Asthma
Conditions
Keywords
Dose Ranging, Fluticasone Propionate, Dry Powder Inhaler (DPI), Non-steroidal, Asthma
Brief summary
This is a randomized, double-blind, placebo- and open-label active controlled, parallel-group, multicenter, dose ranging study in male or female subjects ages 12 years and older with persistent asthma who are uncontrolled on non-steroidal therapy. The primary objective of this study is to evaluate the dose response, efficacy and safety of 4 different doses of fluticasone propionate delivered as Fluticasone Propionate DPI (Dry Powder Inhaler) when administered twice daily.
Interventions
DRUGFp MDPI
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 12.5, 25, 50 or 100 mcg of Fp one inhalation twice a day for a total daily dose of 25, 50, 100 or 200 mcg. Study drug was administered in the morning and in the evening
DRUGFlovent Diskus
Flovent Diskus contains the active ingredient fluticasone propionate (Fp). Flovent Diskus 100 mcg was used twice a day, once in the morning and evening, for a total daily dose of 200 mcg of Fp. This therapy was not blinded as the inhaler device was different than the MDPI used in the other treatment arms.
DRUGalbuterol/salbutamol
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).
DRUGPlacebo MDPI
Placebo multidose dry powder inhaler in the morning and evening. Placebo MDPI was provided in devices identical in appearance to Fp MDPI.
Sponsors
PPD Development, LP
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent/assent signed and dated by the subject and/or parent /legal guardian before conducting any study related procedure. 2. Male or female 12 years and older, as of the Screening Visit. Male or female 18 years and older, as of the Screening Visit, in countries where local regulations or the regulatory status of study medication permit enrollment of adults only. 3. General good health, and free of any concomitant conditions or treatment that could interfere with study conduct, influence the interpretation of study observations/results, or put the subject at increased risk during the study. 4. Asthma Diagnosis: Asthma as defined by the National Institutes of Health (NIH). 5. Severity of Disease: A best forced expiratory volume in one second (FEV1) of 40%-85% of the predicted normal value during the Screening Visit. NHANES III predicted values will be used for subjects aged ≥12 years and adjustments to predicted values will be made for African American subjects. 6. Reversibility of Disease: Demonstrated a ≥15% reversibility of FEV1 within 30 minutes following 2 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) at the Screening Visit. If a subject fails to demonstrate an increase in FEV1 ≥15%, then the subject is not eligible for the study and will not be allowed to re-screen. 7. Current Asthma Therapy: Subjects must be on a short-acting β2-agonist alone or a non-corticosteroid maintenance medication (with or without a short-acting β2-agonist) for ≥ 3 months preceding the Screening Visit. Subjects must not have used an inhaled corticosteroid for at least 6 weeks preceding the Screening Visit. Exception: Based upon the investigator's judgment that there is no inherent harm in changing the subject's current ICS therapy and the subject provides consent, subjects on low dose ICS (100mcg Fp BID or equivalent) may be switched to a short-acting β2 agonist alone at a Pre-screening Visit. The subject will be required to return to the clinic to complete the Screening Visit once the 2-week washout period has been completed. 8. Short-Acting β2-Agonists: All subjects must be able to replace their current short-acting β2-agonists with albuterol/salbutamol inhalation aerosol at the Screening Visit for use as needed for the duration of the study. The use of spacer devices with the metered dose inhaler (MDI) will not be allowed during the study with exception of its use during reversibility testing at the Screening Visit. Nebulized albuterol/salbutamol will not be allowed at any time during the study. Subjects must be able to withhold all inhaled short-acting beta sympathomimetic bronchodilators for at least 6 hours prior to all study visits. 9. If female, is currently not pregnant, breast feeding, or attempting to become pregnant, has a negative serum pregnancy test, and is of 1. Non-childbearing potential, defined as: * Before menarche or \> or =1 year post-menopausal or * Surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy) or * Congenital sterility or * Diagnosed as infertile and not undergoing treatment to reverse infertility or is of 2. Child-bearing potential, willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study: * Systemic contraception used for \> or = 1 month prior to screening, including birth control pills, transdermal patch (Ortho Evra®), vaginal ring (NuvaRing®), levonorgesterel (Norplant®), or injectable progesterone (Depo-Provera®) or * Double barrier methods (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide) or * Intrauterine device (IUD) or is of 3. Child-bearing potential and not sexually active, willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event the subject becomes sexually active. 10. Capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements (visits, record-keeping, etc).
