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.
Condition: Asthma
MeSH terms: Asthma; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): SERETIDE Rotacaps; SERETIDE Diskus
Intervention type(s): Drug; Drug
Intervention description(s): The study consists of four treatment periods of 10 +/- 1 days each in a cross-over fashion. Each patient will be administered SERETIDE delivered via a capsule-based inhaler (Rotacaps) twice for two treatment periods and a placebo delivered via a capsule-based inhaler (Rotacaps) twice for two treatment periods in a randomised, double-blind, double-dummy fashion. Dosing is twice daily in the morning and evening over the duration of each treatment period.; The study consists of four treatment periods of 10 +/- 1 days each in a cross-over fashion. Each patient will be administered SERETIDE delivered via a multi-dose dry powder inhaler (Diskus) twice for two treatment periods and a placebo delivered via a multi-dose dry powder inhaler (Diskus) twice for two treatment periods in a randomised, double-blind, double-dummy fashion. Dosing is twice daily in the morning and evening over the duration of each treatment period.
Other intervention name(s): Placebo delivered via a capsule-based inhaler; Physical examination; adverse event (AE) and serious AE assessments; clinical laboratory safety tests (blood and urine); 12-lead electrocardiogram assessment; SERETIDE delivered via a capsule-based inhaler; Physical examination; adverse event (AE) and serious AE assessments; clinical laboratory safety tests (blood and urine); 12-lead electrocardiogram assessment; SERETIDE delivered via a multi-dose dry powder inhaler; Placebo delivered via a multi-dose dry powder inhaler
Intervention MeSH terms: Fluticasone-Salmeterol Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: safety; replicated cross-over design; pharmacodynamics; Fluticasone propionate/Salmeterol; capsule-based inhaler; COPD; asthma; multi dose dry powder inhaler; bioavailability; pharmacokinetics