| 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 | 19.0 |
| 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 | 19.0 |
| 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 |
To evaluate the antiviral efficacy of treatment with LDV/SOF for 8,12, or 24 weeks in
subjects with chronic hepatitis C virus (HCV) infection who are on dialysis for ESRD, 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 |
To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of each study 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
treatment
To evaluate the emergence of viral resistance to LDV and SOF during treatment and after
cessation of treatment
To evaluate the steady-state pharmacokinetics of LDV and SOF and its metabolites in
subjects who are on dialysis for ESRD |
|
| 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 |
Pharmacokinetic (PK) Substudies
Subjects may consent to participate in either or both PK substudies.
Intensive PK Substudy
In consenting participants (target n=15), serial blood samples will be collected once at the Week 6, 8, or 12 on treatment visit at the following timepoints:
0 (pre-dose -5 minutes), 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose
Plasma concentrations of LDV and SOF and its metabolites will be determined and PK
parameters will be estimated as appropriate.
Hemodialysis PK Substudy
In consenting participants, (target n=10), blood samples will be collected at one hemodialysis
session between Week 6 and Week 12, inclusive (as appropriate based on treatment regimen). A single blood sample will be collected within 10 minutes before hemodialysis initiates. During hemodialysis, a single sample will be collected from both the arterial and venous sides of the dialyzer approximately 1 hour prior to conclusion of hemodialysis. Finally, a single blood sample will be collected within 10 minutes after hemodialysis concludes.
Plasma concentrations of SOF and LDV and its metabolites will be determined and hemodialysis extraction ratio will be estimated as appropriate.
Plasma concentrations of LDV and SOF and its metabolites will be determined and hemodialysis extraction ratio and fraction of dose removed by dialysis will be estimated as appropriate.
Pharmacogenomics (PG) Substudy
In consenting participants, blood sample should be drawn at the
Baseline/Day 1 visit. If not obtained at Baseline/Day1 visit, the sample
may be drawn at any time during the study. |
|
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for participation in this
study.
1) Willing and able to provide written informed consent
2) Male or female age ≥ 18 years
3) Chronic HCV infection (≥ 6 months) as documented by prior medical history or liver biopsy
4) HCV RNA ≥ LLOQ at screening
5) Genotype 1,4, 5 and 6 HCV as determined at Screening
6) End stage renal disease (ESRD) requiring peritoneal dialysis (PD) or hemodialysis (HD)
7)he most recent HCV treatment must have been completed at least 8
weeks prior to Screening.
8) Subjects must have a determination of treatment experience (treatment naïve vs. treatment experienced). Treatment naïve is defined as having never been exposed to an approved or experimental HCV-specific direct acting antiviral agents or prior treatment of HCV with interferon or ribavirin. All other patients will be considered treatment experienced.
9) Subjects must have appropriate testing for determination of cirrhosis status.
a) Presence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of > 12.5 kPa
ii) Liver biopsy showing cirrhosis (e.g., Metavir score = 4 or Ishak score ≥ 5)
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score ≥ 0.75 at screening
b) Absence of cirrhosis is defined as any one of the following:
i) Fibroscan with a result of ≤ 12.5 kPa within ≤ 6 months of Baseline/Day 1
ii) Liver biopsy performed within 2 years of Screening showing absence of cirrhosis
iii) In the absence of liver biopsy or availability of Fibroscan, FibroTest® score < 0.75 at screening
10) Liver imaging within 6 months of Baseline/Day 1 is required in cirrhotic subjects only, to exclude HCC
11) Subjects with HIV-1 coinfection may be eligible, provided they satisfy these additional inclusion criteria:
i) Completed at least 3 months of any prior HIV ARV therapy and maintained HIV RNA<50 copies/mL (or <LLOQ if the local laboratory assay’s LLOQ is 50 ≥ copies/mL) and CD4 T-cell count > 100 cells/mm3 prior to Screening. Subjects with an isolated or
unconfirmed HIV RNA >50 copies/mL (or >LLOQ if the local laboratory assay’s LLOQ
is 50≥ copies/mL) are not excluded ii) On a stable ARV regimen for ≥ 8 weeks prior to Screening and is expected to continue
the current ARV regimen through the end of study (See exclusion criteria 7).
12) A negative serum pregnancy test is required for female subjects (unless permanently sterile
or greater than two years post-menopausal).
13) 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.
14) Lactating females must agree to discontinue nursing before the study drug is administered.
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 |
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1) Current or prior history of any of the following:
a) Clinically-significant illness (other than HCV, HIV and kidney disease or co-morbidities
associated with ESRD except as noted below) 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
or ESRD) are also excluded.
b) Current or prior history of significant cardiac disease including or resulting in:
Hospital admission for significant cardiovascular disease (myocardial infarction,
unstable angina, heart failure, hypertensive emergency) or has had a cardiovascular
procedure (e.g. CABG or PTCA), within 6 months of Screening
Cardiomyopathy with ejection fraction <50%
c) Gastrointestinal disorder or postoperative condition that could interfere with the
absorption of the study drug.
d) Difficulty with blood collection and/or poor venous access for the purposes of
phlebotomy.
e) Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal hemorrhage).
f) Solid organ transplantation other than failed kidney transplants (current use of ≤5 mg/day
of prednisone, or equivalent dose of corticosteroid, allowed).
g) Significant pulmonary disease
h) Psychiatric hospitalization, suicide attempt, and/or a period of disability as a result of
their psychiatric illness within the last 2 years.
i) 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
2) Screening ECG with clinically significant abnormalities
3) Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease,
alfa-1 antitrypsin deficiency, cholangitis).
4) Infection with hepatitis B virus (HBV).
5) Opportunistic infection (Appendix 5) within 6 months prior to Screening
6) Infection (other than HIV or HCV) requiring parenteral therapy within 30 days prior to
baseline.
7) Life threatening SAE during the screening period
8) 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. For subjects receiving ritonavir boosted atazanavir
regimen, a direct bilirubin > 1.5 x ULN will be allowed if < 25% of the total bilirubin
d) Platelets < 25,000/μL
e) HbA1c > 9%
f) Hemoglobin < 9 g/dL
g) Albumin < 2.8 g/dL
h) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant
regimen affecting INR
i) Hepatitis B surface antigen positive
9) Prior exposure to any HCV NS5A inhibitor.
10) Male with pregnant female partner.
11) Females who may wish to become pregnant and/or plan to undergo egg harvesting during the
course of the study and up to 30 days of the last dose of study drug
12) Males who may wish to donate sperm during the course of the study until at least 30 days
after the last dose of study drug.
13) 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.
14) Use of any prohibited concomitant medications as described in Section 5.4.
15) Chronic use of systemically administered immunosuppressive agents (e.g., prednisone
equivalent > 10 mg/day).
16) Known hypersensitivity to LDV, SOF, the metabolites, or formulation excipient.
17) For subjects with HIV-1 coinfection only:
HIV-1 RNA >50 copies/mL
CD4 T-cell count <100 cells/mm3
HIV-2 positive test |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary end point is SVR12 (HCV RNA < LLOQ 12 weeks after cessation of treatment) in
the Full Analysis Set (FAS) population.
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 |
|
| 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
The proportion of subjects who develop viral resistance to LDV and SOF during treatment
and after cessation of treatment
The steady-state pharmacokinetics of LDV and SOF and its metabolites |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• SVR 4 and 24 weeks
• PK Day 7 |
|
| 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 | 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.8.3 |
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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Belgium |
| Germany |
| Italy |
| Switzerland |
| Taiwan |
|
| 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 | |
| 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 |
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