A Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation and ROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol
A Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation and ROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol
The purpose of this study is to optimise the device and/or formulation of the Fluticasone
 propionate (FP)/salmeterol (SALM) unit dose powder inhaler (Rotahaler) to achieve drug
 delivery characteristics comparable to the Fluticasone propionate /salmeterol DISKUS inhaler.
 The indication is asthma and chronic obstructive pulmonary disease. The study is an
 open-label, randomised, cross-over, single centre study in healthy volunteers and will be
 conducted in a maximum of 3 parts, A, B and C. The design is adaptive and pharmacokinetic
 (PK) data analysis follows each part to enable a decision on whether progression to the
 subsequent parts is required.

 Part A of the study will test an alternative version of the Rotahaler with a low airflow
 resistance. The study will then test one or more of the following options depending on the
 outcome of part A. If progressed, part B will test modified Rotacap formulations including:
 (1) modified blend formulation, (2) reduced capsule fill weights, (3) different capsule
 types. Part B will also test other versions of the Rotahaler with intermediate airflow
 resistance. Part C will test the lower strength FP/salmeterol (100/50 mcg or lower) and/or a
 new unit dose DPI device (BUDI).

 A total of 36 subjects will be enrolled in each part to ensure 32 complete. In each
 cross-over arm, subjects will be administered 7 doses (3.5 days bid) with PK sampling
 following administration of the 7th dose. A three-day minimum wash-out period will separate
 each cross-over arm.
BACKGROUND:

 Asthma is a chronic inflammatory disease of the airways characterised by varying and
 recurring symptoms of shortness of breath, chest tightness, wheezing and cough, airflow
 obstruction, bronchial hyper-responsiveness and underlying inflammation.

 The GINA guidelines [Global Initiative for Asthma,(GINA) updated 2009] highlight the need to
 treat airway inflammation in asthma and recognise the importance of inhaled prophylactic
 medications such as inhaled corticosteroids and combinations of Inhaled Corticosteroids (ICS)
 / Long Acting Beta Agonists (LABA) such as SERETIDE™ for the treatment of chronic asthma.

 Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease
 characterised by airflow limitation that is not fully reversible [Celli, 2004]. The airflow
 limitation of COPD is primarily due to small airways disease and parenchymal destruction
 associated with an abnormal inflammatory response of the lungs, mainly caused by cigarette
 smoking [Celli 2004]. COPD is characterised by symptoms of chronic and progressive
 breathlessness (or dyspnea), cough and sputum production which can be a major cause of
 disability and anxiety associated with the disease.

 The GOLD (Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive
 Pulmonary Disease) guidelines on COPD state that the goals of pharmacologic therapy should be
 to control symptoms, improve health status and exercise tolerance, and reduce the frequency
 of COPD exacerbations [GOLD, 2008]. Research has indicated that an inhaled corticosteroid
 (ICS) combined with a long acting β2-agonist (LABA) is more effective than the individual
 components in managing stable COPD to reduce exacerbations and improve lung function and
 health status [Ferguson, 2008; Calverley, 2007; Kardos, 2007].

 The efficacy of the combination product, SERETIDE has been established in the metered dose
 inhaler (MDI) and multidose powder inhaler (Ddpi; DISKUS™/Accuhaler) in both asthma and
 Chronic Obstructive Pulmonary Disease, COPD at a variety of dose strengths.

 Alternative treatment options with respect to the formulation of SERETIDE and its means of
 delivery via an inhaler device are currently being assessed by GSK with a view to developing
 a product with bioavailability characteristics comparable to those of SERETIDE delivered via
 the multi-dose powder inhaler (DISKUS™/Accuhaler). It is intended that the product will then
 be progressed for treatment administration in both asthma and COPD patients.

 STUDY RATIONALE:

 A recently completed study, ASR114334, [GlaxoSmithKline document number YM2010/00082/02]
 evaluated the comparative bioavailability of fluticasone propionate/salmeterol delivered via
 the established multi-dose powder inhaler (Ddpi, DISKUS/Accuhaler) with the Rotahaler unit
 dose fluticasone propionate/salmeterol capsule-based powder inhaler (Rdpi) in both asthma and
 COPD patients. The Rotahaler (Rdpi) inhaler had an airflow resistance similar to the DISKUS
 multi-dose inhaler (Ddpi). Whilst the active ingredients were a combination of fluticasone
 propionate/salmeterol, the devices were different with respect to their handling and
 instructions for operation, although both were designed to deliver at the 250/50mcg bid dose
 strength ie mcg equivalent doses.

 The results showed that plasma exposures of both fluticasone propionate (FP) and salmeterol
 were 1.5 to 2 fold higher following repeat dose administration of FP/salmeterol delivered
 from the Rdpi compared with those from the Ddpi, [GlaxoSmithKline document number
 2011N112456_00]. This was observed for both asthma and COPD patients.

 The purpose of this study, ASR116409 is to optimise the device and/or formulation of the
 FP/salmeterol unit dose powder inhaler to achieve drug delivery characteristics comparable to
 the FP/salmeterol DISKUS.

 DOSE RATIONALE:

 Two doses of FP/salmeterol will be administered in this study: 250/50 mcg and 100/50 mcg or
 lower, both doses are approved for the treatment of asthma. These doses will be administered
 to healthy subjects and are at or below the maximum approved doses for FP and salmeterol
 indicated for chronic therapy in asthma; therefore there are no anticipated safety concerns
 associated with the planned short term (3.5 days bid) dosing in healthy subjects.

 STUDY DESIGN:

 The study is an open-label, randomised, cross-over, single centre study in healthy volunteers
 in 3 parts, A, B and C. It will be conducted with an adaptive design where pharmacokinetic
 data analysis follows each part to enable a decision on whether progression to the subsequent
 parts is required.

 A total of 36 subjects will be enrolled in each part to ensure 32 complete. In each
 cross-over arm, subjects will be administered 7 doses (3.5 days bid) with PK sampling
 following administration of the 7th dose. A three-day minimum wash-out period will separate
 each cross-over arm. Subjects may elect to participate in more than one part.

 Part A will compare the bioavailability characteristics of the following GSK devices: the
 Ddpi (multi-dose dry powder inhaler, DISKUS), the Rdpi(H) (capsule-based inhaler, high
 airflow resistance) and the Rdpi(L) (low airflow resistance). The Rdpi(H) has higher airflow
 resistance to the Ddpi compared to the Rdpi (L) and could allow a closer PK match. Part A
 will consist of a four treatment cross-over sub-study with the following arms, each arm
 replicated twice for each subject.

 Treatment arms for part A will comprise:

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Ddpi

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Rdpi(H). Instructions for subjects will be to take 2 steady, deep inhalations.

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Rdpi(L). Instructions for subjects will be to take 1 fast and deep inhalation

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Rdpi(L). Instructions for subjects will be to take fast and deep inhalations until no
 powder remains in the inhaler.

 The Rdpi(H) device (250/50mcg FP/salmeterol) is being assessed in Part A to bridge the data
 back to the previous study (ASR114334) to show whether it is possible to replicate the 1.5 to
 2 fold systemic exposure ratio for Rdpi(H)/Ddpi in healthy subjects compared to patients seen
 in the previous study (ASR114334).

 Subjects will be dosed twice daily for 3 days and once on the fourth day in the morning. The
 first dose on Day 1 will be administered at the site and the next four doses will be
 self-administered by the subjects at home. They will attend the Unit in the evening of the
 3rd day where they will be administered the 6th dose and remain at the Unit for the night and
 following day. They will be dosed in clinic (7th dose) on the morning of the fourth day and
 remain at site until completion of the 12 hour post-dose PK sample collection.

 Following a 3-day minimum wash-out period after the last dose of study medication (Day 4),
 subjects will participate in the subsequent arms of Part A until they have completed all 4
 arms twice i.e. the 8 periods planned for completion of Part A.

 PK samples will be analysed and reviewed at the conclusion of Part A. If PK equivalence for
 FP and SALM is demonstrated between the Rdpi(L)and the Ddpi, and Rdpi(H)is demonstrated to
 have higher and non-equivalent PK systemic exposure compared to Ddpi, Part C will be
 conducted. If PK equivalence is not demonstrated, Part B will be conducted.

 Part B: Study design for Part B will depend on the PK results from Part A. Prior to the start
 of part B, a decision will be made by the sponsor team as to whether the Rdpi (H) or the
 Rdpi(L) device will be used; this decision will be based on PK data from part A. FP/Salm
 250/50mcg from the Ddpi will be included again in Part B as a control group.

 If the plasma exposures of FP and SALM obtained during Part A from Rdpi(H) are statistically
 higher than those from the Dpi and those from Rdpi (L) are statistically lower than those
 from the Ddpi, Part B will assess two intermediate airflow resistance versions of the Rdpi
 [Rdpi (IM)] and/or the formulation changes below:

 -  modified blend formulations

 -  reduced capsule fill weights,

 -  different capsule types If the plasma exposures of FP and SALM obtained from the Rdpi(H)
 are statistically higher than those from the Dpi and those from the Rdpi(L) are
 statistically higher than those from the Ddpi, Part B will assess the formulation
 changes below using Rdpi(H);

 -  modified blend formulations

 -  reduced capsule fill weights,

 -  different capsule types One variable will be assessed at a time in an open-label,
 randomized, cross-over manner comprising 2 to 3 arms separated by a 3-day minimum
 wash-out period. All comparisons will be done against the DISKUS arm, in order to test
 bioequivalence. The sample size and the use of replicated arms will be evaluated and
 defined after the completion of part A, adapting the design and the sample size to the
 variability observed during the previous part of the study.

 Following PK data analysis for all the variables, two or more variables may finally be
 grouped for combined assessment as an open-label investigation.

 Evaluation of the two intermediate high airflow resistance Rdpi devices [Rdpi(IM)] and of the
 formulation changes will be conducted in a cross-over design. The inhalation instructions
 (number and type of breaths) will be decided after Part A is completed. An additional arm
 whereby subjects will be administered the Ddpi will also be included for comparison.

 Part C will compare bioavailability parameters for 2 dosage strengths of FP/salmeterol:
 100/50 mcg, and 250/50mcg, delivered from the Ddpi and the device/formulation shown to
 demonstrate bioequivalence in Part A and/or Part B.

 Another GSK unit dose device in development, the BUDI inhaler, will also be evaluated for its
 comparative bioavailability characteristics at both doses.

 If PK data from Part A demonstrates that the Rdpi(L) is PK equivalent to the Ddpi at the
 250/50 mcg dose, Part B will not be conducted. We will also test the bovine capsule which may
 be needed for certain markets in Part C if Part B is not conducted.

 The various arms in Part C will not be conducted concurrently as timing of dosing for each
 arm will depend on availability of study medication, device and capsule type.

 Part C will therefore be conducted at two different points in time: Part C1 will consist of a
 3 or 4-way cross-over sub-study with the following arms:

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Ddpi

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
 Ddpi

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
 device/formulation combination selected in Part A or B

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Bovine capsule (if part B is not performed).

 Part C2 will be performed if required when the BUDI inhaler will be made available, a
 cross-over sub-study with the following arms:

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
 Ddpi

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
 Ddpi

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via BUDI
 Inhaler

 -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
 BUDI Inhaler.

 The inhalation instructions (number and type of breaths) will be decided after part A is
 completed

 The option to combine Parts C1 and C2 will be evaluated according to the:

 -  availability of the BUDI Inhaler and the timing of Part C

 -  PK results from the previous parts (variability could affect the need to have replicated
 arms in part C as well; further, the bovine capsule may have been already tested in part
 B).

 PRIMARY OBJECTIVES:

 -  To select a device and formulation combination of fluticasone propionate/salmeterol
 (250/50mcg or lower) which has pharmacokinetic equivalence (ratio 0.8 to 1.25) to
 fluticasone propionate/salmeterol (250/50mcg) delivered via the Ddpi (multi dose dry
 powder inhaler)

 -  To compare the pharmacokinetic parameters of fluticasone propionate/salmeterol
 (250/50mcg or lower) delivered from a range of devices and/or formulations to those of
 fluticasone propionate/salmeterol (250/50mcg) delivered via the Ddpi in healthy
 volunteers.

 SECONDARY OBJECTIVES:

 -  To determine the pharmacokinetic equivalence of the selected device/formulation
 combination of fluticasone propionate/salmeterol administered at a lower dose to match
 fluticasone propionate/salmeterol administered at the 100/50mcg dose from the Ddpi

 -  To assess the PK characteristics of the BUDI inhaler containing 100/50mcg fluticasone
 propionate/salmeterol and 250/50mcg fluticasone propionate/salmeterol.

 PRIMARY ENDPOINT:

 -Pharmacokinetic endpoint: Area under the plasma fluticasone propionate concentration-time
 curve over dosing interval ; maximum observed concentration for fluticasone propionate and
 salmeterol plasma concentration-time curve on the last day of each study treatment period
 (Day 4).

 SECONDARY ENDPOINT:

 -Pharmacokinetic parameters: time of maximum observed concentration;terminal phase rate
 constant; terminal phase half-life for fluticasone propionate and salmeterol) on the last day
 of each treatment period (Day 4).

 TREATMENT ASSIGNMENT:

 During Part A of the study, subjects will be assigned to one of the four sequences of the
 below reported table (4x4 Williams design with replicates) in accordance with the
 randomization schedule generated by Quantitative Sciences, prior to the start of the study,
 using validated internal software.

 Sequence number Arm

 1. A B D C D A C B

 2. B C A D C D B A

 3. C D B A B C A D

 4. D A C B A B D C

 A indicates Ddpi, B indicates Rdpi(H), C indicates Rdpi(L) fast and deep inhalation, and D
 indicates Rdpi(L) fast and deep inhalations until no powder remains in the inhaler.

 Williams design, with replicates or not, will be adopted for the subsequent and optional
 parts of the study, depending on the results obtained in part A.
INCLUSION CRITERIA:

 A subject will be eligible for inclusion in this study only if all of the following
 criteria apply:

 -  ALT, 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%).

 -  Single QTc, QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch
 Block.

 -  Healthy as determined by a responsible and experienced physician, based on a medical
 evaluation including medical history, physical examination, laboratory tests and
 cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
 outside the reference range for the population being studied may be included only if
 the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
 introduce additional risk factors and will not interfere with the study procedures.

 -  Male or female between 18 and 65 years of age inclusive, at the time of signing the
 informed consent.

 -  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 (<147 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 approved 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 should 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 is abstinent or agrees to use one of the protocol approved
 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

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

 -  BMI within the range 18 and 35 kg/m2 (inclusive).

 -  Able to use the inhaler devices adequately after training

 EXCLUSION CRITERIA:

 A subject will not be eligible for inclusion in this study if any of the following criteria
 apply:

 Medical Condition Exclusions:

 -  Subjects who have a current diagnosis or a history of asthma, excluding childhood
 asthma which has been discharged by physician (e.g., for any FTIH where risk of
 bronchoconstriction is unknown, or compound specific where risk of
 bronchoconstriction). This must be documented in the subject's medical notes.

 -  Subjects who have a current and previous diagnosis of COPD. This must be documented in
 the subject's medical notes.

 -  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
 result within 3 months of screening

 -  A positive test for HIV antibody.

 -  Pregnant females as determined by positive serum hCG test at screening or prior to
 dosing.

 -  Lactating females.

 -  Subject is mentally or legally incapacitated.

 -  Unwillingness or inability to follow the procedures outlined in the protocol.

 Medical Exclusions:

 -  Unable to refrain from the use of prescription or non-prescription drugs, including
 vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or
 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is
 longer) prior to the first dose of study medication, unless in the opinion of the
 Investigator and GSK Medical Monitor the medication will not interfere with the study
 procedures or compromise subject safety.

 -  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.

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

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

 Lifestyle Exclusions:

 -  A positive pre-study drug/alcohol screen. A minimum list of drugs that will be
 screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
 benzodiazepines.

 -  History of regular alcohol consumption within 6 months of the screening visit defined
 by the following Australian guidelines as:

 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.

 -  Grapefruit, pummelos, or grapefruit juice containing products are excluded from 2
 weeks prior to randomisation (all study parts) until collection of the final blood
 sample on Day 4.

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