Clinical trial NCT02340962: Evaluate the Efficacy and Safety of TG-2349 in Subjects With Hepatitis C Infection
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Lead sponsor: TaiGen Biotechnology Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2015-01-19
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

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).

Primary outcomes:
measure: Proportion of Subjects Achieving Sustained Viral Response at 12 Weeks After the End of Treatment.
timeFrame: 12 weeks after the end of treatment (SVR12), after 12-week treatments
Secondary outcomes:
measure: Proportion of Subjects Achieving Sustained Viral Response at 4, 8, and 24 Weeks After the End of Treatment (SVR4, SVR8, and SVR24)
timeFrame: 4, 8, 24 weeks after the end of treatment (SVR4, 8, 24), after 12-week treatments
measure: Proportion of Subjects Achieving HCV RNA < Lower Limit of Quantification, Target Detected or Target Not Detected (< LLOQ, TD or TND)
timeFrame: The whole treatment period, 12 weeks
measure: Proportion of Subjects Achieving HCV RNA < LLOQ, TND
timeFrame: Treatment period (12 to 24 weeks) and after the end of treatment (12 to 24 weeks)
measure: Mean Absolute Values in HCV RNA (log10 IU/mL)
timeFrame: Treatment period (12 to 24 weeks) and after the end of treatment (12 to 24 weeks)
measure: Proportion of Subjects Experiencing Virologic Failure During Treatment and Viral Relapse After the End of Treatment.
timeFrame: Treatment period (12 to 24 weeks) and after the end of treatment (12 to 24 weeks)
measure: Proportion of Subjects With Abnormal Alanine Aminotransferase (ALT) Levels at Baseline Who Achieved Normal Limit of ALT at Final Treatment Visit.
timeFrame: From baseline (day 1) to the final treatment visit (week 12 or week 24)
measure: Change From Baseline in HCV RNA (log10 IU/mL)
timeFrame: Treatment period (12 to 24 weeks) and after the end of treatment (12 to 24 weeks)
Other outcomes:
Locations:
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Chung-Ho Memorial Hospital
Study officials:
affiliation: Kaohsiung Medical University Chung-Ho Memorial Hospital
name: Ming-Lung Yu
role: PRINCIPAL_INVESTIGATOR
References: