Phase 2
N=60
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.
Asthma
Bottom Line
View on ClinicalTrials.gov: NCT01494610 ↗Enrolled (actual)
60
Serious AEs
0.4%
Results posted
May 2012
Primary outcome: Primary: Mean Area Under the Concentration Time Curve Over the Dosing Period (AUC[0-tau]) for FP — 376.9; 573.1; 350.5; 559.1 Picogram hours per milliliter (pg*h/mL)
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- SERETIDE Rotacaps (Drug); SERETIDE Diskus (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- GlaxoSmithKline
- Primary completion
- Jun 2011
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Mean Area Under the Concentration Time Curve Over the Dosing Period (AUC[0-tau]) for FP |
376.9; 573.1; 350.5; 559.1; 416.4; 593.0 | — |
| PRIMARY Weighted Mean Serum Cortisol (SC) Over 0 to 12 Hours Post Dose |
193.5; 178.3; 187.3; 166.6; 202.4; 195.6 | — |
| SECONDARY Mean Plasma AUC(0-tau) and Plasma AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-tlast]) for Salmeterol |
300.2; 345.1; 305.8; 356.4; 292.7; 330.1 | — |
| SECONDARY Mean AUC(0-tlast) for FP |
380.1; 580.9; 355.7; 558.4; 416.5; 613.2 | — |
| SECONDARY Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of FP |
54.64; 105.79; 53.66; 109.98; 56.02; 100.29 | — |
| SECONDARY Mean Terminal Phase Half-life (t1/2) for FP |
6.660; 5.844; 5.906; 5.238; 7.740; 6.806 | — |
| SECONDARY Time of Occurrence of Cmax (Tmax) for FP |
1.045; 0.530; 1.000; 0.335; 1.173; 0.673 | — |
| SECONDARY Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) for Salmeterol |
59.28; 92.27; 64.97; 110.21; 52.26; 72.27 | — |
| SECONDARY Mean Terminal Phase Half-life (t1/2) for Salmeterol |
6.576; 7.260; 6.429; 7.538; 6.776; 6.905 | — |
| SECONDARY Tmax for Salmeterol |
0.750; 0.080; 0.335; 0.080; 1.000; 0.080 | — |
| SECONDARY Mean Urine Cortisol Excretion Over 0 to 24 Hours Post Dose for FP |
63.53; 59.66; 72.86; 66.28; 52.62; 51.62 | — |
| SECONDARY Serum Cortisol Minimum (Cmin) for FP |
88.6; 79.6; 79.8; 70.0; 102.4; 94.9 | — |
| SECONDARY Weighted Mean Over 0 to 4 Hours Post Dose of Heart Rate for Salmeterol |
66.2; 66.7; 64.8; 65.7; 68.2; 68.1 | — |
| SECONDARY Mean of Maximum Heart Rate Over 0 to 4 Hours Post Dose for Salmeterol |
73.0; 74.3; 72.3; 73.5; 74.0; 75.4 | — |
| SECONDARY Minimum Diastolic Blood Pressure (DBP), Maximum Systolic Blood Pressure (SBP), and Weighted Mean for DBP and SBP Over 0 to 4 Hours Post Dose |
64.7; 66.2; 61.6; 62.6; 69.1; 71.2 | — |
| SECONDARY 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]) |
434.0; 434.4; 423.7; 424.7; 448.1; 447.6 | — |
| SECONDARY Weighted Mean Over 0 to 4 Hours Post Dose of Plasma Potassium and Minimum (Min) Plasma Potassium |
4.11; 4.11; 4.11; 4.10; 4.11; 4.13 | — |
| SECONDARY Weighted Mean Over 0 to 4 Hours Post Dose and Maximum Plasma Glucose |
5.85; 5.95; 5.67; 5.80; 6.11; 6.16 | — |
| SECONDARY Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cell (WBC) Count |
0.05; 0.06; 0.04; 0.04; 0.07; 0.04 | — |
| SECONDARY Mean Hemoglobin and Mean Corpuscular Hemoglobin (MCH) Concentration |
138.2; 135.4; 133.0; 132.3; 133.3; 133.1 | — |
| SECONDARY Red Blood Cell (RBC) Count and Reticulocytes |
4.608; 4.542; 4.460; 4.424; 4.523; 4.530 | — |
| SECONDARY Mean Corpuscule Hemoglobin (MCH) |
29.99; 29.86; 29.80; 29.92; 29.72; 29.72 | — |
| SECONDARY Mean Corpuscle Volume (MCV) |
89.65; 89.41; 89.52; 89.77; 90.21; 90.37 | — |
| SECONDARY Mean Hematocrit |
0.413; 0.405; 0.399; 0.396; 0.405; 0.405 | — |
| SECONDARY Mean Albumin and Total Protein |
43.0; 42.3; 42.0; 41.8; 40.9; 41.4 | — |
| SECONDARY Mean Alkaline Phosphatase (AP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST), and Gama Glutamyl Transferase (GGT) |
64.6; 63.4; 65.0; 63.9; 69.6; 69.9 | — |
| SECONDARY Mean Direct Bilirubin (DB), Total Bilirubin (TB), Creatinine, and Uric Acid |
3.2; 2.7; 3.0; 2.6; 2.9; 2.8 | — |
| SECONDARY Mean Calcium, Chloride, Glucose, Potassium, Sodium, Carbon Dioxide (CO2) Content/Bicarbonate (Bicar), and Urea/Blood Urea Nitrogen (BUN) |
2.191; 2.178; 2.190; 2.170; 2.205; 2.189 | — |
| SECONDARY Number of Participants With an Adverse Event (AE) |
13; 13; 12; 15; 14; 11 | — |
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.
Eligibility Criteria
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 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
Data sourced from ClinicalTrials.gov (NCT01494610). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.