A single-center, non-randomized, open-label, one-sequence, two-period within-subject study to investigate the effect of Rifampicin 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 Disorder (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.

Rifampicin, an approved drug for the treatment of tuberculosis, is known to
interfere with the activity of the liver enzyme CYP3A4. This enzyme is involved
in the breakdown of balovaptan in the body and may therefore interfere with the
presence of balovaptan in the body. Rifampicin induces the enzyme CYP3A4,
thereby increasing the activity of this enzyme. It will be investigated if
increasing the activity of the CYP3A4 will affect the concentration of
balovaptan in the blood. If so, rifampicin will be expected to decrease your
blood levels of balovaptan during this study, though may increase the levels of
its breakdown products (metabolites).

The objective 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 in combination with rifampicin. It will also be investigated to
what extent balovaptan is tolerated by volunteer if administered alone or in
combination with rifampicin.

In Period 1 you will stay in the research center for 12 days (11 nights). Day 1
is the first day of administration of the study compound. You are 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). You will leave the research
center on Day 11.

There will be a period of at least 14 days (and a maximum of 21 days) between
the last administration of study compound in Period 1 and the first
administration of study compound in Period 2. This is the so-called washout
period.

You are expected to return to the research center at 14:00 hr in the afternoon
on Day -1 of Period 2. In Period 2 you will stay in the research center for 18
days (17 nights). Then you will leave the research center on Day 17 of Period
2.

In Period 1, balovaptan will be given once daily for 10 consecutive days, at a
dose of 10 mg. Balovaptan will be given as an oral tablet with 240 milliliters
(mL) of water after consumption of a standardized breakfast.

In Period 2, rifampicin will be given once daily at a dose of 600 mg for 6
consecutive days. Thereafter, rifampicin will be administered together with
balovaptan for 10 consecutive days. When balovaptan and rifampicin are given on
the same day, they will be given at the same time. Rifampicin will be given as
2 capsules of 300 mg with 240 mL of water.

The study compounds will be administered after an overnight fast (no eating and
drinking for at least 8 hours). A breakfast will be administered 30 minutes
after study compound administration. On Day 10 of Period 1 and Days 6 and 16 of
Period 2, you will receive a standardized breakfast 30 minutes after
administration of study compound, which has to be completed. A standardized
lunch and standardized dinner will be provided 4 and 8 hours after
administration of the study compounds.

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

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 effect reported by healthy subjects was headache. The most
common side effects reported by patients with ASD are listed below. The
majority of the side effects were of mild or moderate intensity.

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


Rifampicin
The most common side effects for rifampicin reported are listed below.
• Thrombocytopenia (decrease in platelets) with or without purple-colored spots
that are most recognizable on the skin
• Dizziness
• Headache
• Nausea
• Vomiting
• Increase in liver function enzymes
As rifampicin has a bright red color by itself, rifampicin may produce a
reddish discoloration of the urine, sweat, sputum and tears. Please be aware
that soft contact lenses (but also white clothes) may be permanently stained.

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

To monitor your 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).