Safety Study of the Effects of Inhaled Fluticasone Furoate/GW642444 on the Hypothalamic-Pituitary-Adrenal (HPA) Axis

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of six weeks' treatment with two once-daily strengths of Fluticasone Furoate/GW642444 Inhalation Powder on the HPA axis system

Official Title
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Study HZA106851: A Study of the Effects of Inhaled Fluticasone Furoate/GW642444 Versus Placebo on the HPA Axis of Adolescent and Adult Asthmatics

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo Inhalation Powder
* Drug: Fluticasone Furoate/GW642444 Inhalation Powder
* Drug: Fluticasone Furoate/GW642444 Inhalation Powder
* Drug: Placebo Oral Capsule
* Drug: Prednisolone Oral Capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatient with ability to comply with study requirements and complete two 24-hour clinic visits Clinical diagnosis of asthma for greater than/equal to 12 weeks Reversibility FEV1 of at least twelve percent and two hundred milliliters FEV1 greater than or equal to fifty percent of predicted Exclusion Criteria: History of life threatening asthma Respiratory infection or oral candidiasis Asthma exacerbation Uncontrolled disease or clinical abnormality Allergies to study drugs, study drugs' excipients, medications related to study drugs Taking another investigational medication or prohibited medication

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: FF/444 Dose B<br>Fluticasone furoate/GW642444 Dose B inhalation powder once daily for 6 weeks' treatment + 1 oral placebo capsule each day on the last 7 days of the study | Drug: Fluticasone Furoate/GW642444 Inhalation Powder<br>* Dose B inhaled once daily for 6 weeks' treatment<br>Drug: Placebo Oral Capsule<br>* One placebo capsule taken each day on the last 7 days of the study<br>|
| Active Comparator: FF/444 Dose A<br>Fluticasone furoate/GW642444 Dose A inhalation powder once daily for 6 weeks' treatment + 1 oral placebo capsule each day on the last 7 days of the study | Drug: Fluticasone Furoate/GW642444 Inhalation Powder<br>* Dose A inhaled once daily for 6 weeks' treatment<br>Drug: Placebo Oral Capsule<br>* One placebo capsule taken each day on the last 7 days of the study<br>|
| Placebo Comparator: Placebo<br>Placebo inhalation powder once daily for 6 weeks' treatment + 1 oral placebo capsule each day on the last 7 days of the study | Drug: Placebo Inhalation Powder<br>* Placebo Inhalation powder inhaled once daily for 6 weeks' treatment<br>Drug: Placebo Oral Capsule<br>* One placebo capsule taken each day on the last 7 days of the study<br>|
| Active Comparator: Prednisolone<br>Placebo inhalation powder once daily for 6 weeks' treatment + 1 oral prednisolone 10mg capsule each day on the last 7 days of the study | Drug: Placebo Inhalation Powder<br>* Placebo Inhalation powder inhaled once daily for 6 weeks' treatment<br>Drug: Prednisolone Oral Capsule<br>* Prednisolone 10mg oral capsule taken each day on the last 7 days of the study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio From Baseline of the Serum Cortisol Weighted Mean (0-24 Hours) on Day -1/1 (Baseline) and Day 42 | Serum cortisol weighted mean was determined for each participant over the time period 0-12 hours on Day -1/1 (Baseline) and Day 42. Serum cortisol weighted mean was derived by dividing the area under the concentration-time curve (AUC; defined as thearea under the concentration-time curve from time zero up to 24 hours) by the sample collection time interval. The sample collection time interval is defined as the difference between the time of the last cortisol sample and the time of the first cortisol sample. Samples were collected at the following time points: 0 (first blood draw/pre-dose); 2, 4, 9, 12, 14, 16, 20, 22, and 24 hours (relative to the 0 time point). Because values are on a logged scale, the ratio of the endpoint to Baseline is presented, as it is a measure of the difference from Baseline. | Day -1/1 (Baseline) and Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio From Baseline of the Serum Cortisol Area Under the Concentration-time Curve (AUC) (0-24 Hour) on Day -1/1 (Baseline) and Day 42 | Area under the plasma drug concentration-time (AUC[0-24 hour]) curve from time zero (pre-dose) to the last time of quantifiable serum cortisol concentration at 24 hours post-dose on Day -1/1 (Baseline) and Day 42 was measured. AUC reflects the actual body exposure to drug over a specified period of time after administration of a dose. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr. Because values are on a logged scale, the ratio of the endpoint to Baseline is presented, as it is a measure of the difference from Baseline. | Day -1/1 (Baseline) and Day 42 | 
| Ratio From Baseline of Serum Cortisol Trough (0-24 Hours) at Day -1/1 (Baseline) and Day 42 | Serum cortisol trough is defined as the minimum value of serum cortisol measured over the 24-hour period. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr. Because values are on a logged scale, the ratio of the endpoint to Baseline is presented, as it is a measure of the difference from Baseline. | Day -1/1 (Baseline) and Day 42 | 
| Ratio From Baseline of 0-24 Hour Urinary Free Cortisol Excretion on Day -1/1 (Baseline) and Day 42 | A 24-hour urine sample was collected for the measurement of 24-hour urinary cortisol excretion at Day -1/1 (Baseline) and Day 42. Only those participants available at the specified time points were analyzed. Because values are on a logged scale, the ratio of the endpoint to Baseline is presented, as it is a measure of the difference from Baseline. | Day -1/1 (Baseline) and Day 42 | 
| Plasma FF and VI Pharmacokinetic (PK) Concentration | Plasma FF and VI Pharmacokinetic (PK) Concentration were estimates at the following time points:0 (immediately pre-dose inhaled study drug), and post-dose at 5 min, 15 min, 30 min, and 1 hr, 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, 24 hr on Day 42. Only those participants available at the specified time points were analyzed (represented by n=X, X, X, X in the category titles). Different participants may have been analyzed at different time points, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Population. | Day 42 | 
| AUC(0-t) and AUC(0-24) for FF on Day 42 | Area under the plasma drug concentration-time (AUC[0-t]) curve from time zero (pre-dose) to the last time of quantifiable FF concentration and AUC(0-24) is the concentration time curve from zero (pre-dose) to 24 hours of quantifiable FF concentration on Day 42 was measured. AUC reflects the actual body exposure to drug over a specified period of time after administration of a dose. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| Cmax for FF on Day 42 | Cmax is defined as the maximum observed concentration on Day 42. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| Tmax and Tlast of FF at Day 42 | tmax is defined as the time to reach the observed maximum concentration, and tlast is defined as the time of the last observed quantifiable concentration on Day 42. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| AUC(0-t) for VI on Day 42 | Area under the concentration-time (AUC[0-t]) curve from time zero (pre-dose) to the last time of quantifiable VI concentration on Day 42 was measured. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| Cmax for VI on Day 42 | Cmax is defined as the maximum observed concentration on Day 42. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1 hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| Tmax and Tlast of VI at Day 42 | tmax is defined as the time to reach the observed maximum concentration, and tlast is defined as the time of the last observed quantifiable VI concentration on Day 42. Samples were collected at the following times: 0 (immediately pre-dose inhaled study drug); post-dose at 5 minutes (min), 15 min, 30 min, and 1hour (hr), 2 hr, 4 hr, 9 hr, 12 hr, 16 hr, 20 hr, and 24 hr post-dose on Day 42. | Day 42 | 
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of AEs and SAEs. | From the start of study medication until Day 42 (Visit 5)/Early Withdrawal | 
| Change From Baseline in Basophil, Eosinophil, Lymphocyte, Monocyte, and Segmented Neutrophil Values at Day 42/Early Withdrawal (EW) | Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, and segmented neutrophils at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/Early Withdrawal (EW) | 
| Change From Baseline in Eosinophil, Total Neutrophil, Platelet, and White Blood Cell (WBC) Count Values at Day 42/EW | Blood samples were collected for the measurement of eosinophils, total neutrophils, platelets, and WBC count at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Hemoglobin Values at Day 42/EW | Blood samples were collected for the measurement of hemoglobin at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Hematocrit Values at Day 42/EW | Blood samples were collected for the measurement of hematocrit at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), Creatine Kinase (CK), and Gamma Glutamyl Transferase (GGT) Values at Day 42/EW | Blood samples were collected for the measurement of ALT, ALP, AST, CK, and GGT at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Albumin and Total Protein Values at Day 42/EW | Blood samples were collected for the measurement of albumin and total protein at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and Creatinine Values at Day 42/EW | Blood samples were collected for the measurement of direct bilirubin, indirect bilirubin, total bilirubin, and creatinine at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Chloride, Carbon Dioxide (CO2) Content/Bicarbonate, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at Day 42/EW | Blood samples were collected for the measurement of chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at Baseline and Day 42/EW. For all laboratory assessments, Baseline is the most recent recorded value at Screening or prior to Day -1/1. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. | Baseline and Day 42/EW | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Days 14, 28, 42, and Maximum Post-Baseline | SBP and DBP were measured at Baseline and at Days 14, 28, 42, and EW. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. Scheduled, unscheduled, and early withdrawal visits were used for the maximum post-Baseline assessment. | Days 14, 28, 42, and EW | 
| Change From Baseline in Pulse Rate at Days 14, 28, 42, and Maximum Post-Baseline | Heart rate was measured at Baseline and at Days 14, 28, 42, and EW. Change from Baseline was calculated as the Day 42/EW value minus the Baseline value. Scheduled, unscheduled, and early withdrawal visits were used for the maximum post-Baseline assessment. | Days 14, 28, 42, and EW | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPA axis