Pharmacokinetic and Pharmacodynamic (PK and PD) Study of Fluticasone Propionate and Salmeterol Combination Product Delivered in a Capsule-based Inhaler and in a Multi-dose Dry Powder Inhaler in Moderate Asthma Patients and Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Patients.
Pharmacokinetic and Pharmacodynamic (PK and PD) Study of Fluticasone Propionate and Salmeterol Combination Product Delivered in a Capsule-based Inhaler and in a Multi-dose Dry Powder Inhaler in Moderate Asthma Patients and Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD) Patients.
This is a comparative bioavailability study to compare the pharmacokinetics and
 pharmacodynamic effects of Fluticasone propionate and Salmeterol delivered in a capsule-based
 inhaler versus a multi-dose dry powder inhaler in patients with moderate asthma and in
 patients with moderate to severe Chronic obstructive pulmonary disease (COPD).

 Co-primary endpoints will be the area under the curve (AUCτ) measured for plasma Fluticasone
 propionate (pharmacokinetic) and the pharmacodynamic effects of Fluticasone propionate
 (weighted mean serum cortisol over 0-12h) on the last day of each 10 day study treatment
 period. Secondary endpoints will include the following pharmacokinetic parameters for both
 fluticasone propionate and salmeterol: AUClast, AUC(0-t), Cmax, Cmin, tmax, λz, and t1/2 as
 well as the pharmacodynamic effects of salmeterol (pulse rate, blood pressure,
 electrocardiogram [ECG], potassium and glucose) and Fluticasone propionate (urine cortisol
 levels). Safety (adverse events and laboratory abnormalities) will also be assessed as a
 secondary endpoint.

 The study is a randomised, double blind, double dummy, four-period cross-over study.
 Approximately 60 asthma or COPD patients will be randomised. Patients meeting eligibility
 criteria will receive Fluticasone propionate/salmeterol 250/50mcg bid, from a capsule-based
 inhaler and from a multi-dose dry powder inhaler for a period of 10 days each in a randomised
 order. All patients will receive treatment from each device twice. To maintain the double
 blind, each patient will receive active treatment and placebo at the same time from two
 separate devices.
BACKGROUND This study will evaluate the comparative bioavailability of SERETIDE delivered via
 the established multi-dose powder inhaler ie DISKUS/Accuhaler and a new fluticasone
 propionate/salmeterol capsule-based inhaler. Both formulations will be delivered at the
 250/50mcg (micrograms) twice daily (bid) dose strength.

 STUDY RATIONALE The fluticasone propionate/salmeterol capsule-based inhaler has been
 developed for administration in both asthma and Chronic obstructive pulmonary disease (COPD)
 patients. Therefore, both disease populations are included in this study. The study will
 assess the performance of the two devices with respect to systemic exposure and
 pharmacodynamic effects. A replicated cross-over design (four period) was chosen. This design
 reduces subject numbers by about 50% compared to a standard 2-period cross-over design.

 OBJECTIVES Primary Objective

 -To compare the performance of fluticasone propionate/salmeterol administered in a
 capsule-based inhaler with the multi-dose dry powder inhaler by evaluating fluticasone
 propionate pharmacokinetic and pharmacodynamic endpoints.

 Secondary Objectives

 -  To compare the pharmacokinetic and pharmacodynamic effects of the salmeterol component
 of fluticasone propionate/salmeterol after administration from a capsule-based inhaler
 and from the multi-dose dry powder inhaler

 -  To compare the safety and tolerability of fluticasone propionate/salmeterol after
 administration in a capsule-based inhaler with the multi-dose dry powder inhaler.

 ENDPOINTS Primary Endpoints

 -  Pharmacokinetic endpoint: AUCτ for fluticasone propionate (area under the plasma
 fluticasone propionate concentration-time curve over dosing interval) on the last day of
 each study treatment period (Day 10).

 -  Pharmacodynamic endpoint: Weighted mean serum cortisol over 12h on the last day of each
 treatment period (Day 10).

 Secondary Endpoints

 -  Pharmacokinetic parameters (AUClast, AUC(0-t), Cmax, Cmin, tmax, λz, and t1/2 for
 fluticasone propionate and salmeterol) on the last day of each treatment period (Day
 10).

 -  Pharmacodynamic parameters:

 -  Fluticasone propionate: Urine cortisol excretion (0-24h) and serum cortisol Cmin on the
 last day (Day 10) of each treatment period,

 -  Salmeterol: pharmacodynamic parameters for pulse rate, blood pressure, electrocardiogram
 (ECG), plasma potassium and glucose (weighted mean 0-12h and Cmax/Cmin) on the last day
 (Day 10) of each treatment period

 -  Safety and tolerability: Incidence of adverse events and laboratory abnormalities

 STUDY DESIGN This is a randomised, four-period cross-over, double-blind, double-dummy study.
 Patients meeting eligibility criteria will receive fluticasone propionate/salmeterol 250/50
 mcg bid from a capsule-based inhaler and from a multi-dose dry powder inhaler for 10 days per
 each treatment period in a randomised order. To maintain the double blind, each patient will
 receive both active treatment and placebo at the same time from two separate devices.
 Patients already on inhaled corticosteroid (ICS) monotherapy or combination treatment prior
 to randomization will stop their existing treatment and switch to treatment provided by the
 study-provided devices.

