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.
Overview
- Phase
- Phase 1
- Status
- Completed
- Sponsor
- GlaxoSmithKline
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Weighted Mean Serum Cortisol (SC) Over 0 to 12 Hours Post Dose
Overview
Brief 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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Crossover
- Primary Purpose
- Treatment
- Masking
- Triple (Participant, Care Provider, Investigator)
Eligibility Criteria
- Ages
- 18 Years to 80 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
SERETIDE Rotacaps
Fluticasone propionate (250 micrograms [ug])/Salmeterol (50 ug) combination delivered in a capsule-based inhaler
Intervention: SERETIDE Rotacaps (Drug)
SERETIDE Diskus
Fluticasone propionate (250 ug)/Salmeterol (50 ug) combination delivered in a multi-dose dry powder inhaler
Intervention: SERETIDE Diskus (Drug)
Placebo Rotacaps
Placebo delivered in a capsule-based inhaler
Intervention: SERETIDE Diskus (Drug)
Placebo Diskus
Placebo delivered in a multi-dose dry powder inhaler
Intervention: SERETIDE Rotacaps (Drug)
Outcomes
Primary Outcomes
Weighted Mean Serum Cortisol (SC) Over 0 to 12 Hours Post Dose
Time Frame: At pre-morning dose; 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively
Participants' blood samples were collected and analyzed for SC levels. Weighted mean SC levels are evaluted as a measure of the degree of cortisol suppression, allowing for the determination of whether differences in systemic exposure to the inhaled steroid component of two devices can be significant enough to result in the differences in the body's ability to release cortisol. Weighted means were derived by calculating the AUC over the 0-12 hour period, using the linear trapezoidal rule (statistical technique used for numerical analysis) and then dividing it by the actual time interval.
Mean Area Under the Concentration Time Curve Over the Dosing Period (AUC[0-tau]) for FP
Time Frame: At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively
Blood samples of participants (par.) with asthma and chronic obstructive pulmonary disease (COPD) were collected and analyzed for AUC(0-tau), a measure of the amount of drug available at target tissue (in plasma) for a fixed dosing interval (12 hours). Asthma is a disorder that causes the airways of the lungs to swell and narrow, leading to difficulty in breathing. COPD is a chronic lung disease with structural changes in lungs, leading to difficulty in breathing.
Secondary Outcomes
- Mean AUC(0-tlast) for FP(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of FP(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Terminal Phase Half-life (t1/2) for FP(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Time of Occurrence of Cmax (Tmax) for FP(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Terminal Phase Half-life (t1/2) for Salmeterol(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Serum Cortisol Minimum (Cmin) for FP(Day 10 of each study period (Periods 1-4); Study Day 10 (+/-1) (reference day is Study Day 1 or Randomization day), Period 1; Study Day 20 (+/-1), Period 2; Study Day 30 (+/-1), Period 3; Study Day 40 (+/-1), Period 4)
- Mean Plasma AUC(0-tau) and Plasma AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-tlast]) for Salmeterol(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Urine Cortisol Excretion Over 0 to 24 Hours Post Dose for FP(0-24 hours post dose on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Hemoglobin and Mean Corpuscular Hemoglobin (MCH) Concentration(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Corpuscule Hemoglobin (MCH)(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Corpuscle Volume (MCV)(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Calcium, Chloride, Glucose, Potassium, Sodium, Carbon Dioxide (CO2) Content/Bicarbonate (Bicar), and Urea/Blood Urea Nitrogen (BUN)(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) for Salmeterol(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Tmax for Salmeterol(At pre-morning dose; 5, 10, 30 minutes post-dose (PD); and 1, 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Weighted Mean Over 0 to 4 Hours Post Dose of Heart Rate for Salmeterol(At pre-morning dose; 15, 30, 60, 90 minutes post-dose (PD); and 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Minimum Diastolic Blood Pressure (DBP), Maximum Systolic Blood Pressure (SBP), and Weighted Mean for DBP and SBP Over 0 to 4 Hours Post Dose(At pre-morning dose; 15, 30, 60, 90 minutes post-dose (PD); and 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Weighted Mean Over 0 to 4 Hours Post Dose and Maximum Plasma Glucose(At pre-morning dose; 30, 60 minutes post-dose (PD); and 2 and 4 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean of Maximum Heart Rate Over 0 to 4 Hours Post Dose for Salmeterol(At pre-morning dose; 15, 30, 60, 90 minutes post-dose (PD); and 2, 4, 8, 10, and 12 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Maximum and Weighted Mean Over 0 to 4 Hours Post Dose of the QT Interval Corrected According to Bazett's Formula (QTc[B]) and the QT Interval Corrected According to Fridericia's Formula (QTc[F])(At pre-morning dose; 15, 30, 60, 90 minutes post-dose (PD); and 2, 3 and 4 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Weighted Mean Over 0 to 4 Hours Post Dose of Plasma Potassium and Minimum (Min) Plasma Potassium(At pre-morning dose; 30, 60 minutes post-dose (PD); and 2 and 4 hours PD on Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Albumin and Total Protein(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Number of Participants With an Adverse Event (AE)(Randomization (Day 1) up to Follow-up (Days 47-50))
- Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cell (WBC) Count(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Red Blood Cell (RBC) Count and Reticulocytes(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Hematocrit(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Alkaline Phosphatase (AP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST), and Gama Glutamyl Transferase (GGT)(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)
- Mean Direct Bilirubin (DB), Total Bilirubin (TB), Creatinine, and Uric Acid(Day 10 of each study period (P): Study Day (SD) 10 (reference day is SD 1 or Randomization day), 20, 30, and 40 (+/-1) for P 1, 2, 3, and 4, respectively)