| 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 | 12.0 |
| 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 antiviral efficacy (sustained virologic response; SVR) of 48 weeks of GS-9190 versus placebo when administered in combination with 48 weeks of peginterferon alfa 2a (PEG) and ribavirin (RIBA) |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate and compare the safety (including QTcF interval assessment) and tolerability of 48 weeks of GS-9190 versus placebo in combination with PEG and RIBA
• To compare the antiviral efficacy of GS-9190 versus placebo in combination with PEG and RIBA at 4 weeks (rapid virologic response; RVR), 12 weeks (early virologic response; EVR), 24 weeks, and 48 weeks
• To evaluate the incidence of mutations in HCV NS5B polymerase gene
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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 |
Long-term SVR Follow-up Registry Substudy:
Objective: To evaluate the durability of response in subjects who achieve SVR
Included in the protocol for GS-US-196-0116, therefore the same dates and version numbers apply
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| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years of age
2. Chronic HCV infection for at least 6 months prior to Baseline (Day 1) documented by
• a positive anti-HCV antibody test, positive HCV RNA assay, or HCV genotype test at least 6 months prior to Baseline (Day 1) and currently positive for HCV RNA and anti-HCV antibody, or
•currently anti-HCV antibody positive and positive for HCV RNA and a liver biopsy performed ≥ 6 months prior to Baseline (Day 1) with evidence of HCV infection
3. Liver biopsy results (performed no more than 2 years prior to Screening) indicating the absence of cirrhosis. If a liver biopsy performed more than 1 year prior to Screening indicates Stage 3 fibrosis, the medical monitor must be consulted prior to enrollment (i.e., consensus must be reached that progression to cirrhosis with hepatic impairment is unlikely to have occurred in the time interval from liver biopsy to enrollment).
4. HCV treatment-naive, defined as no prior exposure to PEG, RIBA, any interferon alfa, or experimental HCV therapy
5. Mono-infection with HCV genotype 1
6. Detectable plasma HCV RNA at Screening
7. BMI between 18 and 36 kg/m2
8. Subjects must have the following laboratory parameters: hemoglobin
≥ 12 g/dL for females and ≥ 13 g/dL for males, platelets ≥ 90,000/mm3, white blood cell count > 2,500 cells/microlitre, neutrophils > 1500/mm3 (unless considered a physiologic variant discussed with and approved by the Gilead Medical Monitor), potassium and magnesium within normal limits, and TSH within normal limits (unless currently being treated for hypothyroidism in which case the medical monitor must be consulted prior to enrollment)
9. Creatinine clearance (CLcr) ≥ 50 mL/min
10. Willing and able to provide written informed consent and to comply with all study requirements
11. Has not been treated with any investigational drug within 45 days of the randomization visit in this study.
12. 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 or slit lamp evaluation)
13. 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 beta-human chorionic gonadotropin (hCG) at screening and negative urine beta-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 non-heterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study treatment and for at least 7 months after the last dose of RIBA.
• 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 at least 7 months after the last dose of RIBA
•Lactating females must agree to discontinue nursing during the course of the study.
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|
| E.4 | Principal exclusion criteria |
1. Pregnant women or women who may wish to become pregnant during the course of the study
2. Males who have partners who are pregnant or are planning to become pregnant
3. 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 at least 7 months after the last dose of RIBA. One method should include a condom with spermicide for males.
4. Infection with non-genotype 1 HCV
5. Poorly controlled diabetes mellitus (hemoglobin A1c > 9) unless treatment intervention has been reviewed with the Gilead Medical Monitor and improved glucose control is anticipated
6. History of hemoglobinopathy (e.g. thalassemia)
7. History of known retinal disease
8. History of sarcoidosis
9. 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); subjects under evaluation for malignancy are not eligible
10. Suspicion of hepatocelluar carcinoma; if alpha-fetoprotein > 50 ng/mL, enrollment is only allowed if results of appropriate diagnostic studies are inconsistent with a diagnosis of hepatocellular tumor
11. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
12. Decompensated liver disease defined as conjugated bilirubin > 1.5 x ULN, prothrombin time (PT) > 1.5 x ULN, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g. ascites, jaundice, encephalopathy, variceal hemorrhage)
13. Untreated or significant psychiatric illnesses including severe depression, schizophrenia, or psychosis, or a history of a suicide attempt
14. Co-infection with HIV or HBV
15. Chronic use of systemic immunosuppressive agents
16. Use of any prohibited concomitant medications
17. Presence of autoimmune disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, psoriasis of greater than mild severity). Subjects with hypothyroidism whose TSH is controlled on medication may be enrolled.
18. Severe chronic obstructive pulmonary disease (e.g., FEV1 < 1.5 L, or a daily requirement for inhaled bronchodilators or corticosteroids)
19. History of significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction < 40% ) or a family history of Long QT Syndrome. The following ECG abnormalities at screening are exclusionary: QTcF (QT corrected using Fridericia’s formula) of > 450 msec; QRS > 120 msec (left or right hemiblock is not exclusionary); bradycardia (< 45 beats per minute); second or third degree heart block. A history of clinically significant coronary artery disease without prior myocardial infarction will require consultation with a cardiologist and the medical monitor prior to enrollment
20. Positive urine screen for amphetamines, cocaine, opiate (i.e. heroin, morphine), or methadone use
21. Ongoing alcohol abuse in the judgment of the investigator (e.g., excessive alcohol ingestion, averaging > 3 drinks/day for females and > 4 drinks/day for males) or current binge drinking
22. 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
23. History of solid organ transplantation
24. Known hypersensitivity to the study drugs, their metabolites or formulation excipients
25. Participation in any other clinical trial within 45 days of randomization or intention to participate in another clinical trial during participation in this study.
26. In the judgment of the Investigator, should not participate in the study due to potential clinical or compliance issues course of the study
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is SVR (HCV RNA undetectable 24 weeks after the last
scheduled on-treatment visit [i.e., at Week 72]) in all randomized and treated subjects. |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 |
|
| 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
|
| End of trial is defined as LPLV assessed in the sub-study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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