Een fase 1 dubbel-blind, gerandomiseerde, placebo-gecontrolleerde studie in
gezonde vrijwilligers om de veiligheid, verdraagbaarheid en farmacokinetiek van opklimmende orale doseringen van TMC435350 te onderzoeken na enkelvoudige en meervoudige doseringen, gevolgd door een herhaalde open label dosering in 6 HCV-genotype-1 geinfecteerde patienten, niet placebo gecontroleerd.

The drug TMC435350 is a new, investigational study drug that may eventually be
used for the treatment of hepatitis-C infections. The study drug is a protease
inhibitor (PI), a class of drugs that selectively inhibit the replication of
the virus thereby inhibiting the progression of hepatitis-C infection.

The purpose of this study is to investigate how safe the study drug (TMC435350)
is and how well it is tolerated. The study will also investigate how quickly
and to what extent the study drug is absorbed and eliminated from the body
either after a period of fasting as well as after intake of breakfast.
Depending on the first study results the effects of the study drug will as well
be investigated when administered together with ritonavir. Ritonavir is a
medicine that is available on the market for the treatment of HIV-1 infections.
It is available as Norvir. This medicine is known for it*s influence on the
processing of drugs in the body.

This study is a randomized, double blind, placebo-controlled study to determine
the safety, tolerability and pharmacokinetics of TMC435350 after single and
multiple oral intakes in healthy subjects, followed by an open label repeated
dosing session in 6 HCV-genotype -1 infected patients (non placebo controlled).
This study consists of two parts. In the first part (group 1 and 2, 9
volunteers each) a single doses of the drug will be administered and in the
second part (group 3, 4, 5 and 6, 9 volunteers each) multiple doses will be
administered. Patient group (7) consist of 6 Subjects who will receive
multriple dosing of TMC435350.
SRD: First Part
The subjects who participate in group 1 will receive a single dose of 50, 200
or 800 mg TMC435350 or placebo on day 1 of period 1, 2 and 3 respectively,
followed by a dose of 200 mg TMC 435350 or placebo on Day 1 of period 4. A
placebo is a solution without the active ingredient.
The subjects who participate in group 2 will receive a single dose of 100, 400
or 1200 mg TMC435350 or placebo on day 1 of period 1, 2 and 3 respectively,
followed by a dose of 400 mg TMC 435350 or placebo on Day 3 of period 4. In
this period (period 4) the subjects will receive a dose of 100 mg ritonavir
twice daily, as well, on Day 1 to 5.
It may be the case that in the periods 4 the dose will be adjusted to one of
the previous used doses. This will be decided based on the results obtained
during the previous dosing.
Second Part
MRD: The subjects who participate in group 3, 4, 5 or 6 will receive multiple
daily doses of 50, 100, 200 or 400 mg or placebo, respectively, split over two
administrations each day during 4 days and a single dose on Day 5. Based upon
the results from the previous groups it might be decided to provide the full
daily dose once daily.
Group 7: Starts after completion of the healthy volunteers sessions. This is an
open
label treatment in HCV-genotype 1 infected patients (N=6). The dose regimen
will be selected which was shown to be safe in healthy volunteers and as close
as possible to a maximum tolerated dose, which will be adminstered for 5 days.
TMC435350 will be administered as an oral solution. Ritonavir will be
administered in the form of a capsule.
Full PK profiles of TMC435350 will be determined up to 72 hours after the last
dose. Safety and tolerability will be evaluated continuously and documented
(safety report) ), with 24 hours interim PK data after the last dose, before
stepping up to the next dose and between each session. Dose escalation will
continue only if the previous dose was found safe and tolerable by the
investigator, sponsor and METC.

The single dose escalation part of the trial will consist of 6 sessions (Sessions Ia to VIa) and the trial population will include 2 panels of 9 healthy subjects each (Panels 1 and 2). The dose of the test drug will be consecutively escalated. Doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg and 1200 mg of TMC435350 or placebo will be administered as a single oral administration alternating over the 2 panels. In each session, 6 subjects will receive active treatment and 3 subjects will receive placebo after a standardized breakfast. The treatment schedule will ensure that over 3 sessions each subject will receive active treatment twice and placebo once. A washout period of at least 10 days will be respected between consecutive TMC435350 or placebo dosings within each panel. Subjects of Panel 1 will have an additional session to investigate food effect: a single dose of TMC435350 will be tested in fasted conditions (Session VIIa). Food effect will be investigated for the 200 mg dose in Panel 1, unless the pharmacokinetic (PK) and safety data from previous sessions prove otherwise. Subjects of Panel 2 will have an additional session to investigate potential effects of twice daily (bid) dosing of 100 mg ritonavir on the pharmacokinetics, safety and tolerability of a single dose of TMC435350 (Session VIIIa), unless PK enhancement by boosting with ritonavir (Norvir®) is not expected from the PK data obtained in previous sessions. PK enhancement with ritonavir will be investigated for the 400 mg dose in Panel 2, unless the PK and safety data from previous sessions prove otherwise, and this dose will be co-administered on Day 3 of a 5 day regimen of 100 mg ritonavir b.i.d. For Session VIIa (Panel 1) and Session VIIIa (Panel 2) the same randomization scheme as in the session of the selected dose will be used. Multiple dosing will be started when Sessions Ia (single dose of 50 mg), IIa (single dose of 100 mg) and IIIa (single dose of 200 mg) are found to be safe and tolerable. The multiple dose escalation part of the trial will consist of 4 consecutive sessions (Sessions Ib to IVb) in 4 panels of 9 healthy subjects each (Panels 3, 4, 5 and 6). In each session, 6 subjects will receive active treatment and 3 subjects will receive placebo. TMC435350 or placebo will be administered during 5 consecutive days. After completion of the healthy volunteers sessions, an open label sessions will be added in HCV-genotype-1 infeced patients. TMC435350 will be administered during 5 consecutive days. The dose regimen will be selected which was shown to be safe in the healthy volunteers group. The final dose selection will be presented to the METC for approval.

The associated risks to this study are the occurence of possible side effects
of the use of TMC435350 and or in combination with Ritanovir. The burden of the
subjects are the confinement periods in the study unit, venapunction, the
insertion of the canula and an echo of the heart will be recorded. All subjects
will be carefully monitored regarding possible adverse events by experienced
study personel and physicians.
For HCV infected patients, there is a risk of development of resistance to
TMC435350. The short term nature of the study makes this less likely. In
addition, studies with other PIs for the treatment of HCV have shown that, when
resistance develops, it rapidly reverses to wild type virus upon
discontinuation of the compound.