To Evaluate Efficacy and Safety in TG-2349 Combination With DAG181 (± Ribavirin) in HCV Genotype I Infected Patients

Study Overview
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Brief Summary
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A phase II study to evaluate the efficacy and safety in TG-2349 combination with DAG181 (± Ribavirin) in treatment naïve subjects with chronic hepatic C virus genotype I infection.

Detailed Description
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The purpose of this phase II study is to evaluate the efficacy and safety in TG-2349 combination with DAG181 (± Ribavirin) in treatment naïve subjects with chronic hepatic C virus genotype I infection. Approximately 132 subjects will be enrolled in this study and divided into six groups: Group 1 to 4: Chronic hepatics C virus (HCV) genotype 1 infected, treatment naïve, non-cirrhotic subjects. Group 5 to 6: Chronic hepatics C virus (HCV) genotype 1 infected, treatment naïve, cirrhotic subjects.

Official Title
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A Multicenter, Randomized, Open-label, Dose-ranging, Phase II Study to Evaluate the Efficacy and Safety in TG-2349 Combination With DAG181 (± Ribavirin) in Treatment naïve Subjects With Chronic Hepatic C Virus Genotype I Infection

Conditions
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Chronic Hepatics C Virus (HCV) Genotype 1, Non-Cirrhotic, Cirrhosis, Treatment naïve

Intervention / Treatment
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* Drug: non-cirrhotic subjects. low TG-2349+ low DAG181+Ribavirin
* Drug: non-cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin
* Drug: non-cirrhotic subjects. low TG-2349+ low DAG181
* Drug: non-cirrhotic subjects. high TG-2349+ high DAG181
* Drug: cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin
* Drug: cirrhotic subjects. high TG-2349+ high DAG181


