| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis C Virus Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 a 3-drug regimen of GS-9451 with peginterferon alfa 2a (PEG) and ribavirin (RBV) followed by response guided PEG/RBV versus a control arm og PEG/RBV therapy for 48 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the safety and tolerability of therapy in each treatment arm
• To evaluate the emergence of viral resistance following therapy with GS-9451 when
administered with PEG and RBV with and without tegobuvir
• To characterize viral dynamics and steady state pharmacokinetics of GS-9451 and
tegobuvir when administered 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. |
|
| 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 resistant
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 GS-9451, tegobuvir, PEG and RBV in subjects who fail to respond to PEG and RBV in the control arm of this study , or who relapse
following 16 weeks of therapy with GS-9451, tegobuvir, PEG and RBV. |
|
| 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 nonchildbearing 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.
4. Subjects must have liver biopsy results (performed no more than 2 years prior to
screening) indicating the absence of cirrhosis.
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 ≤ 450 msec as
determined from screening ECG.
10. Subjects must have the following laboratory parameters at screening: ALT and AST ≤ 10 × 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; TSH not elevated
above upper limits of normal.
11. Creatinine clearance (CLcr) ≥ 50 mL/min.
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 (i.e., a non-menopausal female or a female postmenopausal < 2 years, who have 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 (see also Inclusion criterion 1). 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) from screening throughout the duration of study treatment and 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. |
|
| 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 and does not become 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 Screening or fasting glucose≥ 150 mg/dL) 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. 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
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 α-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 × 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
26. Have a history of clinically-relevant drug abuse
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
31. Have received treatment with an H2-receptor antagonist (histamine blocker) within 14 days prior to Day 1 or are expected to receive such therapy during the course of study drug dosing.
32. Have consumed grapefruit, grapefruit juice, pomegranate juice or Seville orange juice (non-Seville orange juice is allowed) within 7 days prior to Day 1.
33. 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.
34. Known hypersensitivity to PEG, RBV, the study investigational medicinal products, the metabolites, or formulation excipients. |
|
| 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after cessation of therapy |
|
| E.5.2 | Secondary end point(s) |
• To evaluate the safety and tolerability of therapy in each treatment arm
• To evaluate the emergence of viral resistance following therapy with GS-9451 when
administered with PEG and RBV with and without tegobuvir
• To characterize viral dynamics and steady state pharmacokinetics of GS-9451 and
tegobuvir when administered with PEG and RBV
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 64 |
| 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 |
| Austria |
| Belgium |
| France |
| Germany |
| Netherlands |
| Poland |
| United Kingdom |
| United States |
|
| 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
|
| Last Patient Last Visit (LPLV) for the Long-Term SVR Registry Sub-Study |
|
| 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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