A Single Center, Non-Randomized, Open-Label, One-Sequence, Two-Period Within-Subject Study to Investigate the Effect of Itraconazole on the Pharmacokinetics of Multiple Doses of Balovaptan in Healthy Volunteers

Balovaptan (also known as RO5285119) is a new investigational compound that may
eventually be used for the treatment of Autism Spectrum Disorders (ASD), a
diverse neurodevelopmental disorder. This disorder is typically characterized
by social deficits, communication difficulties, repetitive behaviors, and in
some cases, learning disabilities. 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. Balovaptan reduces
signaling via vasopressin and is in development for treatment of ASD.
Balovaptan is not yet registered as a drug but has been given to adults with
ASD before at doses of up to 10 mg for a period of 12 weeks and to healthy
volunteers at doses of up to 52 mg for a period of two weeks.

Itraconazole, an approved drug for the treatment of fungal infections, is known
to interfere with the activity of the liver enzyme CYP3A. This enzyme is
involved in the breakdown of balovaptan in the body and may therefore interfere
with the presence of balovaptan in the body. In a previous study involving
itraconazole and a single dose of balovaptan, the blood levels of balovaptan
were increased by at least 3.1-fold. Therefore, itraconazole will be expected
to increase the blood levels of balovaptan in this study.

The purpose of the study is to investigate how quickly and to what extent
balovaptan is absorbed and eliminated from the body (pharmacokinetics) when it
is administered alone or in combination with itraconazole. It will also be
investigated to what extent balovaptan is tolerated by volunteers if
administered alone or in combination with itraconazole.

This study will be performed in 14 to 18 healthy male or female volunteers,
divided into 2 groups: Group A (Group 1) and Group B (Group 2).

In Period 1 the volunteer will stay in the research center for 12 days (11
nights). Day 1 is the first day of administration of the study compound. The
volunteer is expected at the research center at 14:00 hr in the afternoon prior
to the day of first administration of the study compound (Day -1). the
volunteer will leave the research center on Day 11.

There will be a period of at least 7 days between the last administration of
study compound in Period 1 and the first administration of study compound in
Period 2.

The volunteer is expected to return to the research center at 14:00 hr in the
afternoon on Day -1 of Period 2. In Period 2 the volunteer will stay in the
research center for 22 days (21 nights). Then the volunteer will leave the
research center on Day 21 of Period 2.

Between 14 to 21 days after volunteers last dose in Period 2, volunteers health
will be checked for the last time.

Balovaptan will be given once daily, at a dose of 5 mg, for the initial 4
volunteers (Group A). Based on the results from Group A, the dose of balovaptan
may either:

- remain at 5 mg once daily in a second group of 10 volunteers (Group B), or
- be increased to 10 mg once daily a second group of 14 volunteers (Group B)

Balovaptan will be given as an oral tablet with 240 milliliters (mL) of water
after consumption of a standardized breakfast.

Itraconazole will initially be given twice daily at a dose of 200 mg (in total
400 mg a day), a typical dose for this medication. When given together with
balovaptan (5 or 10 mg) once daily, itraconazole will be given once daily at a
dose of 200 mg (in total 200 mg a day). On those days, balovaptan will be given
first and then itraconazole. Itraconazole will be given as capsules with 240 mL
of water after consumption of a standardized breakfast (morning) or snack
(evening).

One of the investigators will inspect volunteers hands and mouth after each
intake of study compound.

The study will consist of two periods. We refer to the table below to see the
days at which the volunteer will receive the study compounds:

Period 1:
Day -1 - none
Day 1 to 10 - balovaptan once daily
Day 11 - none
Day 12 to 16 - none

Period 2:
Day -1 - none
Day 1 to 4 - itraconazol twice daily
Day 5 - itraconazol once daily
Day 6 to 20 - balovaptan once daily and itraconazol once daily
Day 21 - none

The study compound may cause side effects. Balovaptan has had limited testing
in humans. Side effects that were observed in clinical trials with balovaptan
are listed below. However, it is not clear whether balovaptan has been the
cause of these side effects. On the other hand, there may be side effects that
are not known at this time.

The most common side effects reported are listed below.

Side Effects Reported in Previous Clinical Trials with Balovaptan:
Aggression
Anxiety, nightmares, and insomnia
Arthralgia (joint pain)
Back pain
Bronchitis
Diarrhea
Digestion troubles
Dizziness
Dysgeusia (affecting sense of taste)
Dyspepsia (indigestion)
Fatigue
Headache
Irritability
Muscle pain
Nasopharyngitis (runny nose and sore throat)
Nausea
Runny nose
Skin lesion
Syncope (fainting) after standing up quickly
Taste alteration
Upper respiratory tract infection

Also, should the volunteer experience lightheadedness or dizziness when
standing up or even fainting, or should the volunteer experience muscle ache or
cardiovascular symptoms, such as chest pain, palpitations, or breathlessness,
the volunteer should inform the study doctor as soon as possible.

Itraconazole
The most common side effects of itraconazole are the following:
gastrointestinal disturbances, nausea, vomiting, diarrhea, abdominal pain, and
rash. Other adverse effects include itching, angioedema, anaphylaxis fatigue,
headache, dizziness, hypertension, decreased libido, impotence, and somnolence.
Itraconazole is rarely associated with hepatotoxicity.

Tests
Drawing blood and/or insertion of the indwelling cannula may be painful or
cause some bruising.

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

This study includes a test exploring how well the body manages blood pressure
control when standing up quickly after about 15 to 20 min in a supine position.
The blood pressure and pulse rate will be measured several times while in a
supine position as well as 3 minutes after having moved into a standing
position. Should the volunteer experience dizziness, sweating, or any
pre-fainting symptoms the volunteer should tell the site staff and do not
hesitate to interrupt the test by moving back into a sitting or supine
position. After the volunteer moved from supine to standing position a study
nurse will be with the volunteer until the end of the test.

This test will be performed at screening and should the volunteer experience
pre-fainting symptoms or fainting, the volunteer will not be enrolled into this
study. After enrollment, the test is also scheduled for study Day 9 in Period 1
and study Days -1, 4 and 16 in Period 2.


Procedures: pain, minor bleeding, bruising, possible infection