E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Genotype 1 Hepatitis C Virus Infection |
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E.1.1.1 | Medical condition in easily understood language |
Hepatitis C Virus Infection |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10019751 |
E.1.2 | Term | Hepatitis C virus |
E.1.2 | System Organ Class | 100000004848 |
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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:
• To determine the antiviral efficacy of combination treatment with sofosbuvir/GS-5885 fixed-dose combination ± RBV as measured by the proportion of subjects with SVR
12 weeks after discontinuation of therapy (SVR12).
• To evaluate the safety and tolerability of each treatment regimen as assessed by review of the accumulated safety data |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To determine the proportion of subjects who attain SVR at 4 and 24 weeks after discontinuation of therapy (SVR4 and SVR24)
• To evaluate the kinetics of circulating HCV RNA during treatment and after treatment discontinuation
• To evaluate the emergence of viral resistance to sofosbuvir and GS-5885 during treatment and after treatment discontinuation
• To characterize the steady state pharmacokinetics of study drugs
• To assess the effect of treatment on health related quality of life |
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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 |
Pharmacokinetic Substudy:
An intensive serial PK sample collection will be performed at the Week 2 or Week 4 on-treatment
visit to determine the steady-state pharmacokinetics of sofosbuvir (and its metabolites GS-566500 and GS-331007), GS-5885, and RBV (if appropriate).
Pharmacogenomics Substudy:
The objective of this substudy is to identify or validate host markers that may be predictive of the natural history of disease, virologic response to therapy and/or the tolerability of medical therapies through genetic discovery research (e.g., pharmacogenomics), in subjects who provide their separate and specific consent. |
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E.3 | Principal inclusion criteria |
1) Willing and able to provide written informed consent
2) Male or female, age ≥ 18 years
3) Body mass index (BMI) ≥ 18
4) HCV RNA ≥ 104 IU/mL at Screening
5) HCV treatment-naïve, as defined as no prior exposure to any IFN, RBV, or other approved or experimental HCV-specific direct-acting antiviral agent
6) HCV genotype 1a, 1b, or mixed 1a/1b at Screening. Any non-definitive results will exclude the subject from study participation
7) Confirmation of chronic HCV infection documented by either:
a) A positive anti-HCV antibody test or positive HCV RNA or positive HCV genotyping test at least 6 months prior to the Baseline/Day 1 visit, or
b) A liver biopsy performed prior to the Baseline/Day 1 visit with evidence of chronic HCV infection
8) Cirrhosis determination [up to 20% of study subjects may have cirrhosis]:
a) Cirrhosis is defined as any one of the following:
i) Liver biopsy showing cirrhosis (e.g. Metavir score = 4 or Ishak score ≥ 5)
ii) Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
iii) FibroTest® score of > 0.75 AND an AST:platelet ratio index (APRI) of > 2 during Screening
b) Absence of cirrhosis is defined as any one of the following:
i) Liver biopsy within 2 years of Screening showing absence of cirrhosis
ii) Fibroscan (in countries where locally approved) within 6 months of
Baseline/Day1 with a result of ≤ 12.5 kPa
iii) FibroTest® score of ≤ 0.48 AND APRI of ≤ 1 during Screening
c) In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required; liver biopsy results will supersede any imaging or blood test results and be considered definitive.
9) Liver imaging within 6 months of Baseline/Day 1 to exclude hepatocellular carcinoma
(HCC) is required in patients with cirrhosis
10) Screening ECG without clinically significant abnormalities
11) Subjects must have the following laboratory parameters at screening:
a) ALT ≤ 10 × the upper limit of normal (ULN)
b) AST ≤ 10 × ULN
c) Direct bilirubin ≤ 1.5 × ULN
d) Platelets ≥ 50,000
e) HbA1c ≤ 8.5%
f) Creatinine clearance (CLcr) ≥ 60 mL /min, as calculated by the Cockcroft-Gault equation {2202}
g) Hemoglobin ≥ 11 g/dL for female subjects; ≥ 12 g/dL for male subjects.
h) Albumin ≥ 3g/dL
i) INR ≤ 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.