 The study has been designed to compare the administration of fluticasone
 propionate/salmeterol from two inhalation devices, a capsule-based inhaler and a multi-dose
 dry powder inhaler. Fluticasone propionate/salmeterol administered via the multi-dose dry
 powder inhaler will be the reference product. Fluticasone propionate/salmeterol is being
 developed by GlaxoSmithKline (GSK) as a capsule-based inhaler for administration for the
 treatment of both asthma and COPD.

 TREATMENT ASSIGNMENT Subjects will be assigned to one of two treatment sequences in
 accordance with the randomisation schedule Sequence ABBA (Periods 1 to 4): A: Fluticasone
 propionate/salmeterol from a multi-dose dry powder inhaler; B: Fluticasone
 propionate/salmeterol from a capsule-based inhaler; B: Fluticasone propionate/salmeterol from
 a capsule-based inhaler; A: Fluticasone propionate/salmeterol from a multi-dose dry powder
 inhaler Sequence BAAB (Periods 1 to 4): B: Fluticasone propionate/salmeterol from a
 capsule-based inhaler; A: Fluticasone propionate/salmeterol from a multi-dose dry powder
 inhaler; A: Fluticasone propionate/salmeterol from a multi-dose dry powder inhaler; B:
 Fluticasone propionate/salmeterol from a capsule-based inhaler.
INCLUSION CRITERIA:

 ALL PATIENTS:

 -  Available for the duration of the study and able to attend the clinic for all study
 visits.

 -  Gender: male or female

 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; or postmenopausal defined as 12 months of spontaneous
 amenorrhea [in questionable cases a blood sample with simultaneous follicle
 stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 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 protocol allowed 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 and agrees to use one of the protocol allowed 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 they
 have attended the site for the follow-up visit.

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

 -  Body mass index between 18 and 35 kg/m2 inclusive at Screening

 -  Able to use the inhaler devices adequately after training

 -  AST and ALT < 2xULN (upper limit of normal); alkaline phosphatase and bilirubin less
 than or equal to 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
 fractionated and direct bilirubin <35%).

 -  QT interval corrected for heart rate (QTc)* <450 millisecond (msec)** QTc <480 msec
 for patients with bundle branch block

 -  either QTcB (QTc Bazzett's formula) or QTcF (QTc Fridericia's formula), machine
 or manual overread, males or females. The specific formula that will be used in a
 study should be predetermined prior to the initiation of the study. The QT
 correction formula used to determine inclusion and discontinuation should be the
 same throughout the study.

 -  based on single or averaged QTc values of triplicate ECGs obtained over a
 brief recording period

 COPD PATIENTS:

 -  Diagnosis: COPD patients, defined as either Stage III to Stage IV COPD diagnosis
 according to GOLD criteria (Global Strategy for the Diagnosis, Management, and
 Prevention of COPD, updated 2009) [GOLD, 2009]. Individuals must be otherwise healthy
 individuals who are free from significant cardiac, gastrointestinal, hepatic, renal,
 haematological malignancy, endocrine, neurological and psychiatric disease as
 determined by history, physical examination and screening investigations.

 -  Age: 40-80 years inclusive at the time of signing the informed consent.

 -  Post-bronchodilator forced expiratory volume in one second (FEV1) < 50% of predicted
 normal values at Screening. Patients must abstain from short acting beta agonist
 (SABA) use for 6 hours prior to the screening visit.

 -  Post-bronchodilator FEV1/FVC ratio ≤ 0.70 at Screening

 -  An increase of less than 15% from baseline FEV1 or an absolute change of < 200ml, 30
 minutes after inhalation of 400mcg of salbutamol by metered-dose inhaler (MDI) and
 spacer or 2.5mg by nebuliser at Screening.

 -  Ex smokers for at least the past 3 months with a pack history ≥10 pack years [number
 of pack years = (number of cigarettes per day / 20) x number of years smoked].

 -  COPD therapy:

 -  Patients on fluticasone propionate/salmeterol combination 250/50mcg bid via a
 multi-dose dry powder inhaler prior to the study will be allowed to remain on their
 treatment regimen until randomization provided all other eligibility criteria are met.

 -  Patients on fluticasone propionate/salmeterol combination 250/50mcg bid via a metered
 dose inhaler or the equivalent dose of budesonide/formoterol, 800/24mcg (total daily
 dose) via a turbuhaler will be switched to fluticasone propionate/salmeterol
 combination 250/50mcg bid via the GSK provided multi-dose dry powder inhaler for
 between 14 and 28 days prior to randomization.

 -  Patients on tiotropium in addition to ICS/LABA (long-acting beta agonist) treatment
 (up to a total daily dose of 500mcg fluticasone propionate or other ICS equivalent eg.
 800mcg budesonide) may continue their tiotropium treatment throughout the study.