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Before starting the study, an informed consent form (ICF) approved by the Institutional Review Board (IRB) is obtained from the subject or his/her legal representative； Male or female, and 18 to 45 years of age inclusive when signing ICF； Body mass index (BMI) in the range of 18.0 to 35.0kg/m2 and body weight ≥ 40 kg at Screening； 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； Positive for anti-HCV antibody at Screening； Presence of an HCV RNA level ≥ 1 x 104 IU/mL at Screening as determined by the Central Laboratory； Presence of genotype 1a, 1b, or 1a/1b combination HCV-infection at Screening as determined by the Central Laboratory； HCV treatment naïve defined as no prior therapy with any interferon (IFN), ribavirin (RBV), or other approved or investigational HCV-specific agent； Without (group 1 to 4) or with (group5 to 6) cirrhosis: (1) Without cirrhosis as defined as any one of the following: (a) Liver biopsy without showing cirrhosis (e.g., Metavir score < F4 or Ishak score < 5) within one year prior to Screening or at Screening. (b) FibroScan showing cirrhosis or results ≤ 12.5 kPa within six months prior to Screening or at Screening. (2) With cirrhosis as defined as any one of the following: (a) Liver biopsy showing cirrhosis (e.g., Metavir score = F4 or Ishak score ≥ 5) within one year prior to Screening or at Screening. (b) FibroScan showing cirrhosis or results > 12.5 kPa within six months prior to Screening or at Screening；NOTICE: If there is liver biopsy, liver biopsy results will supersede non-invasive testing results and be considered definitive. ECG without clinically significant abnormalities at Screening； Subjects must have the following laboratory parameters at Screening: (1) ALT ≤ 10 × the upper limit of normal (ULN). (2) AST ≤ 10 × ULN. (3) Without cirrhosis: 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. With cirrhosis: Total bilirubin ≤ 2 × ULN. (4) Platelet count ≥ 90,000 cells/mm3. (5) Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3. (6) HbA1c ≤ 8.5%. (7) Creatinine clearance (CLcr) ≥ 50 mL /min, as calculated by the Cockcroft-Gault equation. (8) Hemoglobin ≥ 110 g/L for female subjects; ≥ 120 g/L for male subjects. (9) Without cirrhosis Albumin ≥ 3.5 g/dL；With cirrhosis Albumin ≥30g/L. (10) Without cirrhosis INR ≤ 1.5 x ULN；With cirrhosis INR ≤ 1.7 x ULN. (11) Alpha fetoprotein (AFP)<100 ng/mL；20ng/mL≤AFP≤100ng/mL need to take Liver Ultrasonic testing to exclude subjects with suspicious liver cancer cells. (12) Anti-nuclear antibodies (ANA) ≤ 1:320； A female subject is eligible to enter the study if it is confirmed that she is: (1) 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 (2) Of childbearing potential (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 agree to consistently and correctly use an approved contraceptive method (i.e. abstinence, vaginal ring, cervical cap, contraceptive diaphragm, or intrauterine devices) from screening until at least 6 months after the last dose of study drug(s)； Male subjects must agree to consistently and correctly use an approved contraceptive method (i.e. abstinence, condom, or spouses using contraceptive drugs, vaginal ring, cervical cap, contraceptive diaphragm, or intrauterine devices) from screening until at least 6 months after the last dose of study drug(s)； Male subjects must agree to refrain from sperm donation from screening until at least 6 months after the last dose of study drug(s)； Subject must be of generally good health, with the exception of chronic HCV infection, as determined by Investigator； 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. Exclusion Criteria: Positive serological test for IgM anti-HAV or anti-HEV antibody at Screening； Positive serological test for HBsAg at Screening； Positive test for HIV-1 or HIV-2 at Screening； Donation or loss of more than 400 mL blood within 3 months prior to Baseline/Day 1； Clinically-relevant drug abuse within 12 months of signing the ICF. 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； Alcohol misuse as defined by an AUDIT score of ≥ 8； Contraindications to RBV or IFN therapy, including hemoglobinopathies (e.g., thalassemia major or sickle-cell anemia)； Pregnant or nursing female or male with pregnant female partner； Use of any prohibited medications within 30 days of the Baseline/Day 1 visit； Known hypersensitivity to TG-2349, DAG181, RBV, sulfa drugs, or formulation excipients； Current or prior history of any of the following: (1) Chronic hepatic disorder not induced by HCV (including but not limited to Hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cholangitis, autoimmune hepatitis, alcoholic liver disease, drug-induced liver disease. (2) Decompensated liver cirrhosis (Child-Pugh class B and C). (3) Any dysphagia, malabsorption syndrome, or other gastrointestinal disturbances affecting drug absorption. (4) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy. (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 (e.g. lung infiltration or impaired lung function). (9) Pancreatitis. (10) Autoimmune disease (systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, psoriasis). (11) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years. (12) 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. (13) Serious acute drug allergy (such as anaphylaxis or hepatotoxicity) or serious skin hypersensitive reaction (such as vesicular rash, Stevens Johnson Syndrome)； As determined by Investigator, a subject that would affect the therapy, evaluation or compliance with the protocol is not suitable to take part in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: non-cirrhotic subjects. low TG-2349+ low DAG181+Ribavirin<br>HCV genotype 1 infected, treatment naïve, non-cirrhotic subjects. low dose TG-2349+ low dose DAG181+Ribavirin | Drug: non-cirrhotic subjects. low TG-2349+ low DAG181+Ribavirin<br>* Group1: TG-2349 200 mg + DAG181 100 mg + Ribavirin 1000 mg or 1200 mg<br>|
