A Multi-cohort, Randomized Study in Healthy Subjects to Assess the Pharmacokinetics and Safety of Single and Multiple Ascending Doses of JNJ-61393215 (Suspension), and to Assess the Relative Bioavailability, and the Effect of Food on the Pharmacokinetics, of a New Solid Formulation (Capsules) of JNJ-61393215

JNJ-61393215 is a new drug being investigated for the treatment of people with
mood and/or anxiety disorders. It might normalize certain mechanisms in the
brain that cause anxiety (for example panic attacks) without causing sleepiness
or reduced awareness.

This study will be performed in 56 healthy volunteers. The study will be
performed in 3 parts, Part 1, Part 2 and Part 3.

Part 1 will be performed in 16 healthy volunteers divided over 2 groups of 8
volunteers each.
The purpose of Part 1 of the study is to investigate how safe the new compound
JNJ-61393215 is and how well it is tolerated when it is administered as single
doses to healthy volunteers. It will also be investigated how quickly and to
what extent JNJ-61393215 is absorbed by and eliminated from the body
(pharmacokinetics). JNJ-61393215 will be compared with a placebo.

Part 2 will be performed in 24 healthy volunteers divided over 2 groups of 12
volunteers each.
The purpose of Part 2 of the study is to investigate the pharmacokinetics (how
quickly and to what extent JNJ-61393215 is absorbed by and eliminated from the
body) of JNJ-61393215 when administered as an oral solution compared to an oral
capsule. In addition, the effect of food on the pharmacokinetics of
JNJ-61393215 will be investigated. It will also be investigated how safe the
new compound JNJ-61393215 is and how well it is tolerated when it is
administered to healthy volunteers.

Part 3 will be performed in 16 healthy volunteers divided over 2 groups of 8
volunteers each.
The purpose of Part 3 of the study is to investigate how safe the new compound
JNJ-61393215 is and how well it is tolerated when it is administered as
multiple doses to healthy volunteers. It will also be investigated how quickly
and to what extent JNJ-61393215 is absorbed by and eliminated from the body
(pharmacokinetics). JNJ-61393215 will be compared with a placebo.

Part 1:
The study will consist of 1 period during which the volunteer will stay in the
research center Martini Hospital location for 4 days (3 nights).
Day 1 is the day of administration of the study compound. The volunteer is
expected at the research center at 14:00 h in the afternoon prior to the day of
administration of the study compound (Day -1). The volunteer will leave the
research center on Day 3 of the study.
The follow-up visit is between 7-14 days after administration of the study
compound.

Part 2:
The study will consist of 4 periods during which the volunteer will stay in the
research center Martini Hospital location for 5 days (4 nights) each period.
The time interval between administrations of the study compound on Day 1 of
each period is at least 7 days.
Day 1 is the day of administration of the study compound. Each period, the
volunteer is expected at the research center at 14:00 h in the afternoon prior
to the day of administration of the study compound (Day -1). Each period, the
volunteer will leave the research center on Day 4 of the study.
The follow-up visit is on Day 4 of the last treatment period (Period 4).

Part 3:
The study will consist of 1 period during which the volunteer will stay in the
research center Martini Hospital location for 9 days (8 nights). This will be
followed by 1 day during which the volunteer will visit the research center for
a short visit. This short visit will take place on Day 9.
Day 1 is the first day of administration of the study compound. The volunteer
is expected at the research center at 14:00 h in the afternoon prior to the
first day of administration of the study compound (Day -1). The volunteer will
leave the research center on Day 8 of the study.
The follow-up visit is between 14-21 days after the last administration of the
study compound

Part 1:
The study will consist of 1 period during which the volunteer will receive
JNJ-61393215 or placebo as a single dose. JNJ-61393215 and placebo will be
given as an oral solution with 240 milliliters (mL) of tap water.

When JNJ-61393215 or placebo is administered on Day 1, the volunteer should has
fasted for at least 10 hours (no eating and drinking). Also, after
administration of the study compound, the volunteer will be required to fast
for a period of 4 hours. Then the volunteer will receive lunch. During fasting
the volunteer is allowed to drink water, except for 1 hour before until 1 hour
after administration of the study compound (apart from the water taken with the
dose as described above).

Whether the volunteer will receive JNJ-61393215 or placebo will be determined
by chance; *a randomized study*. Per group, 6 volunteers will receive
JNJ-61393215 and 2 volunteers will receive placebo. Neither the volunteer, nor
the responsible doctor knows if JNJ-61393215 or placebo will be administered;
*a double-blinded study*. However, if it is important for volunteers health,
for example in case of a serious side effect, this information can be looked up
during the study.

For safety reasons, in both groups initially 2 volunteers will receive the
study compound. One volunteer will receive JNJ-61393215, and 1 will receive
placebo. After administration, the safety and tolerability of the study
compound in these 2 volunteers will be closely monitored. If there are no
concerns about the safety and tolerability 24 hours after administration, then
the remaining 6 volunteers (5 will receive JNJ-61393215 and 1 will receive
placebo) will receive the study compound.

Please refer to the table below to see the planned dose levels for the groups.

Group: 1
Day: 1
Treatment A: 145 mg JNJ-61393215 or placebo
How often: once

Group: 2
Day: 1
Treatment B: 225 mg JNJ-61393215 or placebo
How often: once

The dose of JNJ-61393215 of Group 2 can be adjusted based on the results of the
previous group. The dose for the next group will only be increased if the lower
dose of the previous group was found to be well tolerated and in case of no
objection by the Medical Research Ethics Committee. The study will be
discontinued if, in the opinion of the responsible doctor, unacceptable side
effects appear.

Part 2:
The study will consist of 4 similar treatment periods, separated by a washout
period in which no study compound is given. In each treatment period the
volunteer will receive JNJ-61393215 once per period. JNJ-61393215 will be given
as an oral solution with 240 milliliters (mL) of tap water in 1 period and as
an oral capsule with 240 mL of tap water in 3 periods. When JNJ-61393215 is
administered as an oral capsule, the volutneer will receive the study compound
when he/she has fasted for at least 10 hours in 1 period, with a high-fat and
high-calorie breakfast in 1 period, and with a standardized breakfast in 1
period.

Please see below an overview of the planned treatments.

Group: 3
Treatment C: 30 mg JNJ-61393215 as oral solution
Condition: fasted
How often: once

Treatment D: 30 mg JNJ-61393215 as oral capsule
Condition: fasted
How often: once

Treatment E: 30 mg JNJ-61393215 as oral capsule
Condition: high-fat/high calorie breakfast
How often: once

Treatment F: 30 mg JNJ-61393215 as oral capsule
Condition: Standardized breakfast
Hoe vaak: éénmaal

Groep 4:
Treatment G: X* mg JNJ-61393215 as oral solution
Condition: fasted
How often: once

Treatment H: X* mg JNJ-61393215 as oral capsule
Condition: fasted
How often: once

Treatment I: X* mg JNJ-61393215 as oral capsule
Condition: high-fat/high calorie breakfast
How often: once

Treatment J: X* mg JNJ-61393215 as oral capsule
Condition: standardized breakfast
How often: once

*The dose level of JNJ-61393215 for Group 4 is not known yet and will be
determined based on the results of Part 1 of the study. The dose level will be
the same for all treatments of Group 4. Each treatment will be given once. The
order in which the volunteer will receive the treatments will be determined by
chance.

Treatments C, D, G and H
Before administration of the study compound on Day 1, the volunteer should has
fasted for at least 10 hours (no eating and drinking). Also, after
administration of the study compound, the volunteer will be required to fast
for a period of 4 hours. Then the volunteer will receive lunch. During fasting
the volunteer is allowed to drink water, except for 1 hour before until 1 hour
after administration of the study compound (apart from the water taken with the
dose as described above).

Treatments E, F, I and J
After the volunteer has fasted for at least 10 hours (no eating and drinking),
the will receive a high-fat and high-calorie breakfast (Treatments E and I) or
a standardized breakfast (Treatments F and J) in the morning of Day 1. The
breakfast will have to be finished within 30 minutes and the entire breakfast
must be consumed. Within 10 minutes after completion of the breakfast the
volunteer will receive the study compound; this will not be later than 30
minutes after the start of breakfast. During fasting the volunteer is allowed
to drink water, except for 1 hour before until 1 hour after administration of
the study compound (apart from the water taken with the dose as described
above).

Part 3:
The study will consist of 1 period during which the volunteer will receive
JNJ-61393215 or placebo once daily for 7 consecutive days (Day 1 to Day 7).
JNJ-61393215 and placebo will be given as an oral solution with 240 milliliters
(mL) of tap water.

When JNJ-61393215 or placebo is administered on Days 1 to 7, the volunteer
should has fasted for at least 10 hours (no eating and drinking). Also, after
administration of the study compound, the volunteer will be required to fast
for a period of 4 hours on Day 1 and on Day 7. Then the volunteer will receive
lunch. On all other dosing days (Days 2 to 6) the volunteer will receive a
breakfast 2 hours before or 1 hour after administration of the study compound.
During fasting the volunteer is allowed to drink water, except for 1 hour
before until 1 hour after administration of the study compound (apart from the
water taken with the dose as described above).

Whether the volunteer will receive JNJ-61393215 or placebo will be determined
by chance; *a randomized study*. Per group, 6 volunteers will receive
JNJ-61393215 and 2 volunteers will receive placebo. Neither the volunteer, nor
the responsible doctor knows if JNJ-61393215 or placebo will be administered;
*a double-blinded study*. However, if it is important for volunteers health,
for example in case of a serious side effect, this information can be looked up
during the study.

For safety reasons, in both groups initially 2 volunteers will receive the
study compound. One volunteer will receive JNJ-61393215, and 1 will receive
placebo. After administration, the safety and tolerability of the study
compound in these 2 volunteers will be closely monitored. If there are no
concerns about the safety and tolerability 24 hours after administration, then
the remaining 6 volunteers (5 will receive JNJ-61393215 and 1 will receive
placebo) will receive the study compound.

Please refer to the table below to see the planned dose levels for the groups.

Group 5
Day: 1 to 7
Treatment: 145 mg JNJ-61393215 or placebo
How often: once daily

Group 6
Day: 1 to 7
Treatment: 225 mg JNJ-61393215 or placebo
How often: once daily

The dose of JNJ-61393215 of Group 6 can be adjusted based on the results of the
previous group. The dose for the next group will only be increased if the lower
dose of the previous group was found to be well tolerated and in case of no
objection by the Medical Research Ethics Committee. The study will be
discontinued if, in the opinion of the responsible doctor, unacceptable side
effects appear.

All potential drugs cause side effects; the extent to which this occurs
differs.

JNJ-61393215 is a novel drug that is being developed for the treatment of mood
and/or anxiety disorders.

This is the fourth study with JNJ-61393215. Preliminary data from the previous
studies show no significant side effects. In the first study, 62 healthy
subjects have received JNJ-61393215. In the second study, 49 healthy subjects
have received JNJ-61393215; the third study is currently on-going. Side effects
most frequently reported by the subjects were headache and sleepiness. Healthy
subjects will not benefit from treatment with JNJ 61393215. Therefore, special
precautions are taken to limit the risk to the volunteer.

The results from the study on heart in animals suggest that overall,
JNJ-61393215 is considered not to pose a cardiovascular safety concern for
humans. JNJ-61393215 did not show any adverse effects on genetic material. In
rats and dogs, high JNJ-61393215 levels were measured in the blood after oral
dose administration. At high JNJ-61393215 doses, changes in coagulation
(clotting) parameters in the blood were detected; those effects were dependent
on the dose and were considered adverse only for the highest dose tested, which
is associated with higher exposure than what is anticipated in this study. At
high JNJ-61393215 doses an increase in liver weight was detected.
Importantly, all observed changes were reversible and can be monitored in the
clinic.

Specifically in rats, a condition characterized by lack of response to external
stimuli and by muscular rigidity was observed in 2 animals at a high dose. Rats
receiving a high dose of JNJ 61393215 also were less active and less alert than
normal.

Coagulation (clotting) and liver parameters in the blood will be monitored
during all parts of the study to identify potential risks early. Regarding the
brain and behavioral side effects, it is expected that these side effects will
not be seen in humans because the exposure in human studies will stay lower
than the exposure that resulted in these effects in rats.

In this study, doses of JNJ-61393215 are higher than the range of dose which
have been previously administered to other healthy subjects in previous
studies. It is possible that those doses may be less tolerable than doses
previously administered to human subjects. Throughout the study, the volunteer
will be supervised by the responsible doctor.

There may be risks with the use of JNJ-61393215 that are not yet known.
Sometimes during a study the Sponsor may learn new facts about the study
compound. It is possible that this information might change volunteers mind
about being in the study. If new information is discovered, the responsible
doctor will tell the volunteer about it right away.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising. In total, we will take about 115 mL Part 1, 391 mL Part 2
and 188 mL Part 3 of blood from you. This amount does not cause any problems in
adults. To compare: a blood donation involves 500 mL of blood being taken each
time.

To monitor the heart rate, electrodes (small, plastic patches) will be pasted
at specific locations on the chest and arms and legs. Prolonged use of these
electrodes can cause skin irritation (rash and itching).

Procedures: pain, minor bleeding, bruising, possible infection.