Exclusion criteria
1. History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures. 2. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks prior to the Screening Visit. In addition, the subject must be excluded if such infection occurs between the Screening Visit and the Randomization Visit. 3. Any asthma exacerbation requiring oral corticosteroids within 3 months of the Screening Visit. A subject must not have had any hospitalization for asthma within 6 months prior to the Screening Visit. Note: An exacerbation of asthma is defined as any worsening of asthma requiring any treatment other than rescue albuterol/salbutamol HFA MDI and/or the subject's regular non-corticosteroid maintenance treatment. This includes requiring the use of systemic corticosteroids and/or emergency room visit or hospitalization, a change in the subject's regular non-corticosteroid maintenance treatment, or the addition of other asthma medications. 4. Presence of glaucoma, cataracts, ocular herpes simplex, or malignancy other than basal cell carcinoma. 5. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular (e.g., congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia or coronary heart disease), hepatic, renal, hematological, neuropsychological, endocrine (e.g., uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison's disease, Cushing's syndrome), gastrointestinal (e.g., poorly-controlled peptic ulcer, GERD), or pulmonary (e.g., chronic bronchitis, emphysema, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia, chronic obstructive pulmonary disease). Significant is defined as any disease that, in the opinion of the investigator, would put the safety of the subject at risk through participation, or which could affect the efficacy or safety analysis if the disease/condition exacerbated during the study. 6. Have any of the following conditions that, in the judgment of the investigator, might cause participation in this study to be detrimental to the subject, including, but not limited to: * Current malignancy excluding basal cell carcinoma; History of malignancy is acceptable only if the subject has been in remission for one year prior to the Screening Visit. (Remission is defined as no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to the Screening Visit) * Current or untreated tuberculosis; History of tuberculosis is acceptable only if a subject has received an approved prophylactic treatment regimen or an approved active treatment regimen and has had no evidence of active disease for a minimum of 2 years • Uncontrolled hypertension (systolic BP ≥160 or diastolic BP \>100) * Stroke within 3 months prior to the Screening Visit * Immunologic compromise 7. History of a positive test for HIV, hepatitis B or hepatitis C infection. 8. Clinical visual evidence of oral candidiasis at the Screening Visit. 9. History of any adverse reaction, including immediate or delayed hypersensitivity to any β2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the dry powder inhalers (Spiromax or Diskus) used in the study (i.e., lactose). 10. History of severe allergy to milk protein. 11. Use of systemic, oral or depot corticosteroids within 12 weeks prior to the Screening Visit * Use of topical corticosteroids (≤1% hydrocortisone cream) for dermatological disease is permitted * Use of intranasal corticosteroids at a stable dose for at least 4 weeks prior to the Screening Visit and throughout the study is permitted 12. Use of immunosuppressive medications within 4 weeks prior to the Screening Visit and during the study. 13. Immunotherapy at a stable dose for at least 90 days prior to the Screening Visit and throughout the study for the treatment of allergies is permitted. 14. Use of potent Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, ketoconazole, itraconazole) within 4 weeks prior to the Screening Visit. 15. History of alcohol or drug abuse within two years preceding the Screening Visit. 16. Current smoker or a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). A subject may not have used tobacco products within the past one year (e.g., cigarettes, cigars, chewing tobacco, or pipe tobacco). 17. Study participation by clinical investigator site employees and/or their immediate relatives. 18. Study participation by more than one subject from the same household at the same time. However, after the study completion or discontinuation by one subject another subject from the same household may be screened. 19. Participation in any investigational drug study within the 30 days (starting at the final follow-up visit) preceding the Screening Visit or planned participation in another investigational drug study at any time during this study. 20. Pregnancy, nursing, or plans to become pregnant or donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days following the subject's last study related visit (for eligible subjects only - if applicable). Eligible female subjects unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | Baseline (Day 1, pre-dose), During Study (Days 7, 14, 28, 56 and 84 pre-dose) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | Day 1 to Day 84 | The time to withdrawal due to stopping criteria was compared between the treatment groups with the log rank test. The Kaplan-Meier estimate of the probability of remaining in the study at week 12 with 95% CI was presented by treatment group. Subjects who completed the study were censored at the date of completion, subjects who withdrew for reasons other than stopping criteria were censored at the time of withdrawal. Stopping criteria were based on day subject first met stopping criteria, using subject's diary data and asthma exacerbations recorded in CRF. |
| Time of Maximum Concentration (Tmax) of Fp | 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 | Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments. |
| Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Day 1 -84 | 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. |
