A 2-Part, Randomized, Placebo-controlled, Double-blind, Single Ascending Dose Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-55375515 in Healthy Male Subjects

JNJ-55375515 is a new compound that may eventually be used for the treatment of
mood disorders, like major depression.
Besides the changes in mood that occur with major depression, there are also
cognitive problems, such as deficits in memory and attention. The effectiveness
of current antidepressant treatments leaves a lot to be desired. In addition,
they do not improve the deficits in cognitive function found in depressed
patients.
Glutamate is the most important neurotransmitter (chemical messenger) in the
brain, and disturbances in this glutamatergic system are thought to be related
to several mood disorders, like major depression. Medication that targets this
system would provide a novel approach for the treatment of mood disorders.
JNJ55375515 targets the so-called metabotropic glutamate 2 receptor. Via this
route it is thought to improve glutamate release,and thus strengthening network
connectivity in the brain. It is expected that this would result in improved
mood and cognition, especially, in depressed patients who are not helped by the
currently available treatments.

The purpose of this study is to investigate how safe the new compound
JNJ55375515 is when it is administered to healthy subjects. JNJ-55375515 has
been administered to humans before and will be investigated at various dose
levels.
It will also be investigated how quickly and to what extent JNJ-55375515 is
absorbed and eliminated from the body (this is called pharmacokinetics). In
addition, the effect of JNJ55375515 on the body will be investigated (this is
called pharmacodynamics).
The effects of JNJ55375515 will be compared to the effects of a placebo. A
placebo is a medicine without any active ingredient. It is a *fake* medicine.

Part 1.
Participation of the volunteer from the pre-study screening until the last
follow-up visit will last about 8 weeks.

Screening
We will first evaluate whether the volunteer may participate. The investigator
will do a physical examination, make a heart tracing (ECG), measure weight,
height, blood pressure, heartbeat and body temperature and will do tests on the
volunteers blood and urine. A neurological examination will also be done,
including testing the motor (muscle) and sensory (senses) functions, and
coordination of the volunteer. The investigator will also ask the volunteer
about your medical history, ethnic origin and medication use. These factors are
important for the study because they can influence the effects of the study
drug. The volunteer will also be tested for the use of alcohol and drugs of
abuse (hard drugs and soft drugs), and for the diseases HIV, hepatitis B and
hepatitis C. If the volunteer has any of these diseases, either we or the
volunteers general practitioner will tell them. If the volunteer does not want
to know, they cannot participate in this study.
The screening sometimes reveals findings that require further medical
examination. We will always tell the volunteer about these findings. Further
medical examination will have to be done by the volunteers own GP or
specialist. The costs of this will be charged to their own insurance. The
volunteer may also be healthy but may still not be eligible for participation,
for example when the volunteers body weight is too high or too low according to
the requirements of the study.
Just before administration of the study drug it will be decided based on the
latest test results whether the volunteer is suitable for participation or not.

Administration of the study drug
JNJ-55375515 and placebo will be given as a liquid (suspension). The volume can
range from 0.4 milliliters to 8 milliliters. After administration of the study
drug, the pipet will be rinsed with water, which the volunteer will also be
required to drink. Thereafter the volunteer is also required to drink the
reminder of the 240 mL of water.
The study drug will be administered within 30 minutes after consumption of a
standardized breakfast between 07:00 and 11:00 h. The entire breakfast must be
consumed.
The study consists of 3 periods. In which period the volunteer will receive
JNJ-55375515 or placebo will be determined by chance. All volunteers will
receive JNJ-55375515 twice (2 different doses) and placebo once.
In the table below the volunteer can see how much of the study drug they will
receive. The doses in Periods 2 and 3 can be adjusted based on the results of
the other group and previous period. However, the dose will not be lower than
0.3 mg and not higher than 30 mg. 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 investigation will be discontinued if, in the opinion of the investigators,
unacceptable adverse effects appear.
A third group with a maximum of 12 subjects might be added to investigate 3
additional doses. The highest dose will not exceed 80 mg.
Neither the volunteer, nor the responsible doctor knows if JNJ55375515 or
placebo will be dosed; we call this *the study is blinded*. However, if it is
important for the volunteers health, for example in case of a serious adverse
event, this information can be looked up during the study.
General information on this the volunteer will find in the brochure *medical-
scientific research*.

Visits and tests
The actual study will consist of 3 periods during which the volunteer will stay
in the research center in Groningen Martini Hospital for 4 days (3 nights).
Each period will be followed by 2 short visits to the research center. These
short visits will take place on Day 4 and 5. Day 1 of each period will be
separated by at least 10 days.
Day 1 is the day of administration of the study drug. The volunteer is expected
at the research center at 10:00 h in the morning prior to the day of
administration of the study drug. The volunteer will leave the research center
on Day 3 of the study. This is the case for each of the 3 periods.
During the study, the following will take place
- We ask about side effects
- We will give the volunteer the study drug
- We will do a physical examination
- We will do a neurological examination
- We will make a heart tracing (ECG)
- We will use telemetry to continuously monitor the volunteers ECG
- We will measure the volunteers brain activity (EEG)
- For Part 2 only: We will measure the volunteers sleep pattern
- We will measure blood pressure, heart rate, number of breaths per minute and
body temperature of the volunteer. Blood pressure and heart will also be
measured while the volunteer is standing.
- We will draw blood. This is to see how well JNJ-55375515 is absorbed in the
volunteers blood and how it affects the volunteers body. In total, about 400
milliliter blood will be taken during the study.
- We will measure the volunteers eye movements.
- We will ask the volunteer to do several cognitive tests.
- We will ask the volunteer to complete questionnaires about feelings of
anxiety, sleepiness,mood.
- We will give the volunteer a standardized breakfast.
- We will draw one blood sample for genetic tests (DNA tests) to study genes
related to drug activity and for research into what the volunteers body does
with the drug. For this study genetic tests are obligatory. These genotyping
tests do not have the capability to identify the volunteer or the volunteers
general state of health. Genes not related to drug activity or what the
volunteers body does to the study drug will not be examined. The volunteers
samples will be stored usually for 2 years, but no more than 15 years after the
completion of the study and will be used
solely for specific genes related to drug activity or the disposition of the
study drug as defined for this study.

Follow-up visit
Between Day 7 and 14 after the last study drug administration the volunteers
health will be checked for the last time. The appointment for this follow-up
visit will be made during the study. During this health check a physical and
neurological examination will be done including measurement of blood pressure,
heart rate and body temperature, a heart trace, motor and sensory functions.
And a number of blood and urine tests will be done.


Part 2.
The volunteers participation from the pre-study screening until the last
follow-up visit will last about 9 weeks.

Screening
We will first evaluate whether the volunteer may participate. The investigator
will do a physical examination, make a heart tracing (ECG), measure weight,
height, blood pressure, heartbeat and body temperature of the volunteer and
will do tests on the volunteers blood and urine. A neurological examination
will also be done, including testing the volunteers motor (muscle) and sensory
(senses) functions, and coordination. The investigator will also ask the
volunteer about your medical history, ethnic origin and medication use. These
factors are important for the study because they can influence the effects of
the study drug. The volunteer will also be tested for the use of alcohol and
drugs of abuse (hard drugs and soft drugs), and for the diseases HIV, hepatitis
B and hepatitis C. If the volunteer has any of these diseases, either we or the
volunteers general practitioner will tell them. If the volunteer does not want
to know, the volunteer cannot participate in this study.
The screening sometimes reveals findings that require further medical
examination. We will always tell the volunteer about these findings. Further
medical examination will have to be done by their own GP or specialist. The
costs of this will be charged to their own insurance. The volunteer may also be
healthy but may s

Part 1
Administration of the study drug
JNJ-55375515 and placebo will be given as a liquid (suspension). The volume can
range from 0.4 milliliters to 8 milliliters. After administration of the study
drug, the pipet will be rinsed with water, which the volunteer will also be
required to drink. Thereafter the volunteer is also required to drink the
reminder of the 240 mL of water.

The study drug will be administered within 30 minutes after consumption of a
standardized breakfast between 07:00 and 11:00 h. The entire breakfast must be
consumed.

The study consists of 3 periods. In which period the volunteer will receive
JNJ-55375515 or placebo will be determined by chance. All volunteers will
receive JNJ-55375515 twice (2 different doses) and placebo once.
In the table below the volunteer can see how much of the study drug they will
receive. The doses in Periods 2 and 3 can be adjusted based on the results of
the other group and previous period. However, the dose will not be lower than
0.3 mg and not higher than 30 mg. 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 investigation will be discontinued if, in the opinion of the investigators,
unacceptable adverse effects appear.
A third group with a maximum of 12 subjects might be added to investigate 3
additional doses. The highest dose will not exceed 80 mg.
Neither the volunteer, nor the responsible doctor knows if JNJ55375515 or
placebo will be dosed; we call this *the study is blinded*. However, if it is
important for the volunteers health, for example in case of a serious adverse
event, this information can be looked up during the study.
General information on this the volunteer will find in the brochure *medical-
scientific research*.

Part 2
Administration of the study drug
JNJ-55375515 and placebo will be given as a liquid (suspension). The volume can
range from 0.4 milliliters to 8 milliliters. After administration of the study
drug, the pipet will be rinsed with water, which the volunteer will also be
required to drink. Thereafter the volunteer is required to drink the reminder
of the 240 mL of water.

The study drug will be administered approximately 4 hours after dinner, between
22.00 and 0.00 h (midnight), and within 15 minutes prior to bedtime.

The study consists of 4 periods. In which period the volunteer will receive the
study drug or placebo will receive the study drug or placebo will be determined
by chance. The doses that will be used will be determined based on the outcome
of Part 1 of this study. In Periods 1 to 3 volunteers will receive JNJ55375515
twice (2 different doses) and placebo once, or the volunteer will receive
placebo 3 times (the chance of this occurring is 25%). During Period 4 all
volunteers will receive JNJ55375515, either dose x or y, which dose will be
determined by chance. Dose x and y in Period 4 will be two of the doses tested
in Period 1 to 3.

Neither the volunteer, nor the responsible doctor knows if JNJ55375515 or
placebo will be dosed (except for Period 4, when all volunteers will receive
JNJ-55375515); we call this *the study is blinded*. However, if it is important
for the volunteers health, for example in case of a serious adverse event, this
information can be looked up during the study.
General information on this the volunteer will find in the brochure *medical-
scientific research*.

The study drug may cause some side effects. Overall JNJ-55375515 was well
tolerated in the first clinical trial done, where the compound was given both
in a single dose (with doses ranging from 0.5mg to 12mg) and a multiple dose
regimen (2, 6 and 9mg per day for 10 days). All side effects were reversible
and of mild intensity, except for 1 case of nausea being of moderate intensity.
The most frequently reported side effects were dizziness (often described by
the subject as lightheadedness), irritability, headache and nausea.
A serious adverse event of aggression was reported in a subject being dosed
with the highest dose in the multiple dosing regimen. This event was looked at
with special attention and was deemed possibly caused by JNJ-55375515, but
resolved while the subject was further dosed with the study drug.
Drawing blood and insertion of the indwelling cannula may be painful or cause
some bruising.