A double-blind, randomised, placebo-controlled, combined single and multiple ascending dose study to investigate the safety, tolerability, pharmacokinetic, including food interaction, and pharmacodynamic profile of BIA 5-1058, in healthy male volunteers.

The drug to be given is a new investigational compound that may eventually be
used for the treatment of hypertension and chronic heart failure.
The compound inhibits the action of the enzyme dopamine *-hydroxylase. Dopamine
*-hydroxylase is involved in the synthesis of the neurotransmitter
norephinprine, a compound that is involved in the function of the autonomic
nervous system that regulates certain body functions which include blood
pressure (autonomic = can not be controlled by the mind). It has been studied
for many decades that inhibition of dopamine *-hydroxylase has a positive
effect on hypertension and heart failure. The application of previously
investigated agents with the same mechanism was limited because they not only
had an effect on the heart, but also on the central nervous system (the brain).
This new product, however, cannot reach the brain via the blood and, therefore,
would not have the adverse effects as have agents studied in the past.

Primary
to assess the tolerability of the compound after single and multiple oral doses

Secondary
to measure the plasma and urine concentrations of the compound and its
metabolites after single and multiple oral doses and to characterise its
pharmacokinetic (PK) parameters and steady state PK profile

to investigate the effect of the compound on blood pressure, on plasma dopamine
* hydroxylase (D*H) activity, and on the urinary levels of norepinephrine (NE),
dopamine (DA) and the amine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC)
and homovanillic acid (HVA)

to investigate the effect of food on the PK of a single dose of the compound

a double blind, randomised, placebo-controlled combined single ascending dose
(SAD), including food interaction analysis, and multiple ascending dose (MAD)
study. SAD part consists of 8 groups of 8 healthy young male subjects each
receiving a single oral dose of the study compound or placebo (6 verum and 2
placebo): in the first group, 2 subjects (1 verum and 1 placebo) are dosed 24 h
before remaining 6 subjects (5 verum and 1 placebo). If the maximum tolerated
dose (MTD) is not reached after completing the planned sequential groups,
additional groups can be included to a maximum of 12 sequential groups in
total. Food interaction part consists of 12 healthy young male subjects each
receiving a single dose of the study compound in either the fed or fasted state
in an open-label, two-way crossover design. Each treatment will be separated by
at least 7 days. MAD part consists of 4 groups of 8 young healthy male subjects
each receiving an oral dose of the study compound or placebo (6 verum and 2
placebo) once daily for 10 days. If the MTD is not reached after completing the
planned sequential groups, additional groups can be included to a maximum of 8
sequential groups in total.

SAD
In each group subjects will receive a single dose of the study compound (n=6)
or matching placebo (n=2) on Day 1

FOOD INTERACTION
The subjects will receive a single dose of the study compound on Day 1 under
fasted (one period) and fed (one period) conditions

MAD
In each group subjects will receive multiple doses of the study compound or
matching placebo once daily on Days 1 to 10

Not applicable.