| Oropharyngeal Exam Findings at Each Study Visit | Screening (week -3 to -2), Baseline (Week 0), Weeks 1, 2, 4, 8, 12 | Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at all study visits. If the visual oropharyngeal examination was abnormal at the screening visit, the subject was excluded from entering the study and subjects with an abnormal oropharyngeal exam on Day 1 were not eligible for randomization. Any visual evidence of oral candidiasis during the treatment period of the study was evaluated by obtaining and analyzing a swab of the suspect area. 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. If a subject required a protocol-prohibited medication for therapy, the subject was to be discontinued from the study. Data format: Time frame, \<signs of oral candidiasis?\> yes or no |
| 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 | Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose) | 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. |
| Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose) | 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. |
| Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | Baseline (Days -7 to -1), During Study (Days 1-84) | The number of inhalations of rescue medication used each day and each night was recorded in the subject's diary device. Change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model. The model included 2 time points of measurement for each subject: the baseline and the treatment period. The model contained covariates for sex, age, and treatment. The model for the 2 time points was considered as an incomplete randomized block model, with each subject as a block, receiving the baseline level in 1 sub-block and either active treatment or placebo in the other sub-block. The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. Measure type are estimated mean and measure of dispersion is the standard error of the estimated mean. |
| Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 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 | Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments. |
| Maximum Observed Plasma Concentration (Cmax) of Fp | 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 | Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose) | 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 including all treatment groups: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| 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 Inclusive of Flovent Diskus Data | Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose) | 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 including all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
| Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | Baseline (Day 1, pre-dose), During Study (Days 7, 14, 28, 56 and 84 pre-dose) | 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 including data from all treatments: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed. |
Countries
Bulgaria, Croatia, Hungary, Israel, Poland, Serbia, Spain, Ukraine, United States
Participant flow
Recruitment details
A total of 1903 subjects with asthma were screened for enrollment into this study. Of the 994 subjects who were not enrolled, 983 were excluded on the basis of inclusion/exclusion criteria and 6 subjects withdrew consent, and for 5 the reason given was other.
Pre-assignment details
909 subjects at 188 centers met entry criteria and were considered to be eligible for enrollment into the run-in period of the study.
Participants by arm
| Arm | Count |
|---|---|
| Fp MDPI 12.5 mcg Fluticasone propionate (Fp) 12.5 mcg per dose twice a day (for a total daily dose of 25 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 103 |
| Fp MDPI 25 mcg Fluticasone propionate (Fp) 25 mcg per dose twice a day (for a total daily dose of 50 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 104 |
| Fp MDPI 50 mcg Fluticasone propionate (Fp) 50 mcg per dose twice a day (for a total daily dose of 100 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 104 |
| Fp MDPI 100 mcg Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 103 |
| Placebo MDPI Placebo twice a day using a multidose dry powder inhaler (MDPI) for 12 weeks in a double-blind manner. During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 104 |
| Flovent Diskus 100mcg Fluticasone propionate (Fp) 100 mcg per dose twice a day (for a total daily dose of 200 mcg) using a multidose dry powder inhaler (MDPI) for 12 weeks in an open-label manner.
During the run-in and the treatment periods, all subjects replaced their current rescue medication with albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) (90 mcg/actuation) for use on an as needed basis for the relief of asthma symptoms. | 104 |
| Total | 622 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Pre-Assignment Period (Run-In Placebo) | Inclusion/exclusion criteria | 93 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Lost to Follow-up | 7 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Other | 15 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Randomization criteria not met | 153 | 0 | 0 | 0 | 0 | 0 | 0 |
| Pre-Assignment Period (Run-In Placebo) | Withdrawal by Subject | 19 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 0 | 0 | 0 | 1 | 2 | 2 |
| Treatment Period | Lost to Follow-up | 0 | 0 | 1 | 0 | 2 | 2 | 1 |
| Treatment Period | Met stopping criteria | 0 | 8 | 7 | 4 | 9 | 20 | 6 |
| Treatment Period | Non-compliance to study drug | 0 | 1 | 0 | 0 | 0 | 0 | 1 |
| Treatment Period | Physician Decision | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
| Treatment Period | Pregnancy | 0 | 0 | 2 | 0 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 0 | 9 | 6 | 5 | 2 | 10 | 6 |
| Treatment Period | Sponsor request subject to be withdrawn | 0 | 2 | 3 | 1 | 1 | 1 | 3 |
| Treatment Period | Withdrawal by Subject | 0 | 4 | 2 | 2 | 5 | 5 | 1 |
Baseline characteristics
| Characteristic | Fp MDPI 25 mcg | Fