| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Genotype 1 and Genotype 4 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 | 16.1 |
| 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 |
The primary objectives of this study are:
• To explore the antiviral efficacy of combination therapy with SOF/LDV FDC + RBV for 12 or 24 weeks in subjects with advanced liver disease (either pre-liver transplant or not currently wait-listed) and post-liver transplant HCV subjects with cirrhosis as measured by 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 + RBV administered for 12 or 24 weeks in each patient population |
|
| 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 2, 4, 8, and 24 weeks after discontinuation of therapy (SVR2, SVR4, SVR8, and SVR24)
• To determine if the administration of SOF/LDV FDC to HCV-infected subjects undergoing liver transplantation can prevent post-transplant recurrence as determined by a sustained post-transplant virological response (HCV RNA <LLOQ) at 12 weeks post-transplant (in those subjects who undergo liver transplants while on study)
• To determine therapeutic efficacy as measured by the change of CPT score and MELD score
• To evaluate the emergence of viral resistance to SOF/LDV FDC during and after treatment discontinuation
• To evaluate the kinetics of circulating HCV RNA during and after treatment
• To characterize steady-state PK of study drugs |
|
| 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 |
Pharmacogenomics (PG) Substudy
All subjects will be eligible to participate in the PG substudy if a separate consent is obtained. A blood sample should be drawn at the Day 1 visit. If not obtained at Day 1 visit, the sample may be
drawn at any time during the study.
Pharmacokinetic (PK) Substudy
Up to 15 subjects per group who provide separate consent will participate in a PK substudy and will have intensive PK sample collection (samples obtained up to 24 hours after dosing) performed at Week 2 or Week 4 following initiation of SOF/LDV FDC + RBV dosing to determine the steady state PK of SOF and metabolites, LDV, and RBV if appropriate.
Liver Explant Substudy
If a subject has a liver transplant during the study, and provides consent, tissue samples from the explanted liver will be obtained (where possible). Multiple tissue samples will be collected and
analyzed for intrahepatic HCV RNA, possible viral sequencing, immunohistochemistry staining, intrahepatic drug concentrations (SOF, its metabolites, LDV, as appropriate and if possible), and
key additional tissue biomarkers associated with fibrosis and fibrogenesis. |
|
| E.3 | Principal inclusion criteria |
1. Willing and able to provide written informed consent or for those subjects where hepatic encephalopathy affects their ability to provide initial or ongoing consent, has an appropriate and legally-authorized representative (LAR) willing and able to provide consent on behalf of the subject.
2. Male or female, Age > or = 18 years
3. Chronic genotype 1 and 4
4. HCV RNA infection with quantifiable virus at Screening
5. Confirmation of chronic (non-acute) 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 Day 1 visit, or
b. A liver biopsy performed prior to the Day 1 visit with evidence of chronic HCV
infection.
6. Screening ECG without clinically significant abnormalities.
7. Negative serum pregnancy test for female subjects (unless surgically sterile or greater
than two years post-menopausal; please see Appendix 4).
8. 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.
9. Lactating females must agree to discontinue nursing before the study drugs are
administered
10. Subject must be able to comply with the dosing instructions for study drug administration
and able to complete the study schedule of assessments, including all required
post-treatment visits.
11. Ability to determine the presence/absence of cirrhosis for all groups except Cohort B,
Group 7 (which may or may not have cirrhosis)
a. Cirrhosis is defined as any one of the following:
• Liver biopsy showing cirrhosis
• Fibroscan (in countries where locally approved) showing cirrhosis or results > 12.5 kPa
• A FibroTest® score of >0.75 AND an AST:Platelet Ratio Index (APRI) of
>2 performed during screening
b. Absence of cirrhosis is defined as any one of the following:
• Liver biopsy within 2 years of Screening showing absence of cirrhosis
• Fibroscan (in countries where locally approved) with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day1
• A FibroTest® score of ≤ 0.48 AND APRI of ≤ 1 performed during Screening 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 blood test results and be considered definitive.
Inclusion Criteria Exclusively for Cohort A
12. Has never received a liver transplant, and if listed for transplant, expected to be at least 12 weeks prior to transplant (from anticipated Day 1 of dosing). The subject may be a candidate for a living donor transplant, as long as it is anticipated to be at least 12 weeks before the transplant surgery will occur.
Inclusion Criteria Exclusively for Cohort B, all Groups
13. Post-liver transplant (primary or secondary, cadaveric or living donor), at least 3 months since transplant procedure for all groups except Cohort B, Group 4, which must be at least 2 months since the transplant procedure).
14. Subjects may be on the waiting list for a second or third transplant. Subjects who are on the waiting list for a liver transplant must be waiting to receive an HCV negative organ.
Inclusion Criteria Exclusively for Cohort B, Group 7 (FCH) only
15. Subject must be within 18 months of transplant at screening
16. Histological evidence of fibrosing cholestatic hepatitis on post-transplant liver biopsy performed within 6 months of screening, confirmed by sponsor medical review prior to randomization
17. Bilirubin ≥ 2.5x ULN
18. Ultrasound of liver and biliary tree with Doppler or other imaging study no finding of hepatic artery thrombosis within 6 months prior to screening |
|
| E.4 | Principal exclusion criteria |
1. Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance
2. HIV infection or chronic hepatitis B virus (HBV) infection (HBsAg positive)
3. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy.
4. Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug.
5. Alpha-fetoprotein (AFP) > 50 unless negative imaging for hepatic masses within the last
6 months or during screening
6. Current malignancy (with exception of certain resolved skin cancers or other early cancer for which surgical resection is considered to be completely curative), including hepatocellular carcinoma
7. Treatment with IFN, RBV, telaprevir or boceprevir or any other approved or experimental medication with known anti-HCV activity within 1 month prior to screening date
8. Any prior exposure to an HCV NS5a specific inhibitor
9. Use of GM-CSF, epoetin alfa or other therapeutic hematopoietic agents within 2 weeks of Screening
10. History of clinically significant medical condition associated with other chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, Wilson’s disease, α-1-antitrypsin deficiency, alcoholic liver disease, non-alcoholic steatohepatitis, or toxin exposures) that may affect the ability to respond to HCV therapy.
11. Active spontaneous bacterial peritonitis at screening
12. Hematological and biochemical parameters, including:
a. Hemoglobin (Hb) < 10 g/dL
b. Platelets ≤ 30,000/ mm3
c. ALT, AST, or alkaline phosphatase ≥ 10 ULN, sodium <125 mmol/L
d. Total bilirubin > 10mg/dL (except for the FCH cohort)
e. Serum creatinine > 2.5x upper limit of normal and/or evidence of renal impairment (CrCl < 40 mL/min).
13. Infection requiring systemic antibiotics at the time of screening
14. Participation in a clinical study with an investigational drug or biologic within 1 month prior to screening visit, unless information on the investigational drug is available to indicate that there is no potential drug interaction (safety or efficacy)
15. Active or recent history (≤ 6 months) of drug or alcohol abuse
16. Any contraindication to RBV therapy, per the approved package insert
17. Any history of organ transplant other than liver or kidney
18. Any medications from Section 5.4 prohibited from used within 28 days prior to the Day 1 visit through the end of treatment
19. Known hypersensitivity to RBV, LDV, SOF, or formulation excipients.
Exclusion criteria Exclusively for Cohort A subjects:
20. Medical justification for any MELD exception points (for HCC, current hepatopulmonary syndrome, intractable encephalopathy, or any other reason)
21. History of hepatopulmonary syndrome
22. Chronic use of systemic immunosuppressive agents (for autoimmune diseases, etc)
Exclusion Criteria Exclusively for Cohort B, all Groups:
23. Current use of corticosteroids at any dose > 10 mg of prednisone/day (or equivalent dose of other corticosteroid)
24. Histological evidence of unresolved rejection requiring treatment or expected to require treatment during the study period
25. Use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents, or cyclosporine at a dose of > 300 mg/day
26. Subjects with a Child-Pugh Score of 13-15, due to the serious medical condition and poor prognosis for these patients
Exclusion criterion Exclusively for Cohort B, Group 3:
27. Any clinical evidence of portal hypertension [history of ascites, esophageal or gastric
varices, hepatic encephalopathy, or coagulopathy (INR >1.2 at screening)]
Exclusion criterion Exclusively for Cohort B, Group 7
28. Presence of alternative explanations for cholestatis/hyperbilirubinemia such as biliary or
hepatic artery complications, and drug induced injury |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is SVR12 (HCV RNA < lower limit of quantitation [LLOQ] 12 weeks after last dose of study drug) for subjects in the Full Analysis Set. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 weeks post last treatment dose |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints include the proportion of subjects who attain SVR at 2, 4, 8 and 24 weeks after discontinuation of therapy (SVR2, SVR4, SVR8 and SVR24); proportion of subjects who have HCV RNA < LLOQ by visit while on treatment; absolute and change from Day 1 in HCV RNA through Week 8; virologic failure; and change from Day 1 in MELD and CPT scores. Subjects who have a liver transplant while on study will have data censored at time of transplant for the primary and secondary efficacy endpoints listed above.
For those subjects who have a liver transplant while on study, the proportion of subjects with post-transplant virologic response (PTVR, defined as HCV RNA < LLOQ at 12 weeks post-transplant) will be summarized for subjects in the FAS who have HCV RNA < LLOQ at their last observed HCV RNA prior to transplant. Subjects who are transplanted with an HCV-infected liver will be excluded from analysis. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary efficacy endpoints will be assessed 2, 4, 8 and 24 weeks following discontinuation of therapy; Other secondary endpoints will be assessed at the On-Treatment visits at Weeks 1, 2, 4, 6 8, 12, 16, 20,and 24 and at post treatment/ post transplant visits at Weeks 2, 4, 8, 12 and 24 |
|
| 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) | 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 | 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 | 7 |
| 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 | 24 |
| 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 |
| Austria |
| Belgium |
| Italy |
| Netherlands |
| New Zealand |
| Spain |
| Switzerland |
| United Kingdom |
| Australia |
| Canada |
| France |
| Germany |
|
| 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 | 7 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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