| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Genotype-1 Chronic Hepatitis C Virus (HCV) 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 early antiviral activity (complete early virologic response rate; cEVR) of GS-9190 versus placebo, in combination with peginterferon alfa 2a (PEG) and ribavirin (RIBA), following 12 weeks of therapy
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| E.2.2 | Secondary objectives of the trial |
To compare the antiviral activity (sustained virologic response; SVR) of GS-9190 versus placebo, in combination with PEG and RIBA, administered for 48 weeks
To determine SVR rates among subjects receiving GS-9190 in combination with PEG and RIBA who stop therapy at 24 weeks after achieving HCV RNA < 25 IU/mL at Week 4 and undetectable HCV RNA (< 10 IU/mL) at Week 12 maintained through Week 24
To evaluate and compare the safety (including QTcF assessment) and tolerability of GS-9190 versus placebo, in combination with PEG and RIBA
To compare the antiviral activity at 4 weeks (RVR) of GS-9190 versus placebo, in combination with PEG and RIBA
To compare the antiviral activity at 24 and 48 weeks of GS-9190 versus placebo, in combination with PEG and RIBA
To evaluate the incidence of mutations in HCV NS5B polymerase gene in each treatment arm of the study |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
The effect of natural variability of baseline HCV NS5B sequence on virologic response will be investigated. Sequence analysis of the HCV NS5B polymerase gene will be conducted at baseline for selected subjects. Sequence analysis of HCV NS5B will be attempted for all subjects with virologic non-response/early discontinuation who have detectable HCV RNA for evidence of resistance.
Long-term SVR follow-up registry substudy:
All subjects who achieve SVR, regardless of initial treatment assignment, will continue to be followed for a 3 year period to evaluate durability of response. |
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| E.3 | Principal inclusion criteria |
• Male or female aged 18 to 70 years
• Chronic HCV infection for at least 6 months prior to Baseline (Day 1) (anti-HCV antibody positive; positive for plasma HCV RNA; medical history consistent with chronicity accepted by the investigator)
• Liver biopsy results within the past 2 years prior to Baseline (Day 1) indicating the absence of cirrhosis
• HCV treatment-naive, defined as no prior exposure to PEG, RIBA, or experimental HCV therapy
• Mono-infection with HCV genotype 1a or 1b
• Detectable plasma HCV RNA at Screening
• BMI between 19 and 36 kg/m2 as calculated per protocol
• Subjects must have the following laboratory parameters: hemoglobin ≥ 11 g/dL, platelets ≥ 90,000/mm3, white blood cell count > 2,500 cells/ μL, neutrophils > 1500/mm3 (unless considered a physiologic variant discussed with and approved by the Gilead Medical Monitor), and TSH within normal limits (can be controlled on medications)
• Creatinine clearance (CLcr) ≥ 50 mL/min, as calculated by the Cockcroft-Gault equation (please refer to the protocol)
• Willing and able to provide written informed consent and to comply with all study requirements
• Of generally good health as determined by the Investigator, based upon physical examination, laboratory parameters, ECG findings, vital signs, and medical history; physical examination must be inclusive of retinal exam (e.g., opthalmoscopic evaluation)
• Subject agrees to use adequate skin protection (e.g., sunblocking agent) when exposed to the sun.
• Women of childbearing potential (i.e., a non-menopausal female or a female with menopausal < 2 years, who has not had a hysterectomy, bilateral oophorectomy or medically documented ovarian failure) must have negative serum β-human chorionic gonadotropin (hCG) at screening and negative urine β-HCG at Baseline (Day 1) prior to the first study drug administration. Female subjects of childbearing potential and male subjects with a female partner of childbearing potential must agree that they and their partner will use effective contraception (two separate forms of contraception simultaneously, one of which must be an effective barrier method, or be nonheterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study treatment and for 24 weeks after the last dose of RIBA and, in Europe, for 28 weeks after the last dose of RIBA for male subjects and their female partners of childbearing potential.
- Female subjects who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing.
- Female subjects who are postmenopausal for less than two years are required to have FSH > 40 mIU/mL. If the FSH is ≤ 40 mIU/mL, the subject must agree to use highly effective method of birth control (as described above) to participate in the study.
- Male subjects who are sexually active must be willing to use effective barrier contraception (e.g., condom with spermicide) during heterosexual intercourse from screening through completion of the study and continue for 24 weeks after the last dose of RIBA and, in Europe, for 28 weeks after the last dose of RIBA. |
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| E.4 | Principal exclusion criteria |
• Pregnant or breast feeding women or women who may wish to become pregnant during the course of the study
• Males who have partners who are pregnant or are planning to become pregnant
• Pregnant or breast feeding women or women who may wish to become pregnant during the course of the study
• Males who have partners who are pregnant or are planning to become pregnant
• Males and females of reproductive potential who are unwilling to use two forms of effective birth control throughout the duration of study treatment and for 24 weeks after the last dose of RIBA; in Europe (EU), this period extends to 28 weeks after the last dose of RIBA for male subjects and their female partners of childbearing potential. One method should include a condom with spermicide for males
• Infection with non-genotype 1 HCV
• Poorly controlled diabetes mellitus (hemoglobin A1c > 7) unless treatment intervention has been reviewed with the Gilead Medical Monitor and improved glucose control is anticipated
• History of hemoglobinopathy (e.g., thalassemia)
• History of known retinal disease
• History of sarcoidosis
• History of invasive malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screen)
• Evidence of hepatocelluar carcinoma (e.g., α-fetoprotein > 50 ng/mL)
• Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
• Decompensated liver disease defined as conjugated bilirubin > 1.5 × ULN, prothrombin time (PT) > 1.5 × ULN, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage)
• Untreated or significant psychiatric illnesses including severe depression, schizophrenia, psychosis, or a history of a suicide attempt
• Co-infection with HIV, HBV, or multiple HCV genotypes
• Chronic use of systemic immunosuppressive agents
• Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, psoriasis of greater than mild severity). Subjects with treated hypothyroidism with normal TSH may be enrolled.
• Severe chronic obstructive pulmonary disease (e.g., FEV1 < 1.5 L, or a daily requirement for inhaled bronchodilators or corticosteroids)
• History of clinically significant cardiac disease, including a family history of Long QT Syndrome, and/or evidence of the following ECG abnormalities at screening: QTcF (QT corrected using Fridericia’s formula) of > 450 msec; complete or incomplete left or right bundle branch block; intraventricular conduction delay with QRS duration of > 120 msec; bradycardia (< 45 beats per minute); pathologic Q-waves (Q-wave of > 40 msec or depth of > 0.4 to 0.5 V); arrhythmia (an isolated premature ventricular contraction on screening/Day 1 is not exclusionary) ; ventricular pre-excitation; second or third degree heart block Fridericia’s formula: QTcF=QT/RR0.333
• Positive urine screen for amphetamines or cocaine
• Known, current heroin, morphine, or methadone use
• Ongoing alcohol abuse in the judgment of the investigator (in no case intake of more than 28 units of alcohol per week [1 unit = ½ pint of beer, 1 glass of wine, 1 shot of spirits])
• Receiving a known potent CYP 3A4 inhibitor within 2 weeks of study drug dosing or are expected to receive such therapy during the course of study drug dosing (see Section 5.4 of the protocol for a list of exclusionary inhibitors)
• Known hypersensitivity to the study drugs, their metabolites or formulation excipients
• In the judgment of the Investigator, should not participate in the study due to potential clinical or compliance issues |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is complete early virologic response (cEVR), defined as HCV RNA undetectable at Week 12.
The primary safety and tolerability endpoint is any AE leading to permanent discontinuation of study drug. |
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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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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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| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 10 |
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