| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10019744 |
| E.1.2 | Term | Hepatitis C |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| 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 objectives of this study are:
* To compare the efficacy of treatment with sofosbuvir (SOF)/GS-5816 fixed dose combination (FDC) for 12 weeks with
that of SOF + ribavirin (RBV) for 24 weeks as measured by the proportion of subjects with sustained viral response 12 weeks
after cessation of treatment (SVR12)
* To evaluate the safety and tolerability of each treatment regimen |
|
| 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 cessation of each treatment regimen (SVR4 and SVR24)
* To evaluate the proportion of subjects with virologic failure
* To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of each treatment regimen
* To evaluate the emergence of viral resistance to SOF and GS-5816 during treatment and after cessation of treatment |
|
| 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 |
Optional Pharmacogenomics (PG) Substudy
All subjects will be eligible to participate in the PG substudy.
For subjects who provide separate consent for optional genetic testing, an additional blood sample will be obtained for possible genetic discovery research to identify or validate genetic markers (e.g., pharmacogenomics) that may be predictive of the safety and/or tolerability of study drug used in this protocol. This sample is recommended to be collected at the Baseline/Day 1 visit, but may be collected at any time during the study or at a separate post-study visit, if necessary. |
|
| E.3 | Principal inclusion criteria |
1) Willing and able to provide written informed consent
2) Male or female, age greater than or equal to 18 years
3) HCV RNA greater than or equal to x 10 000 IU/mL at Screening
4) HCV genotype 3 determined at Screening by the Central Laboratory. Any non-definitive results will exclude the subject from study participation
5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy
6) Classification as treatment naïve or treatment experienced:
a) Treatment naïve is defined as having never been exposed to approved or experimental HCV-specific direct-acting antiviral agents or prior treatment of HCV with interferon or ribavirin
b) Treatment experienced is defined as prior treatment failure to a regimen containing interferon either with or without RBV that was completed at least 8 weeks prior to Baseline/Day 1. Subject must not have discontinued the prior regimen that resulted in virologic failure due to an adverse event.
i) The subject’s medical records must include sufficient detail of prior virologic failure to allow for categorization of prior response, as either:
(1) Non-Responder: Subject did not achieve undetectable HCV RNA levels while on treatment, or
(2) Relapse/Breakthrough: Subject achieved undetectable HCV RNA levels during treatment or within 4 weeks of the end of treatment but did not achieve SVR
7) Cirrhosis determination (approximately 20% of 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) FibroTest® score > 0.75 AND an AST:platelet ratio index (APRI) > 2 during Screening
iii) Fibroscan with a result of >12.5 kPa
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) FibroTest® score ≤ 0.48 AND APRI ≤ 1 performed during Screening
iii. Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
In the absence of a definitive diagnosis of presence or absence of cirrhosis by Fibrotest® /APRI using the above criteria, a liver biopsy or fibroscan is required; liver biopsy results will supersede Fibrotest® /APRI or fibroscan results and be considered definitive.
8) Liver imaging within 6 months of Baseline/Day 1 is required in patients with cirrhosis to exclude hepatocellular carcinoma (HCC)
9) Females of childbearing potential (as defined in Appendix 4) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Baseline/Day 1 prior to randomization.
10) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 4.
11) Lactating females must agree to discontinue nursing before the study drug is administered
12) Subject must be of generally good health, with the exception of chronic HCV infection, as determined by the Investigator
13) Subject must be able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments. |
|
| 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 (without the prior mentioned conditions) 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 within the 5 years prior to screening, with the exception of specific cancers that have been cured by surgical resection (basal cell skin cancer, etc). Subjects under evaluation for possible malignancy are not eligible.
i. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2) Screening ECG with clinically significant abnormalities
3) Subjects has the following laboratory parameters at screening:
a) ALT > 10 x the upper limit of normal (ULN)
b) AST > 10 x ULN
c) Direct bilirubin > 1.5 x ULN
d) Platelets < 50,000/microlitre
e) HbA1c > 8.5%
f) Creatinine clearance (CLcr) < 60 mL /min, as calculated by the Cockcroft-Gault equation
g) Hemoglobin < 11 g/dL for female subjects; < 12 g/dL for male subjects.
h) Albumin < 3 g/dL
i) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR.
4) Prior exposure to SOF or other nucleotide analogue HCV NS5B inhibitor or any HCV NS5A inhibitor.
5) Pregnant or nursing female or male with pregnant female partner.
6) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency, cholangitis).
7) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV).
8) Clinically-relevant alcohol or 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.
9) Use of any prohibited concomitant medications as described in Section 5.6
10) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone equivalent > 10 mg/day).
11) Known hypersensitivity to GS-5816, RBV, SOF, or formulation excipients.
12) History of clinically significant hemoglobinopathy (e.g., sickle cell disease, thalassemia)
13) Contraindications to RBV therapy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is SVR12 (HCV RNA <LLOQ 12 weeks after cessation of therapy) in the Full Analysis Set (FAS) population
The primary safety endpoint is any AE leading to permanent discontinuation of study drug(s). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The safety and tolerability endpoints are evaluated during the course of treatment. The efficacy endpoint is evaluated 12 weeks after discontinuation of therapy. |
|
| E.5.2 | Secondary end point(s) |
- The proportion of subjects with: HCV RNA < LLOQ at 4 and 24 weeks after completion of therapy (SVR4 and SVR24)
- The proportion of subjects with HCV RNA < LLOQ on treatment
- HCV RNA change from Baseline/Day 1
- The proportion of subjects with virologic failure |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The efficacy endpoints are evaluated 4 and 24 weeks after discontinuation of therapy.
The other endpoints are evaluated during the course of treatment. |
|
| 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 | No |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Sofosbuvir and Ribavirin for 24 weeks |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 33 |
| 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 |
| Australia |
| Canada |
| France |
| Germany |
| Italy |
| New Zealand |
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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