12) Subject has not been treated with any investigational drug or device within 30 days of the
Screening visit.
13) A female subject is eligible to enter the study if it is confirmed that she is:
a. Not pregnant or nursing
b. Of non-childbearing potential (as defined in the protocol), or
c. Of childbearing potential (as defined in the protocol). Women ≤ 50 years of age with amenorrhea will be considered to be of childbearing potential. These women must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on the Baseline/Day 1 visit prior
to randomization. They must also agree to one of the following from 3 weeks prior to Baseline/Day 1 until 6 months after last dose of RBV or 30 days after last dose of study drug if not taking RBV (if required by regulations, additional pregnancy tests beyond 6 months may be added):
• Complete abstinence from intercourse for the entire duration specified above,
or
• Consistent and correct use of 1 of the following highly effective methods of birth control, in addition to a male partner who correctly uses a condom from the date of screening until 6 months after the last dose of RBV or 30 days after last dose of study drug if not taking RBV:
— implants of levonorgestrel
— injectable progesterone
• any intrauterine device (IUD) with a documented failure rate of less than 1% per year
— oral contraceptives (either combined or progesterone only)
— female barrier method: cervical cap or diaphragm with spermicidal agent
— contraceptive vaginal ring
— transdermal contraceptive patch
— tubal sterilization
— vasectomy in male partner.
14) All male study participants must agree to consistently and correctly use a condom while their female partner agrees to use 1 of the highly effective methods of birth control listed above from the date of screening until 7 months after their last dose of RBV or 90 days after their last dose of study drug if not taking RBV.
15) Male subjects must agree to refrain from sperm donation from the date of screening until at least 7 months after the last dose of RBV or 90 days after their last dose of study drug if not taking RBV.
16) Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator.
17) Subject must be able to comply with the dosing instructions for study drug administration
and able to complete the study schedule of assessments. |
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E.4 | Principal exclusion criteria |
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol; subjects currently under evaluation for a potentially clinically-significant illness (other than HCV) are also excluded.
b) Gastrointestinal disorder or post operative condition that could interfere with the absorption of the study drug.
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
d) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
e) Solid organ transplantation.
f) Significant pulmonary disease, significant cardiac disease or porphyria.
g) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 5 years. Subjects with psychiatric illness that is well-controlled on a stable treatment regimen for at least 12 months prior to randomization or has not required medication in the last 12 months may be included.
h) 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 screening); subjects under evaluation for malignancy are not eligible.
i) Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Pregnant or nursing female or male with pregnant female partner.
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis).
4) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
5) Donation or loss of more than 400 mL blood within 2 months prior to Baseline/Day 1
6) Clinically-relevant drug abuse within 12 months of screening. A positive drug screen will exclude subjects unless it can be explained by a prescribed medication; the diagnosis and prescription must be approved by the investigator.
7) Alcohol misuse as defined by a Alcohol Use Disorders Identification Test (AUDIT) score ≥ 8
8) Contraindications to RBV therapy, including significant history of clinically significant hemoglobinopathy (e.g., sickle cell disease, thalassemia).
9) Use of any prohibited concomitant medications as described in Section 5.5 within 21 days of the Baseline/Day 1 visit.
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
11) Known hypersensitivity to RBV, GS-5885, sofosbuvir, or formulation recipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is sustained viral response 12 weeks post last dose of any treatment (HCV RNA <LOQ 12 weeks after cessation of therapy) in the ITT population (SVR12). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 weeks post last treatment dose |
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E.5.2 | Secondary end point(s) |
1) Safety: Adverse events (AE), safety labs, electrocardiograms (ECGs) and vital signs
2) Sustained viral response 24 weeks post last dose of any treatment (HCV RNA <LOQ 24weeks after cessation of therapy) in the ITT population (SVR24). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and tolerability will be assessed throughout the study
SVR24 will be assessed 24 weeks post the last treatment dose |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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) | 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 | No |
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 | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
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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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |