A double-blind, placebo controlled, randomized study to evaluate the safety, tolerability, pharmacokinetic profile and cytochrome P450 interaction potential of single and multiple doses of Tonabersat over the dose range of 240 mg to 480 mg in healthy adult subjects.

The drug to be given tonabersat is a new, investigational compound that may
eventually be used for the treatment of migraine. Migraine is a syndrome
characterised by attacks of throbbing headache lasting from 4 to 72 hours
(commonly around 24 hours) accompanied by nausea, vomiting and sensitivity to
light and sounds. Tonabersat is a new compound which has broader spectrum of
activity than the commonly used anti-migraine agent, sumatriptan. Additionally,
tonabersat lacks some of the unwanted neurotoxic and cardiovascular effects
that were seen with sumatriptan, which might make tonabersat a potentially good
drug for the treatment of migraine.

to assess the single-dose safety, tolerability and pharmacokinetic profile of
(6) individual doses of tonabersat ranging from 160 mg to 480 mg (or to
dose-limiting toxicity (DLT)) in healthy subjects under the fasted or fed
conditions
to assess the multiple-dose safety, tolerability and pharmacokinetic profile of
(3) individual dose levels of tonabersat at steady state via a multiple
ascending dose, consecutive group study in healthy subjects in fasted of fed
consitions (to be determined after the SAD)
to assess the potential of tonabersat to undergo pharmacokinetic drug-drug
interactions using a *cocktail* of CYP probe substrates at one of the doses of
tonabersat evaluated at steady state under fasted or fed conditions
to assess the pharmacodynamics of tonabersat on CNS function using EEG
measurements and cognitive and psychomotor performance testing

Design:
A randomized, two-part, double-blind, placebo-controlled, single-,
multiple-ascending dose drug-drug interaction study; Part 1 consists of six
cohorts of 10 healthy male and female subjects each receiving a single oral
dose of tonabersat or placebo (eight verum and two placebo); Part 2 , Cohorts
1-3, consists of three cohorts of 16 healthy male and female subjects each
receiving an oral dose of tonabersat or placebo (twelve verum and four placebo)
once daily for fourteen days and part 2, Cohort 4 (DDI) consists 1 cohort of 16
healthy male and female subjects each receiving an oral dose of tonabersat or
placebo (14 verum and 2 placebo) once daily for fourteen days a single oral
dose of midazolam, metoprolol, omeprazole, caffeine and tolbutamide on Days -1
and 13.

Procedures and assessments
Screening:
Medical history, demographic data (including body weight and height),
genotyping (part 2, cohort 4), clinical laboratory (incl. TSH, T4), alcohol and
drug screen, pregnancy, HBsAg, anti HCV, anti-HIV 1/2, HAVIgm, vital signs,
body temperature, 12-lead electrocardiogram (ECG), EEG (part 2, Cohort 1-3),
physical examination, adverse events from the signing of the Informed Consent
Form, previous and concomitant medication.
Admission:
Drug and alcohol screen, AEs and concomitant medication.
Study drug administration.
Part 1/Cohort 1-6 and Part 2 Cohort 1-4. In Part 4 Cohort 4 CYP Probes.
Follow-up:
Clinical laboratory, vital signs, body temperature, ECG, physical examination,
AEs and concomitant medication.
Observation period:
Part 1 Cohort 1 and 3-6: 13 days plus 2 ambulatory visits
Part 1 Cohort 2: 1 or 2 periods of 13 days plus 2 ambulantory visits after each
period
Part 2 Cohort 1 - 3: 26 days plus 2 ambulatory visits
Part 2 Cohort 4: 17 days

Part 1 (SAD)
Cohort 1: a single oral dose of 240 mg tonabersat or placebo on Day 1 fasted
Cohort 2, period 1: a single oral dose of 320 mg tonabersat or placebo on Day
1 fasted
Cohort 2, period 2: a single oral dose of 320 mg tonabersat or placebo on Day
1 following a high fat breakfast
Cohort 3: a single oral dose of 360 mg tonabersat or placebo on Day 1 fasted or
following a (high fat) breakfast
Cohort 4: a single oral dose of 400 mg tonabersat or placebo on Day 1 fasted or
following a (high fat) breakfast
Cohort 5: a single oral dose of 440 mg tonabersat or placebo on Day 1 fasted or
following a (high fat) breakfast
Cohort 6: a single oral dose of 480 mg tonabersat or placebo on Day 1 fasted or
following a (high fat) breakfast
Part 2 (MAD)
Cohort 1: an oral dose of x mg tonabersat of placebo once daily on Days 1-14
fasted or following a (high fat) breakfast
Cohort 2: an oral dose of y mg tonabersat of placebo once daily on Days 1-14
fasted or following a (high fat) breakfast
Cohort 3: an oral dose of z mg tonabersat of placebo once daily on Days 1-14
fasted or following a (high fat) breakfast
Part 2 (DDI)
Cohort 4: an oral dose of xyz mg tonabersat of placebo once daily on Days 1-14
fasted or following a (high fat) breakfast, and a single oral dose of 2 mg
midazolam, 50 mg metoprolol, 150 mg caffeine, 40 mg omeprazole and 500 mg
tolbutamide on Days -1 and 13

Previous clinical studies were conducted with the same compound in 221healthy
volunteers (148 males and 73 females), and 44 patients with migraine (9 males
and 35 females). In addition, multiple dose prophylactic studies have been
conducted in 39 patients with a diagnosis of migraine with aura (10 males and
29 females). In these studies doses up to 200 mg daily for a maximum of 14 days
have been administered to volunteers aged < 60 years and the following adverse
effects were reported or observed: nausea, diarrhoea , sleepiness, headache,
dizziness, vertigo and scotoma (which is as an area of lost vision, blind spot
in the field of vision). In addition the following 14 serious adverse events
have been reported: low blood pressure and epileptic seizure; lowering of blood
potassium with vomiting dehydration and dizziness; sigmoid diverticulitis; and
complex migraine and left sided weakness.
The insertion of the indwelling canula and the venepuncture may cause some
pain, and sometimes lead to a bruise, but the actual collection of blood will
not be painful. Light bleeding and possibly an infection may occur. Infusion
may cause oedema in the arm where the infusion is given.