SINGLE-CENTER, OPEN-LABEL STUDY INVESTIGATING THE EXCRETION BALANCE, PHARMACOKINETICS AND METABOLISM OF A SINGLE ORAL DOSE OF [14C]-LABELED RO4917523 AND AN INTRAVENOUS TRACER DOSE OF [13C]-LABELED RO4917523 IN HEALTHY MALE VOLUNTEERS

The study medication to be given, RO4917523, is a new investigational compound
that may eventually be used as a treatment to be added to the treatments
usually prescribed for Major Depressive Disorder and Fragile X Syndrome. Major
Depressive Disorder is a mental disorder characterized by an all-encompassing
low mood accompanied by low self-esteem and by loss of interest or pleasure in
normally enjoyable activities. Fragile X Syndrome represents the most common
inherited cause of mental retardation. It is characterized by mental handicap
and behavior resembling autism and it is frequently associated with certain
facial characteristics. The study medication is still under development. The
study medication is thought to block a certain protein (receptor), a subclass
of the metabotropic glutamate (mGlu) receptors in the brain. This receptor is
thought to play a role in anxiety and depressive disorders and in certain
symptoms of the Fragile X Syndrome. This new compound is not registered as a
drug but has been given to 237 healthy subjects and 62 patients before.

Following an oral dose of 1 mg [14C]-labeled RO4917523 of 2.22 MBq (60uCi) and
an intravenous tracer dose of 0.1 mg [13C]-labeled RO4917523:

Primary:
To characterize the mass balance, metabolism routes and rates of elimination of
[14C]-labeled RO4917523
to determine plasma concentration of RO4917523, total drug related
radioactivity and related pharmacokinetic parameters after oral administration
of RO4917523, using conventional analytical methods and AMS if necessary

Secondary:
To identify and quantify circulating and excreted metabolites of RO4917523 in
plasma, urine and fecal samples based on radioactive metabolic profiling, using
conventional analytical methods and AMS if necessary.
to determine the absolute oral bioavailability and further characterize the PK
of RO4917523 using a stable isotope technique

Design:
a non-randomized, open-label ADME study in six healthy male subjects receiving
a single oral dose of [12C/14C]-RO4917523 as capsule, containing approximately
2.22 MBq radiocarbon, followed by a 30 min intravenous microdose of
[13C]-RO4917523

Procedures and assessments:
Screening and follow-up:
Clinical laboratory (including TSH and T4), physical examination, weight,
12-lead ECG; at eligibility screening: medical history, C-SSRS, temperature,
height, alcohol breath test, drug screen, urine cotinine test, psychiatric
assessment on psychiatric condition,HBsAg, anti HCV, anti-HIV 1/2; brief
physical examination, clinical laboratory, vital signs, 12-lead ECG, alcohol
breath test, drug screen and cotinine test to be repeated upon admission

Observation period:
In clinic from -17 h up to 312 h (Day 14) after drug administration with a
possible extension to Day 18 release criteria are not met, and 24 h visits on
Days 25-26, 32-33, 39-40, 46-47, 53-54, 60-61, and 67-68 ; subjects will meet
the release criteria once the cumulative total radioactivity in urine and
faeces excreted is less than 1% of administered dose within 24 h

Blood sampling:
For pharmacokinetics of RO4917523 and its metabolites in plasma: pre-dose and
30, 35, 40, 45, 50, 55 min, 1, 1.5, 2, 4, 6, 8, 10, 12, 24, 48, 72, 96, 120,
168 (Day 8), 216 (Day 10), 264 (Day 12) and 312 h (Day 14) post-dose
for total radioactivity: pre-dose and 30, 35, 40, 45, 50, 55 min, 1, 1.5, 2, 4,
6, 6, 8, 10, 12, 24, 48, 72, 96, 120, 168, 216 and 312 h post-dose and then
every 24 h until the release criteria are met
for metabolic profiling: predose and 2, 4, 8, and 24h post dose
for genotyping: once on day 1

Urine sampling:
For pharmacokinetics of RO4917523, total radioactivity and metabolic profiling:
pre-dose and intervals 0-12, 12-24 h post-dose and thereafter 24 h intervals
until the release criteria are met

Faeces sampling:
For total radioactivity and metabolic profiling: pre-dose and 24 h intervals
until the release criteria are met

vomitus collection: if subject spontaneously vomits within 4 hours after the
oral dose, vomitus will be collected and analyzed for total radioactivity

Safety assessments:
Adverse events: throughout the study; vital signs and 12-lead ECG: pre-dose and
1, 5, 10, 24 and 48 h post-dose and once on the day of discharge; clinical
laboratory: once on Day 10; brief physical examination: once on the day of
discharge; C-SSRS: 48 h post-dose
contnuous cardiac monitoring: 15 min before iv administration until 15 min
after iv administration is completed
Bioanalysis:
Analysis of plasma and urine RO4917523 and its metabolites samples using a
LC/MS-MS method by Sponsor
analysis of total radioactivity in plasma, urine and faeces using validated
methods by PRA
Metabolic profiling by Sponsor

Treatment
A single oral dose of 1 mg [12C/14C]-RO4917523 as capsule, containing
approximately 2.22 MBq radiocarbon, followed by a 30 min intravenous microdose
of 100 µg [13C]-RO4917523

Study medication
Active substance: RO4917523
Activity: potent metabotropic glutamate 5 (mGlu5) receptor antagonist
Indication: serious Depression (TRD) and Fragile X Syndrome
Strength: unknown
Dosage form: capsule and iv infusion

To date, 8 studies testing the study medication have been carried out in
healthy volunteers and 2 studies in patients with Fragile X Syndrome and
Treatment-Resistant Depression (a subclass of Major Depressive Disorder). From
a total of 359 individuals who participated in these studies, 295 received the
study medication: 163 received single oral doses of 0.25 to 2 2 milligrams and
132 subjects received multiple doses of 0.1 to 2 milligrams; 64 received
placebo (drug without active ingredient).

In the previous studies conducted in healthy volunteers, the study medication
was safe and generally well tolerated. The most common adverse events were
linked to the central nervous system (dizziness, somnolence, reduced sense of
touch), or were psychiatric disorders (hallucinations, paranoia, psychotic
episode, acute state of anxiety) and gastrointestinal disorders (mostly
nausea).
Two serious adverse events have been reported by 2 subjects on the study
medication: 1 subject with acute psychotic state and 1 subject with mania with
suicidal ideation

Ten subjects were withdrawn because of adverse events related to the study
medication: 1 subject with acute psychotic state mentioned in the preceding
paragraph, 1 subject with mania with suicidal ideation, 1 subject with acute
state of anxiety, 1 subject with insomnia and nightmares, 1 subject with severe
headache, 4 subjects with elevated liver enzymes and 1 subject with slowing
down of cardiac conduction.

With the dose(s) used in this study no serious adverse effects are expected.
However, the possibility that any of the above-mentioned or other adverse
effects could occur cannot be excluded. The adverse events one may expect to
occur are described above. However, you should take into account that some
risks are still unknown at this moment. Should information become available
from current studies elsewhere, you will be informed immediately. You can then
decide to continue with your participation in the study.


Procedures: pain, light bleeding, haematoma, possibly an infection