An open label, part-randomised, four-way crossover, single and repeat dose study to determine the dose proportionality and absolute bioavailability of fluticasone furoate (FF) when administered as FF inhalation powder from the novel dry powder inhaler in healthy subjects.

Fluticasone furoate is a drug that may also be used for the treatment of
asthma. Fluticasone furoate has not been registered for the treatment of
asthma, however, in many countries including The Netherlands it has been
registered for the treatment of chronic severe rhinitis. The drug has been
administered extensively to asthma patients, COPD patients and healthy
volunteers as part of the clinical development program. Fluticasone furoate is
a corticosteroid, a chemical variant of a hormone produced by the body in the
adrenal cortex which supresses various reactions during infection and
inflammation.
In this study fluticasone furoate will be administered in a new form of
inhalation, namely by an inhaler that contains the dry powder form of
fluticasone furoate.

The purpose of the study is to investigate to what extent blood concentrations
of Fluticasone Furoate increase proportionately to rising doses of Fluticasone
Furoate in three steps administered via a powder inhalator. In addition, the
absolute bioavailability of the drug will be determined, i.e. drug
concentrations reached in the blood following intravenous administration and
inhalation of the drug will be compared.

A part-randomised, open-label, four-way cross-over single and repeat dose study
in healthy male and female subjects.

Procedures and assessments:
Screening: Informed consent, demographics, medical history, clinical
laboratory, full physical examination, ECG, vital signs, drug screen, HBsAg,
anti HCV, anti-HIV 1/2, pregnancy test (females only), spirometry, inhaler
practice.

Observation period: Period 1-3: in clinic from Day -1 up to 48 h after drug
administration on Day 1; from Day 8 until 24 h after last drug administration
on Day 9.
Period 4: from Day -1 up to 48 h after drug administration on Day 1

Blood sampling: for pharmacokinetics periods 1-4: Day 1: pre-dose, and several
timepoints post-dose until 48 h post-dose.

Safety assessments: AE, SAE and concomitant medication review throughout the
study; Brief physical exam: if deemend relevant; drugs of abuse; inhaler
practice; vital signs; pregnancy test (females only)

Treatment A
A single dose of 300mcg FF on Day 1, followed by 50mcg FF once daily for 7
days, on Days 3-9.
Treatment B
A single dose of 600 mcg FF on Day 1, followed by 100mcg FF once daily for 7
days, on Days 3-9.
Treatment C
A single dose of 1200mcg FF on Day 1, followed by 200mcg FF once daily for 7
days, on Days 3-9.
Treatment D
A single dose of 250mcg FF, administered as an IV infusion over 20 minutes on
Day 1.

Fluticasone Furoate Inhalation Powder: The study medicine is prepared with
lactose (which contains milk protein). Allergic reactions may be seen when used
in patients with a severe milk protein allergy or known hypersensitivity
(medication allergy) to any ingredient of the medicine preparation. The study
medicine also contains magnesium stearate, which is a substance commonly used
in the manufacture of medical tablets and has no known side effects.
Side effects observed in previous studies with inhaled Fluticasone Furoate
include:

Very common side effects (that occur in more than 1 in 10 patients)
* Headache
* Irritation and pain of the throat, nose and sinuses

Common side effects (that occur in more than 1 in 100 patients)
* Candidiasis (thrush) of the mouth and throat
* Upper Respiratory Tract Infections / Bronchitis
* Cough
* Loss of voice (Dysphonia)
* Fever (Pyrexia) and flu like symptoms
* Irritation and pain of the nose, throat and sinuses
* Pain and discomfort in the joints and back (Arthralgia)
* Abdominal pain

Rare side effects (that occur in less than 1 in 1,000 patients)
* Hypersensitivity reactions (allergic reactions)
* Abnormalities of heart rate (these were not serious and were seen during
cardiac tests on patients)