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.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01494610
First received: October 27, 2011
Last updated: April 19, 2012
Last verified: April 2012
  Purpose

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.


Condition Intervention Phase
Asthma
Drug: SERETIDE Rotacaps
Drug: SERETIDE Diskus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-availability Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Mean Plasma AUC(0-tau) and Plasma AUC From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-tlast]) for Salmeterol [ 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 ] [ Designated as safety issue: No ]
    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.

  • Mean AUC(0-tlast) 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Terminal Phase Half-life (t1/2) 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 ] [ Designated as safety issue: No ]
    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.

  • Time of Occurrence of Cmax (Tmax) 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) for Salmeterol [ 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Terminal Phase Half-life (t1/2) for Salmeterol [ 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 ] [ Designated as safety issue: No ]
    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.

  • Tmax for Salmeterol [ 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Urine Cortisol Excretion Over 0 to 24 Hours Post Dose for FP [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Serum Cortisol Minimum (Cmin) for FP [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Weighted Mean Over 0 to 4 Hours Post Dose of Heart Rate for Salmeterol [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean of Maximum Heart Rate Over 0 to 4 Hours Post Dose for Salmeterol [ Time Frame: 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 ] [ Designated as safety issue: No ]
    The maximum observed value of heart rate was measured from the time of the morning dose on Day 10 to 4 hours post dose.

  • Minimum Diastolic Blood Pressure (DBP), Maximum Systolic Blood Pressure (SBP), and Weighted Mean for DBP and SBP Over 0 to 4 Hours Post Dose [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • 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]) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Weighted Mean Over 0 to 4 Hours Post Dose of Plasma Potassium and Minimum (Min) Plasma Potassium [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Weighted Mean Over 0 to 4 Hours Post Dose and Maximum Plasma Glucose [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count, and White Blood Cell (WBC) Count [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Hemoglobin and Mean Corpuscular Hemoglobin (MCH) Concentration [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Red Blood Cell (RBC) Count and Reticulocytes [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Corpuscule Hemoglobin (MCH) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Corpuscle Volume (MCV) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Hematocrit [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Albumin and Total Protein [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Alkaline Phosphatase (AP), Alanine Amino Transferase (ALT), Aspartate Amio Transferase (AST), and Gama Glutamyl Transferase (GGT) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Direct Bilirubin (DB), Total Bilirubin (TB), Creatinine, and Uric Acid [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Mean Calcium, Chloride, Glucose, Potassium, Sodium, Carbon Dioxide (CO2) Content/Bicarbonate (Bicar), and Urea/Blood Urea Nitrogen (BUN) [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With an Adverse Event (AE) [ Time Frame: Randomization (Day 1) up to Follow-up (Days 47-50) ] [ Designated as safety issue: No ]
    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.


Enrollment: 60
Study Start Date: October 2010
Study Completion Date: June 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: SERETIDE Rotacaps
Fluticasone propionate (250 micrograms [ug])/Salmeterol (50 ug) combination delivered in a capsule-based inhaler
Drug: 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.
Other Names:
  • 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
Active Comparator: SERETIDE Diskus
Fluticasone propionate (250 ug)/Salmeterol (50 ug) combination delivered in a multi-dose dry powder inhaler
Drug: 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.
Other Names:
  • 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
Placebo Comparator: Placebo Rotacaps
Placebo delivered in a capsule-based inhaler
Drug: 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.
Other Names:
  • 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
Placebo Comparator: Placebo Diskus
Placebo delivered in a multi-dose dry powder inhaler
Drug: 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.
Other Names:
  • 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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 βhCG (β-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].
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01494610

Locations
Australia, New South Wales
GSK Investigational Site
Randwick, New South Wales, Australia, 2031
New Zealand
GSK Investigational Site
Wellington, New Zealand, 6021
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01494610     History of Changes
Other Study ID Numbers: 114334
Study First Received: October 27, 2011
Results First Received: February 16, 2012
Last Updated: April 19, 2012
Health Authority: New Zealand: Medsafe
Australia: Department of Health and Ageing Therapeutic Goods Administration

Keywords provided by GlaxoSmithKline:
safety
replicated cross-over design
pharmacodynamics
Fluticasone propionate/Salmeterol
capsule-based inhaler
COPD
asthma
multi dose dry powder inhaler
bioavailability
pharmacokinetics

Additional relevant MeSH terms:
Asthma
Anti-Asthmatic Agents
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Bronchial Diseases
Respiratory Tract Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Salmeterol
Fluticasone
Fluticasone, salmeterol drug combination
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Respiratory System Agents
Therapeutic Uses
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Dermatologic Agents
Anti-Allergic Agents

ClinicalTrials.gov processed this record on August 19, 2014