| 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 objectives of this study are as follows:
• To describe the antiviral efficacy of GS 9256 plus GS 9190 alone and in combination with ribavirin (RIBA) against genotype 1 hepatitis C virus (HCV), as measured by the percentage of subjects achieving rapid virologic response (RVR; that is HCV RNA undetectable at Day 28).
• To evaluate the safety and tolerability of GS 9256 plus GS 9190 alone and in combination with RIBA for 28 days in subjects with chronic genotype 1 HCV infection.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are as follows:
• To characterize the pharmacokinetics of GS 9256 and GS 9190 following administration of multiple oral doses of GS 9256 plus GS 9190 alone, in combination with RIBA, and in combination with PEG/RIBA.
Exploratory objectives of this study include the following:
• To describe the aniviral efficacy of and to evaluate the safety and tolerability of GS 2956 plus GS 9190 in combination with PEG/RIBA against genotyple 1 HCV.
• To evaluate the emergence of viral resistance during and following treatment with GS 9256 plus GS 9190 alone, in combination with RIBA, and in combination with PEG/RIBA for 28 days and for 72 weeks following discontinuation of study drugs (GS-9256 plus GS-9190).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study.
1. Male or female, aged from 18 to 70 years old, inclusive.
2. Willing and able to provide written informed consent.
3. Body mass index (BMI) from 18 to 36 kg/m^2, inclusive.
Note: BMI may be calculated according to either of the following formulae:
BMI = weight in pounds x 703/(height in inches)^2 or weight in kilograms/(height in meters)^2
4. HCV infection limited to genotype 1.
5. Subjects must have baseline plasma HCV RNA ≥ 3 log10 IU/mL at screening, but < 7.2 log10 IU/mL.
6. Liver biopsy results (or combined results of FibroTest or FibroScan, if considered acceptable by regulators and ethics committess on a country-by-country basis) within the past 2 years prior to screening indicating the absence of cirrhosis. If a liver biopsy or combined FibroTest and FibroScan 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 procedure to enrollment). Alternative methods to evaulate cirrohosis may be used provided they are approved in advance by the Medical Monitor.
7. Chronic HCV infection will be documented by (1) a positive anti-HCV antibody test or evidence of HCV RNA (i.e., viral load or genotype) (2) a liver biopsy (or FibroTest or FibroScan results where appropriate) consistent with chronic HCV infection, or (3) elevated ALT values (i.e. above the normal range) at any point in within one year prior to screening.
On a case-by-case the sponsor will consider permitting enrollment of patients with clear cut clinical histories of chronic infection in circumstances where laboratory documentation cannot be retrieved.
8. Eligible subjects must also be HCV treatment-naïve, defined as no prior exposure to IFNα, RIBA, or experimental HCV therapy, with imminent plans to start standard of care therapy with PEG/RIBA.
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, AST, and GGT ≤ 5 x the upper limit of normal (reference) range (ULN); white blood cell count ≥ 2,500 cells/µL; absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 (unless considered a physiologic variant discussed with and approved by the Gilead medical monitor); potassium and magnesium within normal limits; TSH within normal limits (unless currently being treated for hypothyroidism or the TSH abnormality is not considered to be clinically significant after consultation with the Gilead Medical Monitor); hemoglobin (Hb) ≥ 13 g/dL for males and Hb ≥ 12 g/dL for females.
11. Creatinine clearance (CLcr) ≥ 50 mL/min, as calculated by the Cockcroft-Gault equation using lean body weight:
CLer (mL)/min)= (140-Age) x LBW/72 x Scr (x0.85 for female subjects)
where:
Age is calculated in years and Scr is the subject’s measured serum creatinine (in mg/dL).
LBW is the subject’s lean body weight in kilograms, calculated as:
Male: LBW = 50 + 2.3*[(height in cm – 152.4) / 2.54] OR 50 + 2.3*(height in inches – 60)
Female: LBW = 45.5 + 2.3*[(height in cm – 152.4) / 2.54] OR 45.5 + 2.3*(height in inches – 60)
If a subject’s height is less than or equal to 152.4 cm (60 inches), then his LBW is 50 kg and her LBW is 45.5 kg. If the subject’s actual body weight is less than his or her calculated LBW, then the subject’s actual weight should be used in place of his/her LBW.
12. 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 vasectomy) from screening throughout the duration of study treatment and for 7 months after the last dose of RIBA.
13. If male, agree to refrain from sperm donation for at least 7 months after the last dose of RIBA.
14. Able to comply with the dosing instructions for study drug administration and available to complete the study schedule of assessments.
15. 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)
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| E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1. Female of child-bearing potential (defined as a non-menopausal female or a female who is menopausal < 2 years, who has not had a hysterectomy, bilateral oophorectomy or medically documented ovarian failure), pregnant woman, or nursing woman.
[Note: Female subjects who are post-menopausal for < 2 years are required to have a confirmed folloicle-stimulating hormone (FSH) level of ≥ 40 mIU/mL at the screening evaluation).]
2. Male with a female partner who is pregnant or is planning to become pregnant within 7 months of anticipated last dose of RIBA.
3. Males who are unwilling to use two forms of effective birth control throughout the duration of study treatment and for 7 months after the last dose of RIBA. 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 or fasting glucose ≥ 150 mg/dL) .
6. History of hemoglobinopathy (e.g. thalassemia), retinal disese, sarcoidosis
7. 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
8. Untreated or significant psychiatric illnesses including severe depression, schizophrenia, psychosis, or a history of a suicide attempt
9. Co-infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) or multiple HCV genotypes
10. Chronic use of systemic immunosuppressive agents
11. 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.
12. Severe chronic obstructive pulmonary disease
13. 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
Fridericia’s formula: QTcF=QT/RR0^.333
14. Known cirrhosis, Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
15. History of solid organ transplantation
16. Suspicion of hepatocelluar carcinoma; if a-fetoprotein >50 ng/mL, enrollment is only allowed if results of appropriate diagnostic studies are inconsistent with a diagnosis of hepatocellular tumor
17. Total bilirubin > ULN or known diagnosis of Gilbert’s syndrome
18. 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
19. 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.
20. Have a history of a primary gastrointestinal disorder that could interfere with the absorption of the study drug .
21. Subjects with, or a personal or family history of, acute porphyria.
22. Ongoing alcohol abuse in the judgment of the investigator
23. Have a history of clinically-relevant drug abuse .
24. Positive urine screen for amphetamines, cocaine, opiate (i.e., heroin, morphine), or methadone use.
25. Have a history of difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
26. Had significant blood loss within 56 days prior to Day 1.
27. Use of any prohibited concomitant medications
28. Receiving a known potent inhibitor of CYP 3A4 and/or pgp within 2 weeks of study drug dosing or are expected to receive such therapy during the course of study drug dosing
29. Have received treatment with an H2 receptor antagonist within 14 days prior to Day 1.
30. Have consumed grapefruit, grapefruit juice, pomegranate juice or Seville orange juice within 7 days prior to Day 1.
31. Received any investigational medication in another research study within 45 days prior to Day 1.
32. Known hypersensitivity to PEG, 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 will be viral load suppression at day 28, as measured by the proportion of subjects achieving RVR (i.e. HCV RNA undetectable at Day 28). Plasma HCV RNA reduction from baseline will be evaluated as well. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 18 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 18 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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