| 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 | 20.0 |
| 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 | 20.1 |
| 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 |
|
| 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 evaluate the efficacy of treatment with sofosbuvir/velpatasvir fixed-dose combination with ribavirin for 12 weeks in subjects with chronic hepatitis C virus infection and Child-Pugh-Turcotte class C cirrhosis 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 the treatment regimen. |
|
| 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 the study treatment regimen (SVR4 and SVR24)
To evaluate the proportion of subjects with virologic failure
To evaluate therapeutic efficacy as measured by the change of CPT score and MELD score
To evaluate the kinetics of circulating HCV RNA during treatment and after cessation treatment
To evaluate the emergence of viral resistance to SOF and VEL 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 |
Pharmacogenomics (PG) Substudy
In consenting subjects, a blood sample will be drawn at Day 1 visit. If not obtained at Day 1 visit, the sample may be drawn at any time during the study. |
|
| E.3 | Principal inclusion criteria |
1) Willing and able to provide written informed consent
2) Males and females, age ≥ 18 years old
3) A body mass index (BMI) of ≥ 18 kg/m2
4) Chronic HCV infection (≥ 6 months) as documented by either prior medical history or liver biopsy
5) Quantifiable HCV RNA at Screening
6) Subjects may be non-transplanted or with recurrent HCV post-liver transplant. a. If listed for liver transplant, then the projected date of transplant must be ≥12 weeks after Day1 of treatment b. If post-liver transplant, then Day1 must be ≥ 6 months from date of transplant
7) CPT score of 10 to 12, inclusive, as determined at Screening
8) Liver imaging within 6 months of Day 1 to exclude hepatocellular carcinoma (HCC)
9) If treatment-experienced, the most recent HCV treatment must have been completed at least 8 weeks prior to Screening
10) Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 1 prior to randomization
11) Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
12) Female subjects must agree to refrain from egg donation and in vitro fertilization during treatment until at least 30 days after the last dose of SOF/VEL or 6 months after the last dose of RBV, whichever occurs last
13) Lactating females must agree to discontinue nursing before the study drugs are administered
14) 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 30 days after the last dose of SOF/VEL, whichever occurs last
15) 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 medical or psychiatric illness or subjects is currently under evaluation for a potentially clinically significant illness (other than HCV or comorbidities associated with advanced liver disease except as noted below) or any other medical or psychiatric disorder that may interfere with subject treatment, assessment or compliance with the protocol 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) Significant pulmonary disease, significant cardiac disease or porphyria e) 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 f) Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2) Any history of organ transplant other than liver or kidney
3) Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson’s disease, alfa-1 antitrypsin deficiency, cholangitis)
4) Inability to exclude HCC by imaging within 6 months of Day 1 (including indeterminate hepatic nodule meeting OPTN Class 5 criteria, defined by arterial enhancement with washout on portal venous/delayed phase OR rate of growth maximum diameter increase in the absence of ablative therapy by 50% or more documented on serial MRI or CT obtained <6 month apart)
5) Alpha-fetoprotein (AFP) > 50 unless negative imaging for hepatic masses within the last 6 months or during screening
6) Active spontaneous bacterial peritonitis at Screening
7) Infection requiring systemic antibiotics at the time of Screening
8) Evidence of fibrosing cholestatic hepatitis at Screening
9) Life threatening SAE during Screening
10) Active variceal bleeding within 6 months of Screening
11) Prior placement of a portosystemic shunt (such as TIPS)
12) ECG with clinically significant abnormalities
13) Laboratory parameters at screening
14) Hepatitis B surface antigen positive at Screening
15) Infection with human immunodeficiency virus (HIV)
16) 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.
17) Prior exposure to any HCV NS5A inhibitor
18) Current use of corticosteroids at any dose >10 mg of prednisone/day (or equivalent dose of corticosteroid)
19) Use of any prohibited concomitant medications as described in Section 5.5
20) Use of GM-CSF, epoetin alfa or other hematopoietic stimulating agents within 2 weeks of Screening.
21) Male with pregnant female partner.
22) History of clinically significant hemoglobinopathy (eg, sickle cell disease, thalassemia)
23) Contraindications to RBV therapy
24) Known hypersensitivity to VEL, RBV, SOF, the metabolites, or formulation excipients
25) Participation in a clinical study with an investigational drug or biologic within 3 months prior to Day 1
Exclusion criteria that are specific to subjects who have not had a liver transplant
26) Medical justification for any MELD exception points (such as for HCC, current hepatopulmonary syndrome, intractable encephalopathy, or any other reason)
27) History of hepatopulmonary syndrome
Exclusion criteria that are specific to subjects who have had a liver transplant
28) Recipient of ABO incompatible organ
29) Histological evidence of unresolved rejection of liver transplant
30) Patients who had evidence of HCC at time of transplant must be 5 years posttransplant with no evidence of recurrence at Screening
31) Use or planned use of T-cell depleting/masking antibodies, systemic antineoplastic agents cyclosporine >300mg/day, or use of any prohibited medications |
|
| 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 study treatment regimen) in the Full Analysis Set (FAS).
The primary safety endpoint is any AE that led to permanent discontinuation of study drug. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| SVR 12 after cessation of study |
|
| E.5.2 | Secondary end point(s) |
| The secondary efficacy endpoints include the proportion of subjects who attain sustained virologic response at 4 and 24 weeks after cessation of the study treatment regimen (SVR4 and SVR24); the proportion of subjects who have HCV RNA < LLOQ by visit while on study treatment; CPT and MELD score changes from Day 1; absolute and change from Day 1 in HCV RNA through Week 12; and the proportion of subjects with virologic failure. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| SVR4 and SVR24 weeks after cessation |
|
| 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 | Yes |
| 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 | 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 |
|
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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