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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/study/NCT01494610
Registration number
NCT01494610
Ethics application status
Date submitted
27/10/2011
Date registered
19/12/2011
Titles & IDs
Public title
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.
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Scientific 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.
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Secondary ID [1]
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114334
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Asthma
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Condition category
Condition code
Respiratory
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Asthma
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Respiratory
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Chronic obstructive pulmonary disease
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - SERETIDE Rotacaps
Treatment: Drugs - SERETIDE Diskus
Experimental: SERETIDE Rotacaps - Fluticasone propionate (250 micrograms \[ug\])/Salmeterol (50 ug) combination delivered in a capsule-based inhaler
Active comparator: SERETIDE Diskus - Fluticasone propionate (250 ug)/Salmeterol (50 ug) combination delivered in a multi-dose dry powder inhaler
Placebo comparator: Placebo Rotacaps - Placebo delivered in a capsule-based inhaler
Placebo comparator: Placebo Diskus - Placebo delivered in a multi-dose dry powder inhaler
Treatment: Drugs: SERETIDE Rotacaps
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.
Treatment: Drugs: SERETIDE Diskus
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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Mean Area Under the Concentration Time Curve Over the Dosing Period (AUC[0-tau]) for FP
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Assessment method [1]
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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.
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Timepoint [1]
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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
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Primary outcome [2]
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Weighted Mean Serum Cortisol (SC) Over 0 to 12 Hours Post Dose
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Secondary outcome [1]
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Mean Plasma AUC(0-tau) and Plasma AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-tlast]) for Salmeterol
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Assessment method [1]
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Blood samples of participants with asthma and COPD were collected and analyzed for AUC(0-tau) and AUC(0-tlast). AUC(0-tau) is a measure of the amount of drug available at target tissue (in plasma) for a fixed dosing interval (12 hours). AUC(0-tlast) is a measure of the plasma drug concentration from pre-dose to the last measurable concentration.
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Timepoint [1]
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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
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Secondary outcome [2]
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Mean AUC(0-tlast) for FP
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Assessment method [2]
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Blood samples of participants with asthma and COPD were collected and analyzed for AUC(0-tlast). AUC(0-tlast) is a measure of the plasma drug concentration from pre-dose to the last measurable concentration.
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Timepoint [2]
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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
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Secondary outcome [3]
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Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of FP
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Assessment method [3]
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Blood samples of participants with asthma and COPD were collected and analyzed for Cmax and Cmin of FP in the blood. Cmax and Cmin are used to estimate the time at which the activity of the drug will be at its maximum and minimum, respectively.
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Timepoint [3]
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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
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Secondary outcome [4]
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Mean Terminal Phase Half-life (t1/2) for FP
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Assessment method [4]
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Blood samples of participants were collected for evaluating t1/2. The t1/2 is the time required for the plasma/blood concentration of the drug to decrease by 50% after the false equilibrium of distribution has been reached.
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Timepoint [4]
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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
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Secondary outcome [5]
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Time of Occurrence of Cmax (Tmax) for FP
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Assessment method [5]
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Blood samples of participants were collected for evaluating Tmax. Tmax is a measure of the time required to reach the maximum concentration of the drug.
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Timepoint [5]
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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
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Secondary outcome [6]
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Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) for Salmeterol
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Assessment method [6]
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Blood samples of participants with asthma and COPD were collected and analyzed for Cmax and Cmin of Salmeterol in the blood. Cmax and Cmin are used to estimate the time at which the activity of the drug will be at its maximum and minimum.
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Timepoint [6]
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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
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Secondary outcome [7]
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Mean Terminal Phase Half-life (t1/2) for Salmeterol
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Assessment method [7]
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Blood samples of participants were collected for evaluating t1/2. t1/2 is the time required for the plasma/blood concentration of the drug to decrease by 50% after the false equilibrium of distribution has been reached.
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Timepoint [7]
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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
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Secondary outcome [8]
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Tmax for Salmeterol
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Assessment method [8]
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Blood samples of participants were collected for evaluating Tmax. Tmax is a measure of the time required to reach the maximum concentration of the drug.
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Timepoint [8]
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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
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Secondary outcome [9]
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Mean Urine Cortisol Excretion Over 0 to 24 Hours Post Dose for FP
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Assessment method [9]
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Urine samples of participants were collected to evaluate urine cortisol excretion over 0-24 hours post treatment dose. A 24-hour urine cortisol sample was used to measure the total amount of cortisol excreted in urine in 24 hours. Any differences in systemic exposure as a result of the absorbed steroid component of the two differing inhaled devices should also result in differences in the amount of cortisol excreted in the urine.
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Timepoint [9]
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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
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Secondary outcome [10]
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Serum Cortisol Minimum (Cmin) for FP
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Assessment method [10]
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Blood samples of participants were collected for the evaluation of minimum serum cortisol. Any differences in systemic exposure as a result of the absorbed steroid component of the two differing inhaled devices should also result in differences in serum cortisol concentrations.
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Timepoint [10]
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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
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Secondary outcome [11]
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Weighted Mean Over 0 to 4 Hours Post Dose of Heart Rate for Salmeterol
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Assessment method [11]
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The heart rate (number of heartbeats per unit of time, typically expressed as beats per minute \[bpm\]) of the participants was monitored for evaluating the weighted mean over the course of 0 to 4 hours post dose. The Capsule-MDPI difference for heart rate was calculated for each participant, and the weighted mean value from the time of the morning dose on Day 10 to 4 hours post dose was calculated. The weighted mean was calculated by using all values at the indicated timepoint contributing to the calculation of the mean but with different weightage.
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Timepoint [11]
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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
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Secondary outcome [12]
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Mean of Maximum Heart Rate Over 0 to 4 Hours Post Dose for Salmeterol
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Assessment method [12]
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The maximum observed value of heart rate was measured from the time of the morning dose on Day 10 to 4 hours post dose.
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Timepoint [12]
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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
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Secondary outcome [13]
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Minimum Diastolic Blood Pressure (DBP), Maximum Systolic Blood Pressure (SBP), and Weighted Mean for DBP and SBP Over 0 to 4 Hours Post Dose
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Assessment method [13]
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The diastolic and systolic blood pressure of the participants was measured. The maximum and minimum observed values from the time of the morning dose on Day 10 to 4 hours post dose were measured for SBP and DBP. The weighted mean value from the time of the morning dose on Day 10 to 4 hours post dose was calculated. Weighted mean was calculated by using all values of DBP and SBP at the indicated timepoint contributing to the calculation of the mean but with different weightage.
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Timepoint [13]
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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
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Secondary outcome [14]
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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])
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Assessment method [14]
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The electrocardiogram (ECG) of the participants was taken, and the maximum and weighted mean of QTc(B) and QTc(F) was measured. Weighted mean was calculated by using all values of QTc(B) and QTc(F) at the indicated timepoint contributing to the calculation of the mean but with different weightage. The ECG helps in the assessment of the condition of the heart. The QT interval gives the measure of the heart rate, and the cQT interval gives the corrected value.
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Timepoint [14]
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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
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Secondary outcome [15]
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Weighted Mean Over 0 to 4 Hours Post Dose of Plasma Potassium and Minimum (Min) Plasma Potassium
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Assessment method [15]
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Blood samples of participants were collected for the evaluation of weighted mean over 0 to 4 hours post dose and the minimum plasma potassium level. Weighted mean was calculated by using all values of plasma potassium at the indicated timepoint contributing to the calculation of the mean but with different weightage.
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Timepoint [15]
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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
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Secondary outcome [16]
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Weighted Mean Over 0 to 4 Hours Post Dose and Maximum Plasma Glucose
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Assessment method [16]
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Blood samples of participants were collected for the evaluation of weighted mean over 0 to 4 hours post dose and the maximum plasma glucose level. Weighted mean was calculated by using all values of plasma glucose at the indicated timepoint contributing to the calculation of the mean but with different weightage.
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Timepoint [16]
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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
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Secondary outcome [17]
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Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cell (WBC) Count
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Assessment method [17]
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Blood samples of participants were collected for the evaluation of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count, and WBC count. Data are reported for the first (1st) and second (2nd) administration (admin) of FP/salmeterol via MDPI or capsule-based inhaler. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [17]
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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
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Secondary outcome [18]
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Mean Hemoglobin and Mean Corpuscular Hemoglobin (MCH) Concentration
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Assessment method [18]
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Blood samples of participants were collected for the evaluation of mean hemoglobin (mean level of hemoglobin in the whole blood sample) and MCH concentration. The MCH concentration is the average concentration of hemoglobin in a red blood cell. Hemoglobin is the red pigment in the blood, and it is reponsible for carrying oxygen. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [18]
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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
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Secondary outcome [19]
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Red Blood Cell (RBC) Count and Reticulocytes
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Assessment method [19]
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Blood samples of participants were collected for the evaluation of RBC and reticulocytes count. Reticulocytes are immature red blood cells. Normally, about 1% to 2% of the red blood cells in the blood are reticulocytes. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [19]
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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
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Secondary outcome [20]
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Mean Corpuscule Hemoglobin (MCH)
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Assessment method [20]
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Blood samples of participants were collected for the evaluation of MCH. MCH is the average mass or amount of hemoglobin per red blood cell in a sample of blood. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [20]
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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
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Secondary outcome [21]
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Mean Corpuscle Volume (MCV)
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Assessment method [21]
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Blood samples of participants were collected for the evaluation of MCV. MCV is a measure of the average red blood cell size that is reported as part of a standard complete blood count. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [21]
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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
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Secondary outcome [22]
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Mean Hematocrit
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Assessment method [22]
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Blood samples of participants were collected for the evaluation of hematocrit. The hematocrit is the percentage of the RBCs in the blood. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [22]
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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
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Secondary outcome [23]
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Mean Albumin and Total Protein
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Assessment method [23]
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The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [23]
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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
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Secondary outcome [24]
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Mean Alkaline Phosphatase (AP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST), and Gama Glutamyl Transferase (GGT)
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Assessment method [24]
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Blood samples of participants were collected for the evaluation of AP, ALT, AST, and GGT. All of these parameters are measured to help assess the condition of the liver. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [24]
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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
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Secondary outcome [25]
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Mean Direct Bilirubin (DB), Total Bilirubin (TB), Creatinine, and Uric Acid
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Assessment method [25]
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Blood samples of participants were collected for the evaluation of DP, TB, creatinine, and uric acid. DB and TB are measures that help assess the condition of the liver, and creatinine and uric acid are measures that help assess the condition of the kidneys. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [25]
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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
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Secondary outcome [26]
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Mean Calcium, Chloride, Glucose, Potassium, Sodium, Carbon Dioxide (CO2) Content/Bicarbonate (Bicar), and Urea/Blood Urea Nitrogen (BUN)
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Assessment method [26]
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Blood samples of participants were collected for the evaluation of calcium, chloride, glucose, potassium, sodium, carbon dioxide (CO2) content/bicarbonate, and urea/BUN. All of these parameters are measured to help assess the condition of the kidneys. The timing of the first and second administrations depended on the randomization schedule. If the treatment sequence received was "ABBA," then Days 10 and 40, respectively, correspond to the first and second administrations for treatment A.
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Timepoint [26]
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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
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Secondary outcome [27]
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Number of Participants With an Adverse Event (AE)
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Assessment method [27]
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An AE is defined as any untoward medical occurrence in a patient or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
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Timepoint [27]
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Randomization (Day 1) up to Follow-up (Days 47-50)
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Eligibility
Key inclusion 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 < 40 pg/ml (<140 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 allowed 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 will 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 agrees to use one of the protocol allowed 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 they have attended the site for the follow-up visit.
* Capable of giving informed consent, which includes compliance with the study requirements and restrictions listed in the consent form.
* Body mass index between 18 and 35 kg/m2 inclusive at Screening
* Able to use the inhaler devices adequately after training
* AST and ALT < 2xULN (upper limit of normal); 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%).
* 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% of the predicted normal value at the Screening visit. NHANES (National Health and Nutrition Examination Survey) III predicted values will be used [Hankinson, 2009]. If a subject is recorded as having Hispanic or Latino ethnicity, then the Mexican-American equations will be used (irrespective of race). If a subject is recorded as being of African American/African Heritage race, then the African American equations will be used. If a subject is recorded as being of Asian or of Pacific Islander race, then the Caucasian formula will be used with a conversion factor of 0.88. Otherwise, the Caucasian equations will be used.
* Age: 18 and above at the time of signing the informed consent.
* Best clinic screening pre-bronchodilator FEV1 between 60 and 85% of predicted normal values (NHANES III values). Patients must abstain from SABA use for 6 hours prior to the Screening visit.
* Asthma therapy:
* Patients on fluticasone propionate/salmeterol combination 250/50mcg treatment 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 treatment with ICS alone (up to a total daily dose of 500mcg fluticasone propionate or other ICS equivalent eg. 800mcg budesonide) will be required to switch treatment to fluticasone propionate/salmeterol combination 250/50mcg bid via the GSK provided multi-dose powder inhaler for between 14 and 28 days prior to randomization if deemed appropriate.
* Patients on treatment with budesonide/eformoterol combination (up to a total daily dose of 800/24mcg via a Turbuhaler) will be required to switch to fluticasone propionate/salmeterol combination 250/50mcg bid via the GSK-provided multi-dose powder inhaler for between 14 and 28 days prior to randomization.
* Patients on treatment with fluticasone propionate/salmeterol combination at a dose up to 250/50mcg bid via a metered dose inhaler or multi-dose dry powder inhaler (eg. 100/50mcg) will be required to switch to fluticasone propionate/salmeterol combination 250/50mcg bid via the GSK-provided multi-dose powder inhaler for between 14 and 28 days prior to randomization.
EXCLUSION CRITERIA:
ALL PATIENTS:
* Any clinically relevant medical condition or abnormality identified during the screening medical assessment and procedures, physical examination, or laboratory assessments (including clinical chemistry and haematology), which in the opinion of the GSK Medical Monitor is likely to affect the safety of the subject and/or interfere with the study procedures and outcomes.
* 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 or positive HIV test result within 3 months of screening.
* Patients on treatment with fluticasone propionate either as monotherapy or in combination at a total daily dose higher than 500mcg or budesonide monotherapy or in combination at a total daily dose higher than 800mcg are excluded from the study
* Use of oral/injectable/depot corticosteroid for any indication within 3 months prior to the Screening visit.
* Use of intra-nasal steroids (INS). To be eligible for the study, patients on INS therapy will be required to switch to non-INS therapy at randomization.
* Patients with abnormal levels of serum cortisol at Screening
* Abuse of alcohol consumption within 12 months of the Screening visit defined by the following Australian guidelines:
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.
* A known or suspected history of drug abuse within 12 months of the Screening visit.
* 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.
* Where participation in the study would result in donation of blood or blood products in excess of 500mL within a 56-day period.
* Known hypersensitivity to salbutamol or any ingredient in the study medication preparation and/or history of any other drug or other allergy that, in the opinion of the GSK medical monitor and the investigator contraindicates participation of the subject
* Grapefruit or grapefruit juice containing products are excluded from 2 weeks prior to randomisation until collection of the final blood sample at treatment period 4.
* Drugs that inhibit the cytochrome P450 isoform, 3A4 (CYP3A4), are excluded from 2 weeks prior to randomisation until collection of the final blood sample at treatment period 4. CYP3A4 inhibitors include cimetidine, clarithromycin, erythromycin, ciprofloxacin, ritonavir, ketoconazole, and azole antifungals, a complete list is provided in the protocol.
* Use of prescription or non-prescription drugs, vitamins, herbal and dietary supplements, within seven days or 5 half-lives (whichever is longer) prior to the first dose of study medication, which in the opinion of the Principal Investigator, may interfere with study outcome. Specifically, calcium and vitamin D supplements and bisphosphonates are not allowed throughout the study.
* Pregnant females as determined by positive serum or urine ßhCG (ß-human chorionic gonadotropin) test at Screening or prior to dosing.
* Patients, who, in the opinion of the Investigator, are not able to comply with the protocol requirements.
COPD PATIENTS:
* Subjects with a respiratory disorder in addition to COPD (e.g. bronchiectasis, fibrosis) or significant co-morbidity that might affect lung function (e.g. poorly controlled heart failure, atrial fibrillation or ischaemic heart disease).
* Regular oxygen or nebulised bronchodilator therapy
* The subject has history of a respiratory infection (including sinusitis) within 4 weeks prior to the Screening visit
* Any previous lung resection surgery (eg., lung volume reduction surgery or lobectomy)
ASTHMA PATIENTS:
* Acute exacerbation of asthma requiring hospitalisation in the 6 weeks prior to the Screening visit.
* Subjects may not have used inhaled tobacco products within the past 3 months (ie. cigarettes, cigars or pipe tobacco) or have historical use of 10 pack years or more; [number of pack years = (number of cigarettes per day / 20) x number of years smoked].
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Minimum age
18
Years
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Maximum age
80
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people analysing the results/data
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Intervention assignment
Crossover
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
25/10/2010
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
8/06/2011
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Sample size
Target
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Accrual to date
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Final
60
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
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GSK Investigational Site - Randwick
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment outside Australia
Country [1]
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New Zealand
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State/province [1]
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Wellington
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
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Name
GlaxoSmithKline
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Address
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Ethics approval
Ethics application status
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Summary
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 (AUCt) 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, ?z, 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.
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Trial website
https://clinicaltrials.gov/study/NCT01494610
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Trial related presentations / publications
Daley-Yates PT, Mehta R, Chan RH, Despa SX, Louey MD. Pharmacokinetics and pharmacodynamics of fluticasone propionate and salmeterol delivered as a combination dry powder from a capsule-based inhaler and a multidose inhaler in asthma and COPD patients. J Aerosol Med Pulm Drug Deliv. 2014 Aug;27(4):279-89. doi: 10.1089/jamp.2013.1040. Epub 2013 Sep 28.
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Public notes
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Contacts
Principal investigator
Name
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GSK Clinical Trials
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Address
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GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
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Country
0
0
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Phone
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0
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Fax
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0
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Email
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0
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Contact person for public queries
Name
0
0
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Address
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0
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0
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0
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Fax
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0
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Contact person for scientific queries
Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
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What data in particular will be shared?
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
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When will data be available (start and end dates)?
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Available to whom?
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Available for what types of analyses?
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How or where can data be obtained?
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results are available at
https://clinicaltrials.gov/study/NCT01494610