A double-blind, placebo controlled, randomised, parallel group study with an open-label cross-over part, investigating safety, tolerability, pharmacokinetics, and pharmacodynamics after single ascending oral doses and a single intravenous dose of the vasopressin V2-receptor agonist FE 201836

FE 201836 is a new investigational compound that may eventually be used for the
treatment of excessive night-time urination. FE 201836 is expected to reduce
urinating by decreasing the water excretion in the kidneys. FE 201836
stimulates the vasopressin V2 receptor, which regulates the body*s water
retention and constriction of vessels. A drug with a similar mode of action
(desmopressin) is currently available for the treatment of excessive night-time
urination. However, desmopressin is known to decrease sodium levels in the
blood (hyponatremia); in some cases some to a severe extent. FE 201836 is
designed to be eliminated from the body more quickly and predictably than
desmopressin, thus reducing the risk of hyponatremia.
This is the first time that FE 201836 is being given to humans.

The purpose of the study is to investigate to what extent FE 201836 is
tolerated. It will also be investigated how quickly and to what extent FE
201836 is absorbed and eliminated from the body (this is called
pharmacokinetics). Also the effect on urine production (this is called
pharmacodynamics) will be investigated.

This study is divided in 2 parts (Part 1 and Part 2). Part 1 studies the
tolerability and pharmacokinetics after single dose administration of FE 201836
in 40 healthy volunteers. Part 2 studies the effect of FE 201836 on urine
production after an intravenous (i.v. = via a blood vessel) infusion of FE
201836. Part 2 is performed in 2 groups: one group of 12 healthy male and
female volunteers and one additional group of 8 healthy male and female
volunteers (referred to with Part 2A). The remainder of this document only
refers to Part 2A.

Part 1:
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Zuidlaren for 3 days (2 nights).

Part 2:
The actual study will consist of 3 periods. Each period the volunteer will stay
in the clinical research center in Zuidlaren for 3 days (2 nights). There will
be a resting period of at least 2 days between each period. In each period, the
volunteer will receive the study compound on Day 1 and will leave the clinical
research center on Day 2.

Part 2A;
The actual study will consist of 1 period during which you will stay in the
clinical research center in Zuidlaren for 3 days (2 nights).

Part 1:
during this research the volunteer will receive FE 201836 or placebo as a 20 ml
oral solution following a night of fasting.

Part 2:
in period one and 3 the volunteer will receive the study drug as a one hour 20
mL infusion (FE 201836 in period one and demopressine in period 3). 2 hours
before the IV infusion the volunteer will undergo a waterloading procedure. In
period 2 he will receive FE 201836 as a 20 mL oral solution.

Part 2A:
The study will consists of 1 period during which you will receive a 1 hour i.v.
infusion of a dose in the range of 0.2-1.0 µg FE 201836. The dose of FE 201836
will be determined based on the safety and pharmacokinetic results in Part 1
and 2.

As FE 201836 will be administered to man for the first time in this study,
adverse effects of FE 201836 in man have not been reported to date. However, FE
201836 has been studied in animals (rats and dogs). Up to the highest dose
tested in animals, no side effects were noted other than minimal abnormalities
at cellular level in kidney tissue and a minimal reduction in body weight gain
at the high dose level of FE 201836 tested in rats (500 µg/kg/day for 28 days).
In dogs a transient increase in heart rate and contractility was observed at a
dose of 50 µg/kg FE 201836.

The most common side effects reported in man for compounds with a similar mode
of action are: headache, dizziness, increased blood pressure, nausea, abdominal
pain, diarrhea, constipation, vomiting, water retention and tiredness. One rare
adverse event is hyponatremia. Hyponatremia may be preceded or accompanied by
headache, nausea, vomiting, weight gain, confusion and drowsiness. Therefore,
your blood will be monitored closely for hyponatremia during the study.

Risks associated with catheterization are a feeling of urgency (caused by the
tube) and urinary tract infections. Rare complications are urethral strictures
and sepsis.

Procedures: pain, minor bleeding, bruising, possible infection