A phase 1 open-label study to characterize the metabolism and excretion of a single dose of radiolabeled AL-335 administered in combination with Odalasvir and Simeprevir and administered alone in healthy male subjects

AL-335 is a new investigational compound that may eventually be used for the
treatment of chronic hepatitis C infection. AL-335 works by inhibiting the
replication of the hepatitis C virus. AL-335 is being developed for use in
combination with odalasvir and simeprevir. These compounds have a similar
mechanism of action, but act on a different protein involved in the replication
of the virus. It is hypothesised that the 3 compounds will complement each
other and may thereby reduce the risk of resistance against these compounds.

Odalasvir and AL-335 are not registered as a drug but have been given to humans
before. Simeprevir is no new drug; it is already available in the market under
several dosages.

The purpose of the study is to investigate how quickly and to what extent
AL-335 is absorbed, distributed, metabolized (broken down) and eliminated from
the body (this is called pharmacokinetics). AL-335 to be administered will be
labeled with 14-Carbon (14C) and is thus radioactive (also called
radiolabeled). This radioactive version is called 14C-AL-335 and can be traced
in blood, urine, feces and your breath. It will also be investigated to what
extent AL-335 is tolerated when administered alone or in combination with
odalasvir and simeprevir. In addition, the influence of genetic factors on the
pharmacokinetics of AL-335 will be explored.

This study will be performed in 10 healthy male volunteers, divided over 2
groups (Group 1 and Group 2).

The actual study will consist of 1 period during which the volunteers will stay
in the clinical research center in Groningen (location Martini Hospital). They
are expected at the clinical research center at 14:00 h in the afternoon of Day
-1, one day prior to the (first) day of administration of the study compound
(Day 1). They will be required not to have consumed any food or drinks during
the 4 hours prior to arrival in the clinical research center (with the
exception of water).

If they are assigned to Group 1, they will stay in the clinical research center
for 20 to 25 days (19 to 24 nights). They will leave the clinical research
center between Day 19 and Day 24, depending on the amount of radioactivity
found in their blood, expired air and the excreted urine and feces. In order to
measure the amount of radioactivity in urine and feces, you will be required to
collect all your urine and feces from Day 12 until discharge.
If you are assigned to Group 2, you will stay in the clinical research center
for 7 to 12 days (6 to 11 nights). You will leave the clinical research center
between Day 6 and Day 11, depending on the amount of radioactivity found in
your blood, expired air and your excreted urine and feces. In order to measure
the amount of radioactivity in urine and feces, they will be required to
collect all the urine and feces throughout the stay in the clinic. They are
also required to collect a feces sample at home prior to admission to the
clinical research center on Day -1.

The volunteer should be aware that when radioactivity levels are still above
pre-defined levels at discharge on Day 24 (Group 1) or Day 11 (Group 2), or if
they were not able to produce at least 5 feces samples since administration of
AL-335, they may have to continue the collection of urine and/or feces samples
at home. They will be asked to return these samples to the clinical research
center every other day until the radioactivity levels are below the pre-defined
levels. They will receive instructions on how to deliver these samples to the
clinical research center.
A post-study screening will take place 10 to 14 days after the last intake of
study drug. If needed in case of adverse events, they may need to return for an
additional post-study screening 30 to 35 days after the last intake of study
drug. The appointment for the post-study screening(s) will be made as soon as
it is known when the study will end for the volunteer.
The participation to the entire study, from the pre-study screening until the
post-study screening (excluding an additional post-study screening or any other
visits), will be up to 59 days (Group 1) or 35 days (Group 2).

If the volunteers are assigned to Group 1, they will receive once daily
treatment with odalasvir alone (Days 1-7) or in combination with simeprevir
(Days 8-13; see Table 1 above). On Day 14 they will once receive radiolabeled
AL-335, followed by a dose of odalasvir and simeprevir; the investigational
compounds will be administered within 10 minutes after completion of breakfast
in the morning. Thereafter, the once daily treatment with odalasvir and
simeprevir will be continued on Days 15 and 16.

If they are assigned to Group 2, they will receive radiolabeled AL-335 once,
within 10 minutes after completion of a breakfast on Day 1.
On the day of AL-335 administration (Day 14 in Group 1 or Day 1 in Group 2),
breakfast will be served approximately 30 minutes before administration of
AL-335 and after an overnight fast (no eating or drinking) of at least 10
hours. During fasting, they are allowed to drink water with the exception of 2
hours before and after administration of the study compound (except for the
fluids served with breakfast). Fasting will continue until 4 hours after
administration of the study compound. Then they will receive a standardized
lunch. From approximately 10 hours after administration of the study compound,
they are allowed to resume their normal diet (taking into consideration the
restrictions mentioned in the section *Are there any rules for volunteers?*
below). Except for that night during which they will need to fast one more time
for at least 10 hours until breakfast will be served the next day (on Day 15 in
Group 1, or Day 2 in Group 2).

The volunteers will also be required to fast for at least 4 hours before they
will leave the clinical research center, which will be ultimately on Day 24 in
Group 1 or Day 11 in Group 2.

Group 1;
Days 1-7; 25 mg odalasvir; once daily
Days 8-13; 25 mg odalasvir + 75 mg simeprevir, once daily
Day 14; 25 mg odalasvir + 75 mg simeprevir + 800 mg radiolabeled AL-335; once
Days 15-16; 25 mg odalasvir + 75 mg simeprevir; once daily

Group 2; Day 1; 800 mg radiolabeled AL-335; once

Infection/pain, minor bleedings, bruises, possibly an infection.