A Study in Patients With Moderate Asthma to Compare Pharmacokinetics and Pharmacodynamic Effects of Fluticasone Propionate and Salmeterol Delivered Via the ROTAHALER® Inhaler Relative to the DISKUS® Inhaler
A Study in Patients With Moderate Asthma to Compare Pharmacokinetics and Pharmacodynamic Effects of Fluticasone Propionate and Salmeterol Delivered Via the ROTAHALER® Inhaler Relative to the DISKUS® Inhaler
The Fluticasone Propionate/Salmeterol combination (FSC) at a dose of 100/50 micrograms (mcg)
 twice daily in DISKUS inhaler (also known as ACCUHALER®, Ddpi) inhaler is a recognised and
 licensed therapy for the treatment of asthma. GlaxoSmithKline (GSK) is developing the
 ROTAHALER/ ROTACAPS® (Rdpi) inhaler as an alternative treatment option for asthmatic
 patients. This study is a Phase I, randomised, double-blind, double-dummy, two- treatment,
 four-way cross-over (replicate design), two sequence, repeat dose, two centre study in mild
 to moderate asthmatics to compare the pharmacokinetics and pharmacodynamics of fluticasone
 proprionate/salmeterol (100/50 mcg) delivered via the Rdpi versus the Ddpi. A total of 58
 subjects will be enrolled to ensure 52 subjects complete all dosing occasions. Each subject
 will be allocated to one of two treatment sequences and will participate in four treatment
 periods, receiving each of the treatments twice.

 DISKUS, ACCUHALER, ROTAHALER and ROTACAPS are registered trademarks of GSK groups of
 companies.
Inclusion Criteria:

 -  Subjects with a known physician diagnosis of asthma with a best Forced Expiratory
 Volume in 1 Second (FEV1) of >70% of the predicted normal value at the Screening
 visit. Percent predicted will be calculated using the European Respiratory Society
 Global Lung Function Initiative reference equations. Subjects must abstain from short
 acting beta-2 agonists (SABA) use for 6 hours prior to the Screening visit.

 -  During the screening visit, subjects must either demonstrate the presence of
 reversible airway disease, defined as an increase in FEV1 of >=12.0% over baseline and
 an absolute change of >=200 millilitres (mL) within 60 minutes following 4 inhalations
 of albuterol/salbutamol inhalation aerosol (or equivalent nebulized treatment with
 albuterol/salbutamol solution) or in the absence of reversibility have documented
 evidence of a physician diagnosed asthma for at least 6 months

 -  Male/females aged between 18 and 65 years of age inclusive, at the time of signing the
 informed consent.

 -  Body weight >= 50 kilograms (kg) and body mass index (BMI) within the range 18 - 35.0
 kilogram/square meter (kg/m^2) (inclusive).

 -  A female subject is eligible to participate if she is of: Non-childbearing potential
 defined as pre-menopausal females with a documented tubal ligation or hysterectomy for
 this definition, "documented" refers to the outcome of the investigator's/designee's
 review of the subject's medical history for study eligibility, as obtained via a
 verbal interview with the subject or from the subject's medical records; or
 postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a
 blood sample with simultaneous follicle stimulating hormone (FSH) >40
 milliinternational units per/millilitre (MIU/mL) and estradiol <40 picogram/millilitre
 (pg/mL) (<147 picomoles per liter [pmol/L]) is confirmatory. Females on hormone
 replacement therapy (HRT) and whose menopausal status is in doubt will be required to
 use one of the contraception methods, if they wish to continue their HRT during the
 study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal
 status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will
 elapse between the cessation of therapy and the blood draw; this interval depends on
 the type and dosage of HRT. Following confirmation of their post-menopausal status,
 they can resume use of HRT during the study without use of a contraceptive method.;
 Child-bearing potential with negative pregnancy test as determined by serum or human
 chorionic gonadotropin (hCG) test at screening or urine hCG test prior to dosing AND ;
 Agrees to use one of the contraception methods for an appropriate period of time (as
 determined by the product label or investigator) prior to the start of dosing to
 sufficiently minimize the risk of pregnancy at that point. Female subjects must agree
 to use contraception until the follow-up visit.; OR has only same-sex partners, when
 this is her preferred and usual lifestyle.

 -  Capable of giving written informed consent, which includes compliance with the
 requirements and restrictions listed in the consent form

 -  Subjects who are current non-smokers and who have a pack history of <=10 pack years. A
 subject may not have used inhaled tobacco products within the past 3 months (i.e.,
 cigarettes, cigars or pipe tobacco). [number of pack years = (number of cigarettes per
 day / 20) x number of years smoked].

 -  Alanine transaminase (ALT), alkaline phosphatase and bilirubin <= 1.5x Upper limit of
 normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated
 and direct bilirubin <35%).

 -  Based on single or averaged corrected QT interval (QTc) values of triplicate
 electrocardiogram (ECGs) obtained over a brief recording period: QT duration corrected
 for heart rate by Fridericia's formula (QTcF) <450 milliseconds (msec); or QTcF <480
 msec in subjects with Bundle Branch Block.

 -  Asthma therapy: Subjects must have been on their current therapy for at least eight
 weeks and a stable dose for four weeks prior to the screening visit:

 1. Subjects on fluticasone propionate/salmeterol combination 100/50 microgram (mcg)
 treatment via a DISKUS inhaler prior to the study will be allowed to remain on
 their treatment regimen until randomization provided all other eligibility
 criteria are met.;

 2. Subjects on treatment with fluticasone propionate/salmeterol combination 125/25
 mcg via a metered dose inhaler will be required to switch to fluticasone
 propionate/salmeterol combination 100/50 mcg via the GlaxoSmithkline
 (GSK)-provided DISKUS inhaler for between 14 and 28 days prior to randomization;

 3. Subjects on low dose inhaled corticosteriod (ICS) monotherapy (up to a total
 daily dose of fluticasone propionate 250 total daily dose mcg or other ICS
 equivalent e.g. budesonide up to 400 mcg total daily dose) will switch to
 fluticasone propionate/salmeterol combination 100/50 mcg via the GSK-provided
 DISKUS inhaler for between 14 and 28 days prior to randomization;

 4. Subjects on medium dose ICS monotherapy ( greater than 250 and up to 500 mcg of
 fluticasone propionate total daily dose or other ICS equivalent e.g. budesonide
 greater than 400 mcg and up to 800 mcg total daily dose) will switch to
 fluticasone propionate/salmeterol combination 100/50 mcg twice daily via the
 GSK-provided DISKUS inhaler for 28 days prior to randomization;

 5. Subjects on low dose Symbicort (any doses that are no greater than 400/12 mcg
 total daily dose) will be switched to fluticasone propionate/salmeterol
 combination 100/50 mcg via the GSK-provided DISKUS inhaler for between 14 and 28
 days prior to randomization.

 Exclusion Criteria:

 Criteria Based Upon Medical Histories

 -  Any clinically relevant medical condition or abnormality identified during the
 screening medical assessment and procedures, physical examination, or laboratory
 assessments (including clinical chemistry and haematology), which in the opinion of
 the Investigator and/or GSK Medical Monitor is likely to affect the safety of the
 subject and/or interfere with the study procedures and outcomes.

 -  Acute exacerbation of asthma in the last 6 months prior to the Screening visit.

 -  Subjects on treatment with fluticasone propionate either as monotherapy or in
 combination at a total daily dose higher than 500 mcg or budesonide monotherapy or in
 combination at a total daily dose higher than 800 mcg or beclomethasone (CFC) at a
 total daily dose higher than 1000 mcg or beclomethasone (HFA) at a total daily dose
 higher than 400mcg are excluded from the study

 -  Subjects with other significant pulmonary diseases (pneumonia, pneumothorax,
 atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic
 bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory
 abnormalities other than asthma).

 -  Use of oral/injectable/depot corticosteroid for any indication within 3 months prior
 to the Screening visit.

 -  Use of any anti immunoglobulin E (Anti-IgE) (e.g. Xolair) in any period prior to
 screening.

 -  Use of intra-nasal steroids (INS). To be eligible for the study, patients on INS
 therapy will be required to switch to non-INS therapy at screening

 -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
 (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 -  History of regular alcohol consumption within 6 months of the study defined as: For
 Australian sites: An average weekly intake of >21 units for males or >14 units for
 females. One unit (= standard drink) is equivalent to 10 g of alcohol: 270 mL of full
 strength beer (4.8%), 375 mL of mid strength beer (3.5%), 470 mL of light beer (2.7%),
 250 mL pre-mix full strength spirit (5%), 100 mL of wine (13.5%) and 30 mL of spirit
 (40%); For South African sites: An average weekly intake of >21 units for males or >14
 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint
 (approximately 330 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of
 spirits.

 -  A known or suspected history of drug abuse within 12 months of the Screening visit.

 -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

 -  History of sensitivity to salbutamol or any of the study medications, or components
 thereof (including severe milk protein allergy) or a history of drug or other allergy
 that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their
 participation.

 Criteria Based Upon Diagnostic Assessments

 -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
 result within 3 months of screening

 -  A positive pre-study drug screen.

 -  A positive test for Human Immunodeficiency Virus (HIV) antibody.

 -  Subjects with known abnormal levels of serum cortisol

 -  A subject will not be eligible if he/she has clinical visual evidence of oral
 candidiasis prior to randomisation

 -  Where participation in the study would result in donation of blood or blood products
 in excess of 500 mL within a 56 day period.

 -  Lactating females.

 -  The subject has participated in a clinical trial and has received an investigational
 product within the following time period prior to the first dosing day in the current
 study: 30 days, 5 half-lives or twice the duration of the biological effect of the
 investigational product (whichever is longer).

 -  Exposure to more than four new chemical entities within 12 months prior to the first
 dosing day.

 -  Grapefruit or grapefruit juice containing products are excluded from 2 weeks prior to
 randomisation until collection of the final blood sample at treatment period 4.

 -  Drugs that inhibit the cytochrome P450 isoform, 3A4 (CYP3A4), are excluded from 2
 weeks prior to randomisation until collection of the final blood sample at treatment
 period 4. CYP3A4 inhibitors include cimetidine, clarithromycin, erythromycin,
 ciprofloxacin, ritonavir, ketoconazole, and azole antifungals.

 -  Use of prescription or non-prescription drugs, vitamins, herbal and dietary
 supplements, within seven days or 5 half-lives (whichever is longer) prior to the
 first dose of study medication, which in the opinion of the Principal Investigator,
 may interfere with study outcome. Specifically, calcium and vitamin D supplements and
 bisphosphonates are not allowed throughout the study.

 -  Subjects, who, in the opinion of the Investigator, are not able to comply with the
 protocol requirements.