| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Genotype 4 and Genotype 5 Hepatitis C Virus Infection |
|
| E.1.1.1 | Medical condition in easily understood language |
| Hepatitis C Virus Infection |
|
| 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 | 18.0 |
| 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 |
|
| 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 antiviral efficacy of treatment with SOF/LDV FDC in subjects with chronic HCV infection, as measured by the proportion of subjects with SVR 12 weeks after discontinuation of therapy (SVR12, defined as HCV RNA < lower limit of
quantification [LLOQ] 12 weeks post treatment).
To evaluate the safety and tolerability of SOF/LDV FDC as assessed by review of the accumulated safety data. |
|
| E.2.2 | Secondary objectives of the trial |
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 SOF and LDV during treatment and after treatment discontinuation. |
|
| 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 |
Pharmacogenomic Sub-study
To identify or validate genetic markers that may be predictive of virologic response to therapy and/or tolerability of therapy through genetic discovery research (ie, pharmacogenomics), in subjects who provide their separate and specific consent. |
|
| 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) HCV genotype 4 or 5 at Screening as determined by the Central Laboratory. Any non-definitive results will exclude the subject from study participation
6) HCV treatment status of one of the following:
a) Treatment-naïve, defined as no prior exposure to any IFN, RBV, or other approved or experimental HCV-specific direct-acting antiviral agent; OR,
b) Treatment-experienced, defined as having received treatment with an IFN-containing regimen, with or without RBV and/or an HCV NS3/NS4A PI, and which can be further categorized as
i) Treatment-Intolerant - completed ≤ 12 weeks of treatment (ending ≥ 3 months prior to Screening) and discontinued treatment due to development or significant worsening of a treatment related AE
ii) Non-Response - did not achieve undetectable HCV RNA levels while on treatment
iii) Relapse/Breakthrough - achieved undetectable HCV RNA levels during treatment or within 4 weeks of the end of treatment but did not achieve a SVR
Subjects in categories ii) and iii) must not have discontinued prior therapy due
to an AE.
7) Chronic HCV infection (> 6 months) documented by medical history or liver biopsy:
8) Cirrhosis determination (Up to approximately 50% of subjects enrolled in the study may have compensated cirrhosis):
a) Cirrhosis is defined as any one of the following:
i) Liver biopsy showing cirrhosis (eg Metavir score = 4 or Ishak score 5)
ii) Fibroscan indicative of cirrhosis as evidenced by a result > 12.5 kPa
iii) Fibrotest score > 0.75 AND AST:platelet ratio index (APRI) > 2 during Screening
b) Absence of cirrhosis is defined as any one of the following:
i) Liver biopsy within 2 years of Baseline/Day 1 showing absence of cirrhosis
ii) Fibroscan within 6 months of Baseline/Day 1 with a result of ≤ 12.5 kPa
iii) Fibrotest score ≤ 0.48 AND APRI score < 1 during Screening
In the absence of a definitive diagnosis of the presence or absence of cirrhosis by
Fibrotest and APRI, a Fibroscan or liver biopsy is required; liver biopsy results will
supersede any imaging studies or blood test results and be considered definitive.
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) 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) Clinical hepatic decompensation (ie, ascites, encephalopathy or variceal hemorrhage)
b) Solid organ transplantation
c) Significant pulmonary disease, significant cardiac disease or porphyria
d) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of their psychiatric illness within the last 2 years
Subjects with psychiatric illness (without the prior mentioned conditions) that is well-controlled on a stable treatment regimen for at least 6 months prior to Baseline/Day 1 or that has not required medication in the last 12 months may be
enrolled.
e) Hepatocellular carcinoma (HCC)
Subjects with cirrhosis must have results from liver imaging done within 6 months of Baseline/Day 1 that exclude HCC.
f) Any other malignancy within the 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc.), or current evaluation for possible malignancy
g) Clinically-significant illness (other than HCV) or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol, l, or, current evaluation for a potentially clinically significant illness (other than HCV)
h) Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug
i) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy
j) Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) If treatment-naïve: prior exposure to IFN, RBV, or any approved or experimental HCV-specific DAA agent(s)
If treatment-experienced: prior exposure to approved or experimental HCV-specific DAA(s) other than NS3/4A protease inhibitors
3) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, cholangitis)
4) Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV)
5) Any of 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 ULN
d) Platelets < 50,000/μL
e) HbA1c > 10%
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) International normalized ratio (INR) > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant regimen affecting INR
6) Use of any prohibited concomitant medications as described in Section 5.4
7) Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent > 10 mg/day), azathioprine or monoclonal antibodies such as infliximab
8) Clinically-relevant alcohol or drug abuse within 12 months of Screening, as determined by the investigator
9) Screening electrocardiogram (ECG) with clinically significant abnormalities
10) Pregnant or nursing females
11) Known hypersensitivity to SOF, LDV, or formulation excipients.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint of this study is:
- The proportion of subjects that achieve SVR12 (HCV RNA <LLOQ 12 weeks after discontinuation of therapy)
The primary safety endpoint of this study is:
- Any adverse event (AE) leading to permanent discontinuation of study drug |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the primary efficacy end point - 12 weeks post last treatment dose
For the primary safety end point AEs will be assessed throughout the study. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints of this study include:
- The proportion of subjects that achieve SVR4 and SVR24
- The proportion of subjects with viral breakthrough
- The proportion of subjects who relapse
- HCV RNA change from baseline |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary efficacy endpoints will be assessed at baseline and on treatment visits week 1,2, 4, 8 and 12 weeks and at weeks 4,12 and 24 following discontinuation of therapy according to the study protocol. |
|
| 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 | 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) | 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 1 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | |
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