A multicenter, randomized, double-blind, placebo-controlled, cross-over, proof of concept study comparing the effects of both single dose and repeated dosing treatment for 2 weeks of test compound in patients with chronic subjective tinnitus

The test compound is an experimental (or investigational) drug which has not
been registered as a medicine for the treatment of people with epilepsy,
migraine and tinnitis.

To examine the multiple dose effects of the study medication test compound in
tinnitus after a 2-week treatment.

A multicenter, randomized, double-blind, placebo-controlled, cross-over, proof
of concept study comparing the effects of both single dose and repeated dosing
treatment for 2 weeks of test compound in patients with chronic subjective
tinnitus

The patient will take 1 capsule with 50 mg test compound each, 3 times a day
for 6 weeks. The patient will not be informed when exactly the first treatment
period will end and the second treatment period will start. However, the
patient will receive the test compound only for a maximum duration of 15 days.

Risks emerge from potential side effects of the study medicine and from taking
blood during the patient*s visits at the clinic. To date, the test compound was
investigated in healthy subjects as well as in patients with epilepsy and
migraine. The highest single dose tested was 450 mg and the highest multiple
dose was 150 mg three times a day administered for 14 days. The most frequently
observed side effects, deemed to be related to the test compound, were
dizziness, fatigue, sleepiness, headaches and balance disorder. The majority of
these adverse events were observed in subjects receiving single doses of 250 mg
and higher or receiving a multiple dose treatment of 150 mg three times a day.
In some healthy subjects, changes in their ECG occurred at different time
points after the administration of the test compound. These were (for example)
a slower heart beat or additional heart beats of mild intensity recorded on the
ECG, but no induced symptoms were noted. Since in some subjects such ECG
changes were seen already before intake of the test compound, it is currently
not fully clear whether the ECG changes were caused by the test compound.

In a few healthy subjects transient dizziness during standing was observed.
Most probably this was caused by a short-lasting decrease of blood pressure.

In a study investigating a single dose of 250 mg test compound in patients with
acute migraine (clinical part completed recently), two female patients
experienced dizziness and unsteady gait. One of these patients additionally
developed nystagmus (i.e. involuntary eye movement) about 4 hours after intake
of study medication. Both patients were hospitalized overnight as a precaution.
All events resolved 3 hours after onset.

In a recently completed study, one healthy subject receiving a dose of 150 mg
three times a day test compound for 14 days showed a modest (about two-fold the
upper limit of normal [ULN]) increase of liver enzymes. The increase started on
day 6 of treatment, remained at approximately 2-fold ULN for the rest of the
treatment period and decreased to normal again within a few days after
completing the treatment.

All these described unwanted effects seen in previous clinical studies were
transient and disappeared without any treatment. Except for the few cases of
dizziness most probably caused by a short-lasting decrease of blood pressure
and the single case of increase in liver enzymes, there were no relevant
deviations of vital signs (blood pressure, pulse), ECGs (measurement of the
electrical heart activity), laboratory parameters or in the physical and
neurological examination.

A substance similar to the test compound caused transient vision problems,
mainly hypersensitivity to light, in earlier clinical studies. So far, this was
not observed after the intake of the test compound.

The dose to be administered in the present study (100 mg BGG492 three times a
day) was selected on the basis of results derived from studies in healthy
subjects and epilepsy patients. Due to several subjects enrolled in this study
experiencing adverse events like dizziness, tiredness, disturbed coordination
(gait disturbance), nausea and vomiting (some of them deteriorating the
performance of daily activities) and which may be related to the study
medication intake, Novartis has decided to reduce the dose to 50 mg three times
a day (or 1 capsule three times a day), from the start of the study for
subjects enrolled in the study after 27 June 2011. The risk to health at this
dose level is limited but the patient may experience one of the above mentioned
side-effects or other symptoms not previously reported. The patients health
will be closely monitored during the trial to minimize any risks.

Problems or side effects not now known to date could also occur. The patient*s
will be given any new information that may affect the patient*s willingness to
start or continue in the study.