A single-center, randomized, open-label, four-period, four-treatment, cross-over study to investigate the comparative bioavailability of dispersible tablet and capsule formulations of RO5285119 in healthy volunteers

RO5285119 is a new investigational compound that may eventually be used for the
treatment of Autism Spectrum Disorders (ASD), a group of neurodevelopmental
disorders including Autism Disorder, Asperger*s syndrome, and pervasive
developmental disorder - not otherwise specified (PDD-NOS). These disorders are
typically characterized by social deficits, communication difficulties,
stereotyped or repetitive behaviors and interests, and in some cases, cognitive
delays. Vasopressin is a hormone that regulates blood pressure and the
retention of water in the kidneys. Vasopressin is also present in the brain and
may play a role in autism. RO5285119 blocks activation of the vasopressin
receptor and is in development for treatment of the core deficits in ASD.

RO5285119 is not registered as a drug but has been given to humans before.

The purpose of the study is to investigate how quickly and to what extent
RO5285119 is absorbed from the gut and then eliminated from the body (this is
called pharmacokinetics).

It will also be investigated to what extent RO5285119 is tolerated.

The actual study will consist of 4 periods during which the volunteer will stay
in the clinical research center in Groningen (location University Medical
Center Groningen) for 3 days (2 nights), followed by 4 days during which the
volunteer will visit the Medical Screening Center (location Martini Hospital)
in Groningen for short visits. The time interval between the start of the
different periods is at least 14 days and not more than 21 days.

During the study the volunteer will receive RO5285119 after an overnight fast
(at least 10 hours no eating and drinking) as a tablet or capsule with 240
milliliters of (tap) water.

In each period, fasting will continue until 4 hours after administration of the
study compound. Then the volunteer will receive a lunch. During fasting the
volunteer is allowed to drink water with the exception of 1 hour prior to until
1 hour after administration of the study compound.

The study will consist of 4 periods during which the volunteer will receive
RO5285119 once in each period. During 3 periods, RO5285119 will be given as
oral tablets and during one period as capsules. The oral tablets will be
different with respect to the composition (formulation).

The order in which the volunteer will receive the different tablets and capsule
will be determined by chance. The following orders are possible (see table for
explanation of the code): ABCD, BDAC, CADB, DCBA.

The planning of the study is as follows:

Treatment code* Dose Formulation Number of capsules/ tablets How often
A 10 mg RO5285119 tablet 1 once in 1 of the 4 periods
B 10 mg RO5285119 capsule 2 once in 1 of the 4 periods
C 10 mg RO5285119 tablet 2 once in 1 of the 4 periods
D 10 mg RO5285119 tablet 1 once in 1 of the 4 periods

Sometimes, people participating in studies get headaches. The cause of this may
be that the volunteer is not allowed to eat or drink for some time. In order to
collect blood, a cannula is inserted in a vein of the arm. The insertion may be
painful and sometimes lead to a bruise.

All potential drugs cause adverse effects; the extent to which this occurs
differs. In the previous studies conducted in healthy volunteers, the study
compound was safe and generally well tolerated. The most common side effects
reported were headache, back pain, and muscle ache. In general side effects
were mild in nature and all resolved.

The muscle enzyme values in the blood as well as blood cell counts will be
regularly monitored in this study because toxicities of skeletal muscle and
decreases in white blood cells were observed in animals. Specifically, in dogs,
a severe decrease in white blood cells was noted at drug blood levels higher
than expected in this study. In rats, again at drug blood levels higher than
expected in this study, skeletal muscular toxicity was observed.

The volunteer needs to abstain from unusual physical exercise whilst being in
this study.

Hypothetically, this study compound may lower the blood pressure and may impact
the blood pressure regulation. In particular when standing up quickly which may
result in symptoms like light-headedness and dizziness, and, if severe, even in
syncope. While in clinical trials such adverse events did not appear to occur
more often in drug treated than in placebo treated subjects, the volunteer
needs to move carefully from supine / or seated position into standing position
and watch him- or herself for symptoms like light-headedness and dizziness to
go back to lower body position.

In rats, at treatment duration for several weeks and at drug blood levels
higher than expected in this study tissue changes around nerves and around
small vessels in the brain were noted. Because the duration of treatment is
short in this study, no particular safety precaution in this regard is included
in this study.

Hypothetically, the mode of action of the study compound may interfere with
platelet function and hence exaggerate bleeding events. However, as of now no
such safety alert has emerged from animal studies or clinical trials in human
beings. In case of bleeding abnormalities in the medical history the volunteer
will not be eligible to participate in this study.

The study compound is interfering with the functionality of brain circuits and
as such may hypothetically have the potential to cause side effects of the
nervous system. No neurological or behavioural side effects considered causally
associated with the intake of the study compound have been identified to date.
However, the study compound is in early phase of development and the number of
volunteers who have taken the study compound is rather small.

The volunteer should be aware that the aforementioned adverse effects and
possibly other, still unknown adverse effects, may occur during the study.
However, with the dose used in this study no serious adverse effects are
expected.

Should, in the opinion of the investigators, unacceptable adverse effects
appear, the study will be discontinued.