 -  Patients on tiotropium monotherapy will need to start treatment with fluticasone
 propionate/salmeterol combination 250/50mcg bid via the GSK provided multi-dose dry
 powder inhaler for between 14 and 28 days prior to randomization. They may continue
 their tiotropium treatment throughout the study.

 -  Patients on LABA therapy (eg. salmeterol 50mcg) will need to start treatment with
 fluticasone propionate/salmeterol combination 250/50mcg bid via the GSK provided
 multi-dose dry powder inhaler for between 14 and 28 days prior to randomization.

 ASTHMA PATIENTS:

 -  Diagnosis: Patients with moderate asthma as defined by the Global Initiative for
 Asthma (GINA) guidelines at Screening. A best FEV1 of 60-85% of the predicted normal
 value at the Screening visit. NHANES (National Health and Nutrition Examination
 Survey) III predicted values will be used [Hankinson, 2009]. If a subject is recorded
 as having Hispanic or Latino ethnicity, then the Mexican-American equations will be
 used (irrespective of race). If a subject is recorded as being of African
 American/African Heritage race, then the African American equations will be used. If a
 subject is recorded as being of Asian or of Pacific Islander race, then the Caucasian
 formula will be used with a conversion factor of 0.88. Otherwise, the Caucasian
 equations will be used.

 -  Age: 18 and above at the time of signing the informed consent.

 -  Best clinic screening pre-bronchodilator FEV1 between 60 and 85% of predicted normal
 values (NHANES III values). Patients must abstain from SABA use for 6 hours prior to
 the Screening visit.

 -  Asthma therapy:

 -  Patients on fluticasone propionate/salmeterol combination 250/50mcg treatment via a
 multi-dose dry powder inhaler prior to the study will be allowed to remain on their
 treatment regimen until randomization provided all other eligibility criteria are met.

 -  Patients on treatment with ICS alone (up to a total daily dose of 500mcg fluticasone
 propionate or other ICS equivalent eg. 800mcg budesonide) will be required to switch
 treatment to fluticasone propionate/salmeterol combination 250/50mcg bid via the GSK
 provided multi-dose powder inhaler for between 14 and 28 days prior to randomization
 if deemed appropriate.

 -  Patients on treatment with budesonide/eformoterol combination (up to a total daily
 dose of 800/24mcg via a Turbuhaler) will be required to switch to fluticasone
 propionate/salmeterol combination 250/50mcg bid via the GSK-provided multi-dose powder
 inhaler for between 14 and 28 days prior to randomization.

 -  Patients on treatment with fluticasone propionate/salmeterol combination at a dose up
 to 250/50mcg bid via a metered dose inhaler or multi-dose dry powder inhaler (eg.
 100/50mcg) will be required to switch to fluticasone propionate/salmeterol combination
 250/50mcg bid via the GSK-provided multi-dose powder inhaler for between 14 and 28
 days prior to randomization.

 EXCLUSION CRITERIA:

 ALL PATIENTS:

 -  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 GSK Medical Monitor is likely to affect the safety of the subject and/or interfere
 with the study procedures and outcomes.

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

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

 -  Patients on treatment with fluticasone propionate either as monotherapy or in
 combination at a total daily dose higher than 500mcg or budesonide monotherapy or in
 combination at a total daily dose higher than 800mcg are excluded from the study

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

 -  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 randomization.

 -  Patients with abnormal levels of serum cortisol at Screening

 -  Abuse of alcohol consumption within 12 months of the Screening visit defined by the
 following Australian guidelines:

 Males: An average weekly intake greater than 21 units or an average daily intake greater
 than 3 units. Females: An average weekly intake greater than 14 units or an average daily
 intake greater than 2 units.

 One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of
 spirits and 100 mL of wine.

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

 -  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.

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

 -  Known hypersensitivity to salbutamol or any ingredient in the study medication
 preparation and/or history of any other drug or other allergy that, in the opinion of
 the GSK medical monitor and the investigator contraindicates participation of the
 subject

 -  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, a complete list is
 provided in the protocol.

 -  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.

 -  Pregnant females as determined by positive serum or urine βhCG (β-human chorionic
 gonadotropin) test at Screening or prior to dosing.

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

 COPD PATIENTS:

 -  Subjects with a respiratory disorder in addition to COPD (e.g. bronchiectasis,
 fibrosis) or significant co-morbidity that might affect lung function (e.g. poorly
 controlled heart failure, atrial fibrillation or ischaemic heart disease).

 -  Regular oxygen or nebulised bronchodilator therapy

 -  The subject has history of a respiratory infection (including sinusitis) within 4
 weeks prior to the Screening visit

 -  Any previous lung resection surgery (eg., lung volume reduction surgery or lobectomy)

 ASTHMA PATIENTS:

 -  Acute exacerbation of asthma requiring hospitalisation in the 6 weeks prior to the
 Screening visit.

 -  Subjects may not have used inhaled tobacco products within the past 3 months (ie.
 cigarettes, cigars or pipe tobacco) or have historical use of 10 pack years or more;
 [number of pack years = (number of cigarettes per day / 20) x number of years smoked].