fluticasone propionate/salmeterol

The Reflective Total Ocular Symptom Score (rTOSS) is the sum of 3 individual participant-assessed symptom scores (eye itching/burning, eye tearing/watering, and eye redness), each evaluated using a scale of 0=None, 1=Mild, 2=Moderate, or 3=Severe, for a possible score of 0-9. Subjects completed rTOSS in the evening (PM rTOSS; 12 hours post morning nasal spray use) and once in the morning (AM score: prior to nasal spray use). Daily (i.e. during one dosing interval) rTOSS is defined as the average of the PM rTOSS and the AM rTOSS of the next day prior to AM dosing. The mean change from baseline in (daily, AM, PM) TOSS was calculated as the subject's treatment period mean (over 14 days; from Day 0 PM to Day 14 AM) minus the baseline period (placebo run-in) mean.

PEF is the maximum flow generated during a forceful exhalation, starting from full lung inflation. Participants (if needed with the help of parents or guardian) recorded on diary card the best of three PEF measurements, using a mini-Wright peak flow meter in the morning before taking any study drug. Only data that was drawn from Days 2 to 8 after randomization and on or before one day after the end date of study drug was used for analysis. The outcome measure was considered missing if less than 2 days were recorded in the given treatment assessment period. Two participants from fluticasone propionate group and 4 participants from prednisone group had the missing outcome measure. Analysis was performed using an analysis of covariance (ANCOVA) model with effects due to gender, age, centre and treatment group.

PEF is the maximum flow generated during a forceful exhalation, starting from full lung inflation. Participants (if needed with the help of parents or guardian) recorded on diary card the best of three PEF measurements, using a mini-Wright peak flow meter in the morning before talking any study drug. Only data that was drawn from Days 2 to 8 after randomization and on or before one day after the end date of study drug was used for analysis. The outcome measure was considered missing if less than 2 days were recorded in the given treatment assessment period. Two participants from fluticasone propionate group and 5 participants from prednisone group had the missing outcome measure. Analysis was performed using ANCOVA model with effects due to gender, age ,centre and treatment group.

The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model. Abbreviations used in statistical analysis section: standard deviation (SD) and significance (sig)

The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model.

FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Trough FEV1 is defined as the clinic visit (pre-bronchodilator and pre-dose) FEV1 measurement taken at the clinic visit at the end of the dosing interval. Pre-dose and pre-rescue albuterol/salbutamol trough FEV1 was measured electronically by spirometry in the evening at the Baseline through Week 24 clinic visits. The highest of 3 technically acceptable measurements was recorded. Baseline was the pre-dose value obtained at Visit 2. Change from Baseline was calculated as the Week 24 value minus the Baseline value. Analysis was performed using analysis of covariance (ANCOVA) with covariates of Baseline, region, sex, age, and treatment. The last observation carried forward (LOCF) method was used to impute missing data, in which the last non-missing post-Baseline on-treatment measurement at scheduled clinic visits was used to impute the missing measurements.

Adverse Events reported by the Investigator and judged by the Investigator to be possibly related to study drug, categorized by the Medical Dictionary for Regulatory Activities (MeDRA), were reported. ECG, electrocardiogram. QTc (corrected QT interval) and QT represent intervals on an ECG.

ECGs were transmitted to an independent cardiologist who was responsible for providing interpretation of the ECG as either normal or abnormal (based on personal assessment). The investigator was then responsible for determining the clinical significance of the abnormal ECG in the context of the participants' history and clinical presentation. An abnormal, clinically significant ECG included, but was not limited to: prolonged QT interval, ischemic changes, ventricular hypertrophy, intraventricular conduction abnormalities, and clinically significant arrhythmias. PD, premature discontinuation.

Post-randomization ECGs categorized by the primary investigator as no change, significant change (favorable), significant change (unfavorable) from the ECG performed at Visit 1 (Baseline) are presented. Significant change (favorable) includes any ECG that improved from baseline, whereas significant change (unfavorable) includes any ECG that worsened from baseline. Clinical significance is determined by the primary investigator.

The range of heart rates for this study was between 49-144 beats per minute

Fridericia's formula QTc interval=QT interval/cubed root of the R-R interval. The Bazett's formula QTc=QT/squared root of the R-R interval.

Cardiovascular Adverse Events, as categorized by the Medical Dictionary for Regulatory Activities (MeDRA), reported during Treatment Period. The Adverse Events were identified in any ECG interpretation by a central reader (Cardiologist) for any ECG obtained after the first treatment dose and were then reported by the Primary Investigator as an Adverse Event. Please see the category titles for a list of candidate cardiovascular adverse events.

Cardiovascular Adverse Events, as categorized by the Medical Dictionary for Regulatory Activities (MeDRA), reported during Post-treatment period, defined as 1 day after last dose of study drug. The Adverse Events were identified in any ECG interpretation by a central reader (Cardiologist) for any ECG obtained after the first treatment dose and were then reported by the Primary Investigator as an Adverse Event.

The Primary Investigator determined the severity of the exacerbation based on the participant's clinical presentation and the investigator's understanding of the disease, the participant, and his or her clinical experiences. The severity of the exacerbation was not defined in the protocol. Mild: Usually treated at home. Prompt relief with inhaled short-acting beta2 agonist. Possible short course of oral systemic corticosteroids. Moderate: Usually requires office or emergency department visit. Relief with frequent inhaled short-acting beta2 agonist. Oral systemic corticosteroids; some symptoms last for 1-2 days after treatment begins. Severe: Usually requires emergency department visit and likely hospitalization. Partial relief with frequent inhaled short-acting beta2 agonist. Oral systemic corticosteroids; some symptoms last for more than 3 days after treatment begins. Adjunctive therapies are helpful.

"Abnormal high cortisol excretion" and "Abnormal low cortisol excretion" are defined as above the upper limit of normal and below the lower limit of normal, respectively. The normal range for cortisol levels vary by age and gender. An abnormality is defined as a value of 24-hour urinary cortisol excretion that is outside the normal range. The normal range for 24-hour urinary cortisol excretion was provided by the central laboratory.

Normal range for Cortisol levels vary by age and gender. Geometric mean is the product of the values taken to the Nth root, where N is the number of values in the set of values.

Normal range for Cortisol levels vary by age and gender. The data provided are a direct calculation of the Week 12 geometric mean divided by the baseline value, nanomoles per 24 hours (nmol/24 hrs).

AeroChamber Plus spacers were provided for participants who demonstrated the inability to coordinate the use of an Meter Dose Inhaler at Visit 1. AeroChamber Plus spacer delivers 22% more medication than the original AeroChamber and is available in three mask sizes and without a mask. "Abnormal high cortisol excretion" and "Abnormal low cortisol excretion" are defined as above the upper limit of normal and below the lower limit of normal, respectively. An abnormality is defined as a value of 24-hour urinary cortisol excretion that is outside the normal range. The normal range for 24-hour urinary cortisol excretion was provided by the central laboratory.

AeroChamber Plus spacers were provided for participants who demonstrated the inability to coordinate the use of an Meter Dose Inhaler at Visit 1. AeroChamber Plus spacer delivers 22% more medication than the original AeroChamber and is available in three mask sizes and without a mask. Geometric mean is the product of the values taken to the Nth root, where N is the number of values in the set of values.

AeroChamber Plus spacers were provided for participants who demonstrated the inability to coordinate the use of an Meter Dose Inhaler at Visit 1. AeroChamber Plus spacer delivers 22% more medication than the original AeroChamber and is available in three mask sizes and without a mask. The data provided are a direct calculation of the Week 12 geometric mean divided by the baseline value, nanomoles per 24 hours (nmol/24 hrs).

An overall preference questionnaire (OPQ) was used to evaluate participant's preference for nasal spray therapy for the given treatments. OPQ allows the responder three options, based on products attributes, i.e. preference for product 1 (FF 110 µg); preference for product 2 (FP 200 µg) and no preference. Three participant-related questionnaires were completed during the course of the study, including two attributes questionnaires : Immediate attributes questionnaire (IAQ) and delayed attributes questionnaire (DAQ). An OPQ was completed upon completion of the crossover dosing.

AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include adverse events that result in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF was measured by the participants using a hand-held electronic peak flow meter each evening prior to the dose of study medication and any rescue albuterol/salbutamol inhalation aerosol use each morning. The best of three measurements was recorded. Change from Baseline was calculated as the value of the averaged daily PM PEF over the 4-week Treatment Period minus the Baseline value. The Baseline PEF value is defined as the average of the last 7 days of the Run-in Phase. The analysis was performed using an analysis of covariance (ANCOVA) model with covariates of Baseline, region, sex, age, and treatment. Only those participants contributing data per the daily eDiary were analyzed.

PK Parameters include: area under the plasma fluticasone propionate concentration-time curve over dosing interval (AUCtau), salmeterol maximum plasma concentration-time curve on the last day of each study treatment period (Cmax).