peg-interferon (IFN) and
 Ribavirin (RBV) in HCV-GT1b treatment naïve East Asian subjects. The treatment duration of
 TG-2349+IFN+RBV is 12 weeks, with or without an additional 12-week treatment of IFN+RBV,
 depending on HCV RNA level at On-Treatment Week 4. Approximately 24 subjects will be
 randomized (1:1) to one of the following 2 treatment groups:

 -  Group I (n=12): 200 mg TG-2349 (2 capsules) + IFN + RBV

 -  Group II (n=12): 400 mg TG-2349 (4 capsules) + IFN + RBV Randomization will be
 stratified by IL28B genotype "CC" or "non-CC". Subjects with HCV RNA < LLOQ (lower limit
 of quantification), TD (target detected) or TND (target not detected) at Week 4 will
 receive 12 weeks of TG-2349+IFN+RBV treatment. Subjects with HCV RNA ≥ LLOQ but < 100
 IU/mL at Week 4 will receive 12 weeks of TG-2349+IFN+RBV treatment followed by an
 additional 12 weeks of IFN+RBV treatment. However, subjects with HCV RNA ≥ 100 IU/mL at
 Week 4 will discontinue the study treatment and complete the Early-Termination (ET)
 visit. The study will be terminated if 3 or more of the first 12 subjects enrolled
 across both Groups I and II, or ≥ 25% of subjects thereafter, fail to respond to
 treatment (i.e., confirmed on-treatment virologic failure or post-treatment relapse).
 Patients, except those who have achieved SVR12, will be offered the standard of care
 with Peg-interferon and Ribavirin for duration of 24, 48, or 72 weeks based on Taiwan's
 regulatory guideline and principal investigator's judgment.
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).