A Phase III, open-label trial of TMC435 in combination with peginterferon alpha-2a and ribavirin for HCV genotype-1 infected subjects who participated in the placebo group of a Phase II/III TMC435 study (C201, C205, C206, C208, C216 or HPC3007), or who received short-term (up to 14 days) direct-acting antiviral treatment for hepatitis C infection in a selected Tibotec-sponsored Phase I study.

HCV is a leading cause of liver disease worldwide and has become a focus of
considerable medical research. An
estimated 170 million people (3% of the global population) are infected with
HCV2. More than 50% of HCV infections
become chronic and may lead to the development of liver fibrosis, cirrhosis,
and hepatocellular carcinoma (HCC).
Complications of liver disease due to HCV are the leading cause of liver
failure requiring liver transplantation.
Current HCV therapies are based on peginterferon-alpha (PegIFNa) in combination
with ribavirin (RBV). This combination
therapy yields a sustained virologic response (SVR) in approximately 45% of
treatment-naIve subjects infected with
genotype 1 HCV. In addition to the limited efficacy on genotype 1 HCV, this
combination therapy has significant side
effects and is poorly tolerated in some subjects. Side effects include
influenza-like symptoms, hematological
abnormalities, and neuropsychiatric symptoms.
There is a need for new compounds that may overcome the disadvantages of
current HCV therapy. In recent clinical
studies, new investigational drugs acting directly on the protease target have
demonstrated that significant reductions in
HCV RNA levels and improved SVR rates can be achieved when administered in
combination with PeglFNa and RBV.
The HCV-encoded NS3/4A protease is essential for viral replication and
mUltidisciplinary discovery research has led to
new specific and potent NS3/4A Pis, including TMC435.

The primary objective is to evaluate the antiviral efficacy of TMC435 in
combination with PegIFN*-2a and RBV.
In addition to this, the study provides access to TMC435 treatment in
combination with PegIFN/RBV to (1) subjects who
participated in the placebo group (PegIFN/RBV) of a Phase II/III TMC435 study
and who did not achieve sustained
virologic response (SVR), and (2) subjects who received short-term (up to 14
days) DAA treatment for HCV
infection in a selected Tibotec-sponsored Phase I study.
The efficacy and safety of TMC 435 will be evaluated in this population of
carefully characterized treatment experienced patients.

This is an open label study of TMC435 in combination with PegIFN*-2a and RBV
for subjects with genotype 1
HCV infection who participated in the placebo group of a Phase II/III TMC435
study, or who received short-term
(up tp 14 days) DAA treatment for HCV infection in a selected Tibotec-sponsored
Phase I study. The efficacy of
TMC435 in combination with PegIFN*-2a and RBV in adult subjects will be
evaluated separately for the two
groups of subjects (previously Phase II/III or Phase I, respectively). Safety
and tolerability will be evaluated in the
overall population.
Approximately 270 HCV genotype-1 infected subjects who participated in the
placebo group of a Phase II/III
TMC435 study are expected to be enrolled in this study. In addition, HCV
genotype-1 infected subjects who
received short-term (up to 14 days) DAA treatment for HCV infection in a
selected Tibotec-sponsored Phase I study
will also be allowed to enter this study.
Subjects who participated in the placebo group of a Phase II/III TMC435 study
will be classified by the sponsor as
(1) subjects with viral relapse, (2) subjects with viral breakthrough, or (3)
nonresponders, i.e., null responders,
partial responders, and others, based on their response to the last course of
PegIFN*-2a (2b) and RBV therapy.
Subjects can only enter the study after completion of the last study-related
visit in the previous study.
This study will include a screening period of up to 6 weeks. Only under
exceptional circumstances and after Sponsor
approval, the 6-week period can be exceeded.
All subjects will receive TMC435 150 mg once daily (q.d.) in combination with
PegIFN/RBV for 12 weeks. A
response-guided 24- or 48-week total treatment duration with PegIFN/RBV will be
used for subjects classified as
prior relapsers or having had a prior viral breakthrough. To determine total
treatment duration with PegIFN/RBV
(24 or 48 weeks), HCV RNA plasma levels should be assessed at Week 4 of
treatment:
- If HCV RNA <25 IU/mL undetectable at Week 4: Subjects are to receive
PegIFN/RBV for a total treatment
duration of 24 weeks (i.e., 12 weeks of treatment with TMC435 + PegIFN/RBV,
followed by an additional
12 weeks of treatment with PegIFN/RBV).
- If HCV RNA <25 IU/mL detectable at Week 4: Subjects are to receive PegIFN/RBV
for a total treatment
duration of 48 weeks (i.e., 12 weeks of treatment with TMC435 + PegIFN/RBV,
followed by an additional
36 weeks of treatment with PegIFN/RBV).
Prior relapsers or subjects with prior viral breakthrough who do not meet
criteria for treatment completion after
24 weeks, all prior nonresponder subjects (null responders, partial responders
and others), and subjects
having received short term DAA therapy will be required to continue treatment
with PegIFN/RBV for a total of 48
weeks unless a virologic stopping rule is met prior to Week 48.
Virologic stopping rules (i.e. HCV RNA *25 IU/mL at Week 4, confirmed
detectable at Week 12 or 24 or 36) have
been incorporated for all subjects to ensure that subjects with no or extremely
low chance of treatment success due
to suboptimal response discontinue treatment in a timely manner in order to: 1)
limit unnecessary exposure to
TMC435, PegIFN*-2a and RBV and 2) limit the risk for evolution of resistant
viral variants during continued
therapy with TMC435. In the event virologic stopping rules are met at any given
time point, the study treatment will
be discontinued permanently.
For all subjects, there will be a post-therapy follow-up period of 24 weeks
after the planned end of treatment (i.e.,
Week 24 or Week 48). The total study duration (from screening till final study
visit) for any given subject will be a
maximum of 78 weeks, including a screening period up to 6 weeks. The study is
considered completed with the last
visit of the last subject participating in the study.

Approximately 270 HCV genotype-1 infected subjects who participated in the
placebo group of a Phase II/III
TMC435 study are expected to be enrolled in this study. In addition, HCV
genotype-1 infected subjects who
received short-term (up to 14 days) DAA treatment for HCV infection in a
selected Tibotec-sponsored Phase I study
will also be allowed to enter this study.
Subjects who participated in the placebo group of a Phase II/III TMC435 study
will be classified by the sponsor as
(1) subjects with viral relapse, (2) subjects with viral breakthrough, or (3)
nonresponders, i.e., null responders,
partial responders, and others, based on their response to the last course of
PegIFN*-2a (2b) and RBV therapy.
Subjects can only enter the study after completion of the last study-related
visit in the previous study.
This study will include a screening period of up to 6 weeks. Only under
exceptional circumstances and after Sponsor
approval, the 6-week period can be exceeded.
All subjects will receive TMC435 150 mg once daily (q.d.) in combination with
PegIFN/RBV for 12 weeks. A
response-guided 24- or 48-week total treatment duration with PegIFN/RBV will be
used for subjects classified as
prior relapsers or having had a prior viral breakthrough. To determine total
treatment duration with PegIFN/RBV
(24 or 48 weeks), HCV RNA plasma levels should be assessed at Week 4 of
treatment:
- If HCV RNA <25 IU/mL undetectable at Week 4: Subjects are to receive
PegIFN/RBV for a total treatment
duration of 24 weeks (i.e., 12 weeks of treatment with TMC435 + PegIFN/RBV,
followed by an additional
12 weeks of treatment with PegIFN/RBV).
- If HCV RNA <25 IU/mL detectable at Week 4: Subjects are to receive PegIFN/RBV
for a total treatment
duration of 48 weeks (i.e., 12 weeks of treatment with TMC435 + PegIFN/RBV,
followed by an additional
36 weeks of treatment with PegIFN/RBV).
Prior relapsers or subjects with prior viral breakthrough who do not meet
criteria for treatment completion after
24 weeks, all prior nonresponder subjects (null responders, partial responders
and others), and subjects
having received short term DAA therapy will be required to continue treatment
with PegIFN/RBV for a total of 48
weeks unless a virologic stopping rule is met prior to Week 48.
Virologic stopping rules (i.e. HCV RNA *25 IU/mL at Week 4, confirmed
detectable at Week 12 or 24 or 36) have
been incorporated for all subjects to ensure that subjects with no or extremely
low chance of treatment success due
to suboptimal response discontinue treatment in a timely manner in order to: 1)
limit unnecessary exposure to
TMC435, PegIFN*-2a and RBV and 2) limit the risk for evolution of resistant
viral variants during continued
therapy with TMC435. In the event virologic stopping rules are met at any given
time point, the study treatment will
be discontinued permanently.
For all subjects, there will be a post-therapy follow-up period of 24 weeks
after the planned end of treatment (i.e.,
Week 24 or Week 48). The total study duration (from screening till final study
visit) for any given subject will be a
maximum of 78 weeks, including a screening period up to 6 weeks. The study is
considered completed with the last
visit of the last subject participating in the study.Virologic stopping rules
have been incorporated to ensure that subjects with no or extremely low chance
of
treatment success due to suboptimal response discontinue treatment in a timely
manner in order to: 1) limit
unnecessary exposure to TMC435, PegIFN*-2a and RBV and 2) limit the risk for
evolution of resistant viral
variants during continued therapy with TMC435.

number of visites: max 14
A. PHYSICAL EXAMINATION:
PTN IN PART 1A: SCREENING, DAY 1, DAY 14, DAY 28, WEEK 12, WEEK 24, WEEK 28,
WEEK 36 AND WEEK 48.
PTN IN PART 2B: SCREENING, DAY 1, DAY 14, DAY 28, WEEK 12, WEEK 24, WEEK 36,
WEEK 52, WEEK 60 AND WEEK 72
PTN IN PART 3: AT *WITHDRAWAL* VISIT, 4 WEEKS AFTER THE *WITHDRAWAL* VISIT AND
THAN EVERY 12 WEEKS UNTIL WEEK 48 (PART 1A) OR WEEK 72 (PART 1B).
AT SCREENING AN EYE EXAMINATION IS PERFORMED
B. VITAL SIGNS AND ECG :
PTN IN PART 1A: SCREENING, DAY 1, DAY 14, DAY 28, WEEK 12, WEEK 24, WEEK 28,
WEEK 36 AND WEEK 48.
PTN IN PART 2B: SCREENING, DAY 1, DAY 14, DAY 28, WEEK 12, WEEK 24, WEEK 36,
WEEK 52, WEEK 60 AND WEEK 72
PTN IN PART 3: AT *WITHDRAWAL* VISIT, 4 WEEKS AFTER THE *WITHDRAWAL* VISIT AND
THAN EVERY 12 WEEKS UNTIL WEEK 48 (PART 1A) OR WEEK 72 (PART 1B).

ECG: 1X (AT SCREENING)

C. BLOOD TESTING :
- Hematology/Biochemistry : max. 15x
- Test Hepatitis A/B/C : 1x
- determination HCV subtype : 1x
- Test HIV-1 en HIV-2 : 1x
- HCV RNA : max. 15x
- viral sequencing : max. 14x
- IL28B genotyping : 1x
- DNA: 1x (optional)
- Biomarkers/mRNA and cytokines :6x
- Serum pregnancytest : 1x (at screening)

E. URINE-ANALYSIS (DIPSTICK) : MAX. 15X
URINEPREGNANCYTEST: MAX. 15X

RISK OF TMC435
In healthy volunteers who received TMC435 either in single doses or in multiple
doses up to 14 days, the most frequent adverse events (>10% of patients) was
headache.

Long term safety data in chronic hepatitis C patients who received triple
combination therapy with TMC435 (given in daily doses of either 75mg, 100mg or
150mg for either 12 weeks, 24 weeks or 48 weeks) or placebo, peginterferon
alfa-2a and ribavirin indicated that rates of adverse events were not related
to either dose or duration of TMC435 intake. In general, no substantial
differences in type or incidence of adverse events between placebo and the
TMC435 treatment groups were observed.
There were only 5 types of adverse events which are currently considered
adverse drug reactions to TMC435 during the first 12 weeks of treatment:
1. Mild increases of bilirubin in blood seen in 7.4% of patients as compared to
2.8% in placebo treated patients. This is a transient side effect of TMC435
intake which may make your skin and eyes appear yellow. This side effect is
quickly reversible once TMC435 intake is completed.
2. Pruritus seen in 21.9% patients as compared to 14.6% placebo treated
patients
3. Rash seen in 21.8% patients as compared to 16.6% placebo treated patients
4. Photosensitivity reaction (development of redness, inflammation or itchy
eruptions on patches of sun exposed skin) seen in 4.7% patients as compared to
0.8% placebo treated patients. These photosensitivity reactions typically
resolve without treatment.
2.5. Constipation seen in 2,.6 % of patients as compared to 2.5% in placebo
treated patients.

Most of the adverse events were mild to moderate in severity. Overall, there
was no relevant difference in severity between TMC435 and placebo treated
groups.
Rash is usually mild to moderate in nature and is similar to that seen with
Pegasys® and ribavirin. It can sometimes be serious and therefore needs medical
attention.
In both, healthy volunteers and patients, there were no significant changes in
pulse rate, blood pressure, heart rhythm or blood test results noted for TMC435
as compared to placebo.
When TMC435 is given along with other drugs, there may be interactions which
affect drug levels of either one. Other drugs could lower blood levels of
TMC435 to a level where it is no longer efficient. On the other hand, the
presence of TMC435 may increase levels of the other drugs up to the toxic range.
Patients of Asian origin, may have higher blood levels of TMC435 in their
bodyat the dose being studied in this trial (150 mg once daily) as compared to
Caucasians. However, all available data are consistent with equal tolerability
of this dose in Asians and Caucasians.
[It is possible for the virus to become resistant to TMC435 and this may affect
future treatment options.

Risk of Pegasys® and Ribavirin therapy
The most frequent side effects of Pegasys®/Ribavirin are (Taken from US package
insert)
-flu-like symptoms such as tiredness/fatigue (65%), fever (41%), headache
(43%), muscle aches (40%), and chills (25%)
-psychiatric problems such as anxiety/irritability (33%), sleeplessness (30%)
and depression (20%)
-skin disorders such as alopecia (28%), dermatitis/rash combined (24%),
pruritus (19%), and local reactions at the site the Pegasys® injection was
given (23%)
-gastrointestinal symptoms such as nausea/vomiting (25%) and diarrhea (11%)
-hematologic abnormalities such as neutropenia (27%) and anemia (11%)
.
Liver Biopsy Risks
While liver biopsy is a common procedure most times without complications, some
patients may experience pain (30%). Other risks include bleeding (<5%),
infection (<5%) of an internal organ such as the lung, gall bladder, or kidney
could be punctured (<5%). Care will be taken to prevent these complications.
Blood Draw Risks
Blood drawing may cause some discomfort, bleeding or bruising where the needle
enters the body (1%).
Reproductive Risks: These risks are described in detail in the Participant
Information and Informed Consent
The patient will use 2 methods of contraception during the study in order to
avoid the risk of getting pregnant (the patient or female partner).
UNKNOWN RISKS