| Experimental: non-cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin<br>HCV genotype 1 infected, treatment naïve, non-cirrhotic subjects. high dose TG-2349+ high dose DAG181+Ribavirin | Drug: non-cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin<br>* Group2: TG-2349 400 mg + DAG181 200 mg + Ribavirin 1000 mg or 1200 mg<br>|
| Experimental: non-cirrhotic subjects. low TG-2349+ low DAG181<br>HCV genotype 1 infected, treatment naïve, non-cirrhotic subjects. low dose TG-2349+ low dose DAG181 | Drug: non-cirrhotic subjects. low TG-2349+ low DAG181<br>* Group 3: TG-2349 200 mg + DAG181 100 mg<br>|
| Experimental: non-cirrhotic subjects. high TG-2349+ high DAG181<br>HCV genotype 1 infected, treatment naïve, non-cirrhotic subjects. high dose TG-2349+ high dose DAG181 | Drug: non-cirrhotic subjects. high TG-2349+ high DAG181<br>* Group 4: TG-2349 400 mg + DAG181 200 mg<br>|
| Experimental: cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin<br>HCV genotype 1 infected, treatment naïve, cirrhotic subjects. high dose TG-2349+ high dose DAG181+Ribavirin | Drug: cirrhotic subjects. high TG-2349+ high DAG181+Ribavirin<br>* Group 5: TG-2349 400 mg + DAG181 200 mg + Ribavirin 1000 mg or 1200 mg_<br>|
| Experimental: cirrhotic subjects. high TG-2349+ high DAG181<br>HCV genotype 1 infected, treatment naïve, cirrhotic subjects. high dose TG-2349+ high dose DAG181 | Drug: cirrhotic subjects. high TG-2349+ high DAG181<br>* Group6: TG-2349 400 mg + DAG181 200 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of antiviral efficacy (HCV RNA < lower limit of quantification, target detected or target not detected) at 12 weeks after the end of treatment | To evaluate the antiviral efficacy of two different doses of TG-2349 combination with two different doses of DAG181(± Ribavirin) as measure by the proportion of subjects achieving sustained viral response (defined as HCV RNA < lower limit of quantification, target detected or target not detected) at 12 weeks after the end of treatment (SVR 12) in treatment naïve subjects with chronic hepatic C virus genotype I infection. | 12 weeks after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of subjects achieving HCV RNA < LLOQ, TD or TND after the end of treatment (SVR4, SVR8, and SVR24). | To evaluate the proportion of subjects achieving sustained viral response at 4, 8, and 24 weeks after the end of treatment (SVR4, SVR8, and SVR24). | 24 weeks after the end of treatment | 
| The proportion of subjects achieving HCV RNA < LLOQ, TD or TND during treatment | To evaluate the proportion of subjects achieving HCV RNA < lower limit of quantification, target detected or target not detected (< LLOQ, TD or TND) during treatment. | up to 16 weeks | 
| The proportion of subjects achieving HCV RNA < LLOQ, TND during treatment and after the end of treatment. | To evaluate the proportion of subjects achieving HCV RNA < LLOQ, TND during treatment and after the end of treatment. | up to 40 weeks | 
| the average time of first HCV RNA < LLOQ, TND showing during treatment and after the end of treatment. | To evaluate the average time of first HCV RNA < LLOQ, TND showing during treatment and after the end of treatment. | up to 40 weeks | 
| the change from baseline of circulating blood HCV RNA | To evaluate the change from baseline of circulating blood HCV RNA during treatment and after the end of treatment. | up to 40 weeks | 
| the proportion of subjects with virologic failure | To evaluate the proportion of subjects with virologic failure (including breakthrough, rebound, or non-response) during treatment. | up to 16 weeks | 
| the proportion of subjects with virologic relapse | To evaluate the proportion of subjects with virologic relapse after the end of treatment. | 24 weeks after the end of treatment | 
| For subjects receiving study drugs who do not achieve SVR, the proportion and changes of TG-2349 or DAG181 resistant virus | For subjects receiving study drugs who do not achieve SVR, the proportion and changes of TG-2349 or DAG181 resistant virus will be monitored. | 24 weeks after the end of treatment | 
| Cmax | To evaluate the maximum drug concentration in the blood | up to 2 days | 
| Area Under the Curve [AUC] | To evaluate the drug quantity in the blood | up to 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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non-cirrhotic, Chronic hepatics C virus (HCV) genotype 1, treatment naïve, cirrhotic, efficacy, safety, TG-2349, DAG181, Ribavirin