| 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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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008912 |
| E.1.2 | Term | Chronic hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
| The primary objective of this study is to evaluate the antiviral efficacy (sustained virologic response [SVR]; defined as undetectable HCV RNA 24 weeks following treatment cessation) of 16 and 24 weeks of response guided duration of therapy with GS-9190, GS-9256, ribavirin (RBV), and peginterferon alfa 2a (PEG). |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study include the following:
• To evaluate the antiviral efficacy of 24 weeks of therapy with GS-9256, PEG and RBV
• To evaluate the safety and tolerability of therapy in each treatment arm.
• To evaluate the emergence of viral resistance following initiation of therapy with GS 9190 and GS-9256.
• To characterize the viral dynamics and steady state pharmacokinetics of GS 9190 and GS 9256 when administered in combination with PEG and RBV
Exploratory objectives of this study include the following:
• Assess genetic variation in the human IL28B gene as a predictor of virologic response in each treatment arm.
• Through genetic discovery research (i.e., pharmacogenomics) in subjects who provide their additional and specific consent: to identify or validate genetic markers that may be predictive of the natural history of HCV disease, the virologic response to therapy, and the tolerability of drugs used in HCV therapeutics
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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 |
Resistance Registry Substudy objective:
• To evaluate HCV resistance profiles and the persistence of selected viral resistance mutations in subjects who do not achieve SVR
Long-term SVR Registry Substudy objective:
• To evaluate the durability of response in subjects who achieve SVR
Open-label Retreatment Substudy objectives:
• To evaluate the antiviral efficacy of 24 weeks of therapy with GS-9190, GS-9256, PEG
and RBV followed by an optional 24 additional weeks of PEG and RBV in subjects who
fail to respond to PEG and RBV in the control arm of this study and subjects in Arm 1
who stop treatment at Week 16 and relapse within 12 weeks. |
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| E.3 | Principal inclusion criteria |
1. Male or female, aged from 18 to 70 years old, inclusive. Where required by local law or regulation, the participation of female subjects may be limited to women of non-childbearing potential or, if deemed appropriate, to males only in that country.
2. Willing and able to provide written informed consent.
3. Chronic HCV infection for at least 6 months prior to Baseline (Day 1) in subjects currently positive for HCV RNA and anti-HCV antibody 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) or
• a liver biopsy performed prior to Baseline (Day 1) with evidence of chronic HCV infection (i.e., there must be some degree of fibrosis, in addition to inflammation, for the biopsy criterion to be accepted as the historic data for chronic infection)
4. Subjects must have liver biopsy results (performed no more than 2 years prior to screening) indicating the absence of cirrhosis. Alternatively, in countries where the Competent Authority recommends use of a non-invasive alternative to liver biopsy (such as FibroTest, FibroScan, or Acoustic Radiation Force Impulse imaging), a test result indicating the absence of cirrhosis is allowed, if the test was performed no more than 6 months prior to screening.
5. HCV infection limited to genotype 1a or 1b.
6. Detectable plasma HCV RNA at Screening.
7. BMI between 18 and 36 kg/m2
8. Eligible subjects must also be HCV treatment-naïve, defined as no prior exposure to IFN-α, RBV, or other approved or experimental HCV therapy, and must be eligible to start standard of care therapy with PEG/RBV.
9. QTcF interval (QT corrected using Fridericia’s formula) must be less than or equal to 450 msec as determined from screening ECG.
10. Subjects must have the following laboratory parameters at screening: ALT and AST less than or equal to 10 x the upper limit of normal (reference) range (ULN); hemoglobin (Hb) ≥ 12 g/dL; white blood cell count ≥ 2,500 cells/µL; absolute neutrophil count (ANC) ≥ 1,500 cells/mm3; potassium and magnesium within normal limits; thyroid stimulating hormone (TSH) not elevated above upper limits of normal.
11. Creatinine clearance (CLcr) ≥ 50 mL/min, as calculated by the Cockcroft-Gault equation using lean body weight (performed by the central laboratory).
12. Able to comply with the dosing instructions for study drug administration and available to complete the study schedule of assessments.
13. Has not been treated with any investigational drug within 30 days of the screening visit in this study.
14. 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)
15. Women of childbearing potential 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 a male condom with spermicide; or be non-heterosexually active) from screening throughout the duration of study treatment and for at least 7 months after the last dose of RBV.
- 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 two highly effective methods 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 RBV
16. Lactating females must agree to discontinue nursing during the course of the study.
17. If male, agree to refrain from sperm donation for at least 7 months after the last dose of RBV.
18. Subject understands long-term commitment for study participation and is willing to adhere to study-specific requirements.
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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. Male with a female partner who is pregnant or is planning to become pregnant within 7 months of anticipated last dose of RBV. It is the responsibility of the male subject to ensure that his partner (or partners) is not pregnant prior to entry into the study or becomes pregnant during the treatment and for 7 months after the last dose of RBV.
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 RBV. One method should include a condom with spermicide for males.
4. Evidence of infection or co-infection with a non-genotype 1 HCV strain.
5. Poorly controlled diabetes mellitus (hemoglobin A1c > 9 at) 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; subjects under evaluation for malignancy are not eligible.
10. Untreated or significant psychiatric illnesses including severe depression, schizophrenia, psychosis, or a history of a suicide attempt.
11. Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
12. Chronic use of systemic immunosuppressive agents.
13. 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 (the medical monitor must be consulted prior to enrollment).
14. Severe chronic obstructive pulmonary disease (e.g., FEV1 < 1.5 L, or a daily requirement for inhaled bronchodilators or corticosteroids).
15. History of significant cardiac disease or a family history of Long QT Syndrome.
16. Known cirrhosis.
17. Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis).
18. History of solid organ transplantation.
19. Suspicion of hepatocellular 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.
20. Direct (conjugated) bilirubin > ULN.
21. Other signs of decompensated liver disease, as indicated by prothrombin time > 1.5 x ULN, platelets < 90,000/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).
22. Subjects with or a history of clinically-significant illness or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol.
23. 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.
24. Subjects with, or a personal or family history of, acute porphyria.
25. Ongoing alcohol abuse in the judgment of the investigator or current binge drinking.
26. Have a history of clinically-relevant drug abuse (including the use of prescription drugs outside the care of the prescribing physician) that (in the judgment of the investigator) would interfere with subject treatment, assessment or compliance with the protocol or should otherwise preclude their participation in this study.
27. Positive urine screen for amphetamines, cocaine, opiate (i.e., heroin, morphine), or methadone use.
28. Have a history of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
29. Had significant blood loss requiring transfusion or hemoglobin decline of > 3 g/dL within 56 days prior to Day 1.
30. Use of any prohibited concomitant medications as described in Section 5.10
31. Have consumed grapefruit, grapefruit juice, pomegranate juice or Seville orange juice (non-Seville orange juice is allowed) within 7 days prior to Day 1.
32. Receiving a known potent CYP 3A4 or P-gp inhibitor within 2 weeks of study drug dosing or are expected to receive such therapy during the course of study drug dosing.
33. Known hypersensitivity to PEG, RBV, the study investigational medicinal products, the metabolites, or formulation excipients.
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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 cessation of therapy). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after cessation of therapy |
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| E.5.2 | Secondary end point(s) |
| Antiviral efficacy and safety of 24 weeks of therapy |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 76 |
| 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 | No |
| 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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| Last Patient Last Visit (LPLV) for the Long-Term SVR Registry Sub-Study |
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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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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