A PHASE I, SINGLE CENTER, RANDOMIZED, DOUBLE BLIND, PLACEBO CONTROLLED, SINGLE DOSE STUDY IN HEALTHY FEMALE AND ELDERLY VOLUNTEERS AND MULTIPLE ASCENDING DOSE STUDY IN HEALTHY MALE AND FEMALE VOLUNTEERS BETWEEN THE AGES OF 18-80 YEARS TO INVESTIGATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF GRC 17536

The new compound to be given, GRC 17536, is an investigational compound that
may eventually be used for the treatment of acute or chronic pain, asthma or
COPD, or excessive cough.
This new compound is not registered as a drug, but has been given to humans
before.

The new compound blocks the activity of a protein (called TRPA1) that occurs
naturally on nerve cells in the body. This protein works as a *sensor* for
stimuli (signals) such as pressure, temperature and irritants (such as air
pollution, or tear gas). They allow the body to respond to these stimuli by
avoiding or minimising painful movements (e.g., not using a painful arm), or by
airway constriction or coughing to limit damage by the inhaled irritant.
However, in some cases, the response of the body to the stimulus (i.e., the
pain, airway constriction, or cough) may be a bigger problem than the stimulus
itself, and we may choose to (completely or partially) suppress the body*s
response, e.g., with a drug that blocks TRPA1. The new compound investigated
here (GRC 17536) could play a role in such cases, based on its potential to
make the nerve cells involved in these responses less susceptible to
activation.

This study is part of a larger program of in total 6 parts. This program was
split in two sub programs and each of these sub programs consists of three
parts. The current study originally comprised 3 parts and a fourt part is added.

The purpose of the study is to investigate how safe the compound is and how
well the compound is tolerated. The study will also investigate how quickly and
to what extent the compound is absorbed and eliminated from the body (this is
called pharmacokinetics).

Part 1 of the study will be performed in healthy, young females (aged 18-45
years) and elderly females (aged 46-65 years) and will investigate the
properties of the new compound when it is administered in a single dose, such
to be compared to single doses given to males studied in a previous study.

Part 2 of the study will be performed in healthy, elderly males and females
(65-80 years of age) and will again investigate the properties of the new
compound when it is administered in a single dose, such to be compared to the
young males and females studied in a previous study and in Part 1 of this study.

Part 3 of the study will be performed in healthy, young (18-45 years of age)
and elderly (65-80 years of age) males and females and will investigate the
properties of the new compound when it is administered in multiple (repeated),
ascending doses. This part consists of four cohorts (3 groups of 4 young and 4
elderly males and 4 elderly females each and one group of 4 young and 4 elderly
males and 4 young and 4 elderly females).

Part 4 of the study will be performed in healthy, young (18-45 years of age)
male and will investigate the absorption properties of the new compound in
Cerebrospinal Fluid (liquor) when it is administered in multiple (repeated),
ascending doses. Part 4 is an open label study and consists of 1 group of 6
young healthy males.

Part 1
The study will consist of 1 period, during which you will stay in the clinical
research centre in Groningen for 9 days (8 nights).
You will receive a single dose of 250 mg GRC 17536 or placebo once in the form
of a suspension (a cloudy drinking solution). Placebo is a suspension without
the active ingredient.

Part 2
The study will consist of 1 period, during which you will stay in the clinical
research centre in Groningen for 9 days (8 nights).
You will receive a single dose of 250 mg GRC 17536 or placebo once in the form
of a suspension (a cloudy drinking solution). Placebo is a suspension without
the active ingredient.

Part 3
The study will consist of 1 period, during which you will stay in the clinical
research centre in Groningen for 23 days (22 nights).
The amount of study medication you receive depends on the group you participate
in. See below table for the anticipated dose schedule.
For groups L and M: 30 days (29 nights)

Group Dose level / how often
1 30 mg / once daily for 14 days after a meal
2 30 mg / twice daily for 14 days after a meal
3 90 mg / twice daily for 21 days after a meal
4 250 mg / twice daily *for 21 days after a meal

*The final dose will be determined based on the results obtained in Group 1, 2
and 3.

Part 4
The study will consist of 1 period, during which you will stay in the clinical
research centre in Groningen for 19 days (18 nights).
During the study, you will receive 250 mg GRC 17536, twice daily for the
duration of 14 days.

For all groups:
The screening will include a physical examination including measurement of
supine and standing blood pressure and
pulse rate, respiratory rate, body temperature, weight and height, a heart
trace (electrocardiogram) recording, and a
number of blood and urine tests. There will also be screened for drugs of
abuse, alcohol, Hepatitis B and C, and HIV (=
AIDS test). A pregnancy test will be performed (females only). There will be a
two-time follow-up medical examination
when the study is completed. This two-time examination will take place 10 days
and 14 days after administration of (the
last) study medication. The first post-study examination will consist of
measurements of supine and standing blood
pressure and pulse rate, respiratory rate, and body temperature, a heart trace
(electrocardiogram) recording, and a
number of blood and urine tests; the second follow-up examination will consist
of a physical examination including
measurements of supine and standing blood pressure and pulse rate, respiratory
rate, body temperature and weight, a
heart trace (electrocardiogram) recording, and a number of blood and urine
tests.

GRC 17536 administered as GRC 17536 potassium granules single or multiple doses
in the fed state.

In an ongoing study in healthy male volunteers where GRC 17536 was / will be
administered in single doses up to 1000 mg the following adverse effects were
reported: gastrointestinal tract related symptoms like nausea of short duration
reported directly after drug administration, mild abdominal pain, loose stool
and flatulence. Other adverse effects which were also considered to be related
to the study drug were: feeling weak / fainting (Vasovagal syncope, as response
to blood draw or pain) and tiredness.

For the multiple dose part: you should be aware though that taking the study
drug for 14 days (for groups L and M: 21 days), concentrations of the study
drug and its break-down products (metabolites) in your blood and your organs
can be reached that have not been reached in the single dose study mentioned
above, depending on which dose group you will be in.

Procedures:
Pain, light bleeding, heamatoma, possibly an infection.
Collection of liquor (Part 4 only): Insertion of the needle, for the
collection of liquor, may be painful, similar to drawing blood from the arm by
a direct puncture of the vein. Removing the needle is painless. Usually no
complications occur during an epidural. Sometimes, during the epidural, a nerve
can be hit. Then you will feel an electric pulse or a shooting pain in your
leg. This can be painful, but is not harmful. After the epidural, you may
experience a headache, nausea or subsequent bleeding of the wound (puncture
hole) and there is a small chance of bleeding, infection, or injury to a nerve.