E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Hepatitis C Virus Infection |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008912 |
E.1.2 | Term | Chronic hepatitis C |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy of two oral doses of GS 9450 to placebo in subjects with chronic HCV infection as evidenced by histologic response (at least a 2-point decrease in Knodell necroinflammatory score with no concurrent worsening in the Knodell fibrosis score) at Week 24. |
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E.2.2 | Secondary objectives of the trial |
• To compare the safety and tolerability of two oral doses of GS 9450 to placebo in subjects with chronic HCV • To compare the efficacy of two oral doses of GS 9450 to placebo in subjects with chronic HCV, as evidenced by: — Change from baseline in the Knodell necroinflammatory score — Change from pretreatment in alanine aminotransferase (ALT) levels; — Change from pretreatment in aspartate aminotransferase (AST) levels; — Change from baseline in CK–18 caspase cleavage fragments; — Change from baseline in hepatic collagen content as measured by morphometry of liver biopsy specimens; — Evaluation of Ishak scoring relative to baseline; — Change from baseline in hepatic apoptosis as measured by TUNEL staining of liver biopsy specimens; and — Change from baseline in hepatic CK–18 neoantigen expression as measured by immunohistochemical staining of liver biopsy specimens
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male or female, aged from 18 to 65 years old, inclusive • Chronic HCV infection, defined as having documented HCV infection (antibody or RNA positivity) at least 6 months prior to Baseline (Day 1) with HCV viremia (i.e., detectable plasma HCV RNA levels) at screening • Documented evidence of either 1) having previously failed treatment with PEG-based HCV therapy in combination with RIBA therapy, OR 2) being unable to tolerate or having contraindications to receiving INF or RIBA therapy •Have a Knodell necroinflammatory score at least 3 as determined from the screening liver biopsy evaluation • Have laboratory values at Screen that meet the following criteria: - ALT >ULN but < 10 x ULN; - AST < 10 x ULN; - platelets at least 75,000/mm3; - total bilirubin less than or equal to 1.5 x ULN; - prothrombin time less than or equal to 1.5 x ULN; - albumin at least 3.0 g/dL; - absolute neutrophil count (ANC) at least 1,000 cells/mm3 (Note: physiologic neutropenia may be allowed subsequent to GSI Medical Monitor review and approval); and - hemoglobin (Hb) at least 10 g/dL • Have a BMI between 19 and 36 kg/m2, inclusive • Creatinine clearance (CLcr) at least 70 mL/min • Heterosexually active males must be willing to use a highly effective method of contraception from Screen for at least 3 months (90 days) after receiving the last dose of study drug. Males must also agree not to donate sperm for at least 3 months (90 days) after the last study drug dose(s). • Females who are < 60 years old (testing not required for those who have had a hysterectomy, tubal ligation, or bilateral oophorectomy) must have a negative serum pregnancy test at Screen and a negative urine pregnancy test at Baseline prior to receiving the first dose of study drug. Females of childbearing potential must agree to use an acceptable highly effective method of contraception during heterosexual intercourse from Screen through at least 30 days or one menstrual cycle (whichever is longer) after receiving the last dose of study drug. Female subjects currently using hormonal contraception must have used that method of hormonal contraception for at least 3 months prior to enrolling in the study and must agree to continue using their existing hormonal contraception and supplement it with a barrier method of contraception • In reasonably good health as determined by the Investigator, based on review of the results of a screening evaluation (to include physical examination, vital signs and routine clinical laboratory tests) • Willing and able to provide written, informed consent
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E.4 | Principal exclusion criteria |
• Pregnant or breast feeding women or women who believe they may wish to become pregnant during the course of the study or within 30 days or one menstrual cycle (whichever is longer) of last study drug administration • Males who have partners planning to become pregnant during the course of the study or within 90 days of the last dose of study drug • Females and males of reproductive potential who are unwilling to use effective method(s) of birth control while enrolled in the study and for a minimum of 30 (or one menstrual cycle, whichever is longer) or 90 days, respectively, after ingestion of the last dose of study medication • Infection with HCV genotype 3 • Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) or other liver disease of a non-HCV etiology • Presence of pancreatitis • History of solid organ transplantation • Presence of autoimmune disease • History of malignancy (history of localized squamous or non-invasive basal cell skin cancers successfully treated more than 5 years from screening is permitted) • Current excessive alcohol ingestion, averaging > 3 drinks/day for females and > 4 drinks/day for males or binge drinking • History of seizure, including a single episode • Is a public transportation operator or operates heavy construction machinery • Recent significant infection • History of or current evidence of hepatocellular carcinoma (HCC; e.g., a-fetoprotein > 50 ng/mL or as indicated by recent imaging) [ultrasound or triple-phase IV contrast CT/MRI] performed within 3 months prior to screening or, if recent imaging has not been performed, prescence of hepatic nodule on screening right upper quadrant [RUQ] ultrasound that is consistent with a diagnosis of HCC) • Decompensated liver disease, as indicated by total bilirubin > 1.5 x ULN, prothrombin time > 1.5 x ULN, platelets < 75,000/mm3 or albumin < 3 g/dL at screening OR current or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy or variceal hemorrhage) • Presence of Child-Pugh grade B or C cirrhosis • Hb < 10 g/dL at Screen • ANC < 1,000 cells/mm3 at Screen • Have initiated therapy with agents having potential hepatic anti-inflammatory or anti-fibrotic properties within 90 days prior to Baseline (Day 1) or are expected to initiate such therapy during the study. Such agents include (but are not limited to): angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, peroxisome proliferator-activated receptor agonists, ursodeoxycholic acid, mycophenolate, pentoxifylline. Subjects who have received such agents may be eligible if they have received stable therpay (including dose) for ≥ 90 days prior to Baseline (Day 1) and are anticipated to continue therapy throughout the study; consultation with the GSI Medical Monitor is required prior to enrollment of such subjects • Have initiated therapy with potentially hepatotoxic/cholestatic drugs within 90 days prior to Baseline or are expected to initiate such therapy during the study Subjects who have received such agents may be eligible if they have received stable therapy (including dose) for at least 90 days prior to Baseline and are anticipated to continue therapy throughout the study. Intermittent use of acetaminophen in recommended doses is permitted • Are expected to receive an anti-tuberculosis medication at anytime during the study • Have received therapy with systemic steroids, immunosuppressant therapies or chemotherapeutic agents within 90 days prior to Baseline or are expected to receive such therapy during the study • Have initiated maintainance therapy with or have been non-compliant with a treatment regimen of methadone or buprenorphine within six months prior to Baseline (Day 1) or are expected to initiate such therapy during the study • Are expected to receive anti-HCV therapy from Baseline (Day 1) to week 24 study visit. • Have received prescribed medications that are known to increase the risk of seizure within 30 days prior to Baseline (Day 1) or are expected to receive such therapy during the study • History of or current clinically significant illness or any other major medical disorder that may interfere with subject treatment, assessment, compliance with the protocol or adequate follow-up • Have a history of a primary gastrointestinal disorder that could interfere with the absorption of the study drug or that could interfere with normal gastrointestinal anatomy or motility • Received study medication while participating in another research study within 60 days prior to Baseline • A positive urine drug screen for amphetamines or cocaine at Screen • Known hypersensitivity to the study drugs, the metabolites or formulation excipients
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E.5 End points |
E.5.1 | Primary end point(s) |
Histologic response (at least 2 point decrease in Knodell necroinflammatory score with no concurrent worsening in the Knodell fibrosis score) at Week 24. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LPLV will be defined as date of last Week 28 follow-up visit for the last patient
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |