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 | 18.1 |
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 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
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 |
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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 |
To determine the efficacy of treatment with sofosbuvir (SOF)/velpatasvir (VEL)/GS-9857 fixed dose combination (FDC) for 12 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 treatment with SOF/VEL/GS-9857 |
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E.2.2 | Secondary objectives of the trial |
To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of treatment (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 treatment To evaluate the emergence of viral resistance to SOF, VEL, and GS-9857 during treatment and after cessation of treatment To characterize steady state pharmacokinetics of the study drug To further evaluate efficacy and safety of SOF/VEL/GS-9857 for 12 weeks in subjects who enter the Deferred Treatment Substudy |
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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 |
Deferred Treatment Substudy Subjects randomized to Group 2 that complete treatment with SOF/VEL/GS-9857 placebo and the posttreatment Week 4 visit will be eligible for treatment in the Deferred Treatment Substudy, receiving open-label therapy with SOF/VEL/GS-9857 for 12 weeks. The objective is to further evaluate efficacy and safety of SOF/VEL/GS-9857 for 12 weeks in subjects who initially received placebo. Intensive Pharmacokinetic (PK) Substudy All subjects, with a target of approximately 100 participants, will be eligible to participate in the PK Substudy if consent is obtained. This stidy will characterize steady state pharmacokinetics of the study drug. Pharmacogenomics (PG) Substudy In consenting participants, a blood sample will be drawn at the Day 1 visit. If not obtained at the Day 1 visit, the sample may be drawn at any time during the study. The objective is to identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy, and/or tolerability of medical therapies through genetic discovery research (e.g., pharmacogenomics), in subjects who provide their specific consent
Optional Archive Sample An optional archive plasma sample (non-genetic) will be collected at Day 1 (prior to study drug administration) and Week 12 visits, or Early Termination (ET) visit. Samples will be collected and archived for future analysis once approved by local authorities as applicable according to specific local regulations. Consent will be required to document a subject's agreement to: provide additional biomarker samples for future research, or allow the use of the remainder of their already collected biomarker and PK specimens for optional future research. |
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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 kg/m2 4) HCV RNA ≥ 104 IU/mL at Screening 5) Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy. 6) Treatment experienced with an NS5A inhibitor-containing regimen of at least a 4-week duration a) The most recent treatment must have been completed at least 8 weeks prior to Screening b) Subjects must not have discontinued the most recent regimen due to either an adverse event or virologic failure due to noncompliance c) The subject’s medical records must include sufficient detail of prior treatment(s) to confirm eligibility 7) Cirrhosis Determination a) Presence of cirrhosis is defined as any one of the following: i) FibroTest® score > 0.75 and AST:platelet ratio index (APRI) > 2 during Screening ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥5) iii) Transient elastography (FibroScan®) with a result of > 12.5 kPa b) Absence of cirrhosis is defined as any one of the following, unless the definition of cirrhosis has been met: i) FibroTest® score ≤ 0.48 and APRI ≤ 1 performed during Screening ii) Liver biopsy within 2 years of Screening showing absence of cirrhosis iii) Transient elastography (FibroScan®) with a result of ≤ 12.5 kPa within 6 months of Day 1 8) Liver imaging within 6 months prior to Day 1 is required in cirrhotic subjects 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 Day 1 prior to enrollment 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 starting study drug. 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 |
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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) Hepatic decompensation (e.g., clinical ascites, encephalopathy, and/or variceal hemorrhage) e) Solid organ transplantation f) Significant cardiac disease g) Unstable psychiatric condition including hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within 2 years prior to Screening h) Malignancy within the 5 years prior to Screening, with the exception of specific cancers that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are not eligible i) Significant drug allergy (e.g., hepatotoxicity) 2) Screening ECG with clinically significant abnormalities 3) Subject has 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/L e) HbA1c > 8.5% f) Creatinine clearance (Crcl) < 50 mL/min as calculated by the Cockcroft-Gault equation {2202} g) Hemoglobin < 10 g/dL h) Albumin < 3 g/dL i) International Normalized Ratio of prothrombin time (INR) > 1.5 × ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR 4) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency, cholangitis) 5) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) 6) 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 7) Use of any prohibited concomitant medications as described in Section 5.5 8) Known hypersensitivity to the study drug, the metabolites, or formulation excipient
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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 treatment) in the Full Analysis Set (FAS) in Group 1.
The primary safety endpoint is any AE that led to permanent discontinuation of study drug. |
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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) |
Secondary endpoints include the following: - The proportion of subjects with HCV RNA < LLOQ at 4 and 24 weeks after cessation of treatment (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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints will be assessed on treatment or 4 or 24 weeks following discontinuation of treatment |
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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 | 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 | 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 | Yes |
E.8.2.3 | Other | No |
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 | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
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 |
New Zealand |
United Kingdom |
United States |
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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |