Asthma Clinical Trial
Official title:
A Comparative Bioavailability Study to Compare the Pharmacokinetic (PK) and Pharmacodynamic (PD) Effects of Fluticasone Propionate and Salmeterol Delivered by Fluticasone Propionate/ Salmeterol Combination in a Capsule-based Inhaler and 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.
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