The primary objective of this study is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate (50, 100, 200, and 400mcg) delivered as Fluticasone Spiromax® Inhalation Powder (Fp Spiromax) when administered twice daily in subjects 12 years of age and older with severe persistent asthma who are uncontrolled on high dose ICS therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
889
Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to 50, 100, 200 or 400 mcg of Fp one inhalation twice a day for a total daily dose of 100, 200, 400 or 800 mcg. Study drug was administered in the morning and in the evening.
Placebo multidose dry powder inhaler (MDPI) in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI.
Flovent Diskus contains the active ingredient fluticasone propionate (Fp). Flovent Diskus 250 mcg was used twice a day, once in the morning and evening, for a total daily dose of 500 mcg of Fp. This therapy was not blinded as the inhaler device was different than the MDPI used in the other treatment arms.
A short-acting β2-adrenergic agonists (SABA), albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).
Teva Investigational Site 10504
Birmingham, Alabama, United States
Teva Investigational Site 10565
Homewood, Alabama, United States
Teva Investigational Site 11527
Goodyear, Arizona, United States
Teva Investigational Site 10516
Tucson, Arizona, United States
Teva Investigational Site 10573
Bakersfield, California, United States
Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period
Trough FEV1 was measured electronically by spirometry at morning (AM) investigational site visits, before administration of the AM dose of study drug, and before albuterol/salbutamol administration. The highest FEV1 value from 3 acceptable and 2 reproducible maneuvers was used. All FEV1 data were submitted to a central reading center for evaluation. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Morning Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. On mornings for which a treatment visit was scheduled (TV1 through TV9), the PEF was measured and recorded at the investigational site visit. Baseline trough AM PEF was defined as the average of recorded (non-missing) trough AM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
Change From Baseline In Weekly Average Of Daily Trough (Predose And Pre-Rescue Bronchodilator) Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period
Peak expiratory flow was determined in the AM and in the PM, before administration of study or rescue medications using a handheld electronic peak flow meter. The highest value of triplicate measurements obtained was recorded by the subject's diary device. PM PEF baseline was defined as the average of recorded (nonmissing) PM PEF assessments over the 7 days directly preceding first study drug intake. The p-values for the treatment comparisons to placebo are from an MMRM model excluding FLOVENT DISKUS data: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -6 to Day 1 pre-dose), Weeks 1, 2, 3, 4, 6, 8, 10 and 12
The Kaplan-Meier Estimate Of The Probability Of Remaining In The Study At Week 12
The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma. Worsening asthma was defined as: 1. clinic visit FEV1 below the FEV1 stability limit value calculated on Day 1. 2. any 7-day run-in or treatment window (using information from the patient diary) during which the subject experienced: * 3 or more days in which the highest PEF has fallen below the PEF stability limit calculated on Day 1 * 3 or more days in which ≥12 inhalations/day of albuterol/salbutamol was used * 2 or more days in which the subject experienced a nighttime asthma symptom score of \>2 3. clinical asthma exacerbation, defined as worsening asthma requiring any treatment other than study drug or rescue albuterol/salbutamol including the use of systemic corticosteroids and/or ER visit or hospitalization. Patients who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.
Time frame: Day 1 to Week 12
Change From Baseline In The Percentage Of Rescue-Free 24-Hour Periods
The change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model, with the response being the proportion of rescue-free 24-hour periods. The model included 2 time points of measurement for each subject: the baseline (the last 7 days before the treatment period) and the treatment period. The model contained covariates for sex, age, and treatment. Rescue-free days were as indicated in patient diaries. Data values are estimated means.
Time frame: Baseline (Day -6 to Day 1 predose), Treatment (Day 1 to Week 12)
Area Under The Plasma Concentration-Time Curve From Time Zero To The Time Of The Last Measurable Concentration (AUC0-t)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Maximum Observed Plasma Concentration (Cmax)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Time Of Maximum Observed Plasma Concentration (Tmax)
Time frame: Day 1 predose (within 10 minutes of treatment administration), and 5, 10, 15, 30, and 45 minutes, 1 hour, 1 hour 15 minutes, 1 hour 30 minutes, and 2, 4, 8, and 12 hours postdose
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period
An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time frame: Day 1 to Week 12
Patients With Positive Swab Test Results for Oral Candidiasis
Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at each visit. Any visual evidence of oral candidiasis during the oropharyngeal exam was evaluated by obtaining and analyzing a swab of the suspect area. This outcomes indicates how many patients had positive swab test results. The total number of patients who had oropharyngeal exams at each timepoint are specified in the timepoint field. Appropriate therapy was to be initiated immediately at the discretion of the investigator and was not to be delayed for culture confirmation. Subjects with a culture-positive infection could continue participation in the study on appropriate anti-infective therapy, provided this therapy was not prohibited by the protocol.
Time frame: Screening (Days -21 to -14), Randomization (Day 1), Weeks 1, 2, 3, 4, 6, 8, 10, 12
24-Hour Urinary Cortisol Excretion at Baseline, Week 12 and Endpoint
24-hour urinary cortisol excretion was determined from 24-hour pooled-urine samples; urine was refrigerated until return to the investigational site after each 24-hour collection period. Urine was collected within 7 days of Day 1 and within 7 days of Week 12. Urine cortisol sample collection was not required at endpoint visit for subjects who terminated early from the study.
Time frame: Baseline (Day 1), Week 12, Endpoint
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Teva Investigational Site 11518
Costa Mesa, California, United States
Teva Investigational Site 10590
Fountain Valley, California, United States
Teva Investigational Site 10551
Granada Hills, California, United States
Teva Investigational Site 11520
Huntington Beach, California, United States
Teva Investigational Site 11545
Huntington Beach, California, United States
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