A Phase III Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172/MK-8742 in Subjects who have Failed Prior Treatment with Pegylated Interferon and Ribavirin (P/R) with Chronic HCV GT1, GT4, and GT6 Infection

Every year, 3*4 million people worldwide are newly infected with HCV, and
approximately 80% of these will progress to chronic infection. It is estimated
that 130*170 million people, or 2*3% of the world*s population, are chronically
infected with HCV. Long-term complications of chronic HCV infection develop in
chronically infected individuals over the course of several years to decades,
including cirrhosis, end-stage liver disease and hepatocellular carcinoma
(HCC). More than 350,000 people die from HCV-related liver diseases every year.
HCV has six major genotypes (GT), which can each be split into multiple
subtypes. The global distribution of HCV genotypes is diverse, which reflects
differences in epidemiology, modes of transmission and ethnic variability. HCV
GT 1, 2 and 3 have a fairly broad geographical distribution, whereas HCV GT 4,
5 and 6 are generally confined to specific geographical regions.

The goal of therapy for chronic HCV infection is eradication of the virus,
which is typically measured as a sustained virologic response (SVR). Until
recently, SVR at 24 weeks post treatment (SVR24) has been considered the gold
standard for treatment success; this end point is predictive of long term
eradication of the virus and correlates with a reduction in symptoms and in the
rate of negative clinical outcomes. However, there is evidence that most
patients who have an SVR at earlier time points (such as SVR12) maintain it
until week 24; therefore, the US FDA has concluded that SVR12 is suitable as a
primary end point for regulatory approval.
Until 2011, the standard of care (SOC) treatment for chronic HCV infection with
all genotypes was pegylated-interferon (peg-IFN) plus ribavirin (RBV) (PR)
administered for either 48 weeks (HCV GT 1, 4, 5, and 6) or for 24 weeks (HCV
GT 2 and 3). PR therapy led to SVR rates of 40%-50% in those with GT1 and of
80% or more in those with GT 2 and 3 infections.
Subjects co-infected with HCV and HIV have SVR rates of 27-38% when treated
with peginterferon plus ribavirin (PR) for 48 weeks. In HCV co-infected
patients, the addition of boceprevir and telaprevir to PR has been shown to
increase the efficacy of therapy substantially. Furthermore the safety profile
in co-infected subjects was similar to that in monoinfected persons.

Subjects who have a failed a prior regimen of peg-IFN and RBV are defined in
the Inclusion Criteria Section of the protocol. This population is among one
of the most in need of new therapies since a proportion also have cirrhosis of
the liver. Therefore, this study will enroll both non-cirrhotic and cirrhotic
subjects. Also, this patient population is more likely to be IL28 non-CC and
be infected with HCV GT1a. Studying such a group will provide insight into the
effectiveness of MK-5172/MK-8742 under challenging circumstances.
Among subjects who have failed a prior regimen of peg-IFN and RBV, the null
responders to peg-IFN and RBV may be the most difficult to cure with
alternative regimens, HCV GT1-infected subjects who were null-responders to
peg-IFN and RBV have been effectively treated with several investigational DAA
regimens.

Primary Objective(s) & Hypothesis

Objective:
To evaluate the efficacy of MK-5172 in combination with MK-8742 as assessed by
the proportion of subjects achieving SVR12 (Sustained Virologic Response 12
weeks after the end of all study therapy), defined as HCV RNA TD(u) or TND) 12 weeks after the end of all study therapy.

Hypothesis:
In at least one of the arms, the proportion of subjects receiving MK-5172 in
combination with MK-8742 achieving SVR12 will be superior to 58%.

Objective:
To evaluate the safety and tolerability of MK-5172 in combination with MK-8742.

Secondary Objective

Objective:
To evaluate the efficacy of MK-5172 in combination with MK-8742 (+/- ribavirin)
as assessed by the proportion of subjects achieving SVR24 (Sustained Virologic
Response 24 weeks after the end of all study therapy), defined as HCV RNA (either TD(u) or TND) 24 weeks after the end of all study therapy.

This is a randomized, parallel-group, multi-site, open-label trial of MK-5172
and MK-8742 in subjects with hepatitis C, with and without compensated
cirrhosis who have failed prior treatment with pegylated interferon (peg-IFN)
and ribavirin (RBV) to be conducted in conformance with Good Clinical Practices.
A total of 400 GT 1, 4, 5, or 6 HCV infected subjects will be enrolled. All
subjects will have failed prior therapy with peg-IFN and RBV. Approximately
30% of the enrolled subjects will have evidence of compensated cirrhosis at
screening and approximately 20% of the subjects can be HIV co-infected. The
number of prior peg-IFN and RBV relapsers will be capped to approximately 20%.
Study subjects will receive MK-5172A (Fixed Dose Combination of 100 mg MK-5172
+ 50 mg MK-8742) QD for 12 or 16 weeks, with or without RBV with 24 weeks of
follow-up after dosing is completed.
Safety and tolerability will be carefully monitored throughout the study by the
SPONSOR (or designee) in accordance with standard.

Treatment Groups:
* MK-5172 + MK-8742 (FDC) for 12 weeks
* MK-5172 + MK-8742 (FDC) + ribavirin for 12 weeks
* MK-5172 + MK-8742 (FDC) for 16 weeks
* MK-5172 + MK-8742 (FDC) + ribavirin for 16 weeks

Blood samples: drawing blood from the arm may cause pain, bruising,
lightheadedness, and rarely, infection.
ECG: The electrocardiogram (ECG) procedure may cause minimal discomforts
during the attachment and removal of the ECG leads to and from the skin.
Liver Biopsy: Pain at the biopsy site is the most frequent risk of percutaneous
liver biopsy, occurring in about 20 percent of patients. The risk of excessive
bleeding, called hemorrhage, is about 1 in 500 to 1 in 1,000. Risk of death is
about 1 in 10,000 to 1 in 12,000. If hemorrhage occurs, a procedure called
embolization, assisted by an x-ray procedure used to visualize blood vessels
called angiography, can be used to stop the bleeding. In some cases, a blood
transfusion is necessary. Surgery can also be used to stop a hemorrhage.
Other risks include puncture of other internal organs, infection, and spread of
cancer cells, called cancer seeding.
FibroTest/FibroSure®:. The main risks associated with blood tests are bruising
and some pain around the needle*s entry point.
FibroScan (if applicable for your country): Generally there is no pain or
discomfort associated with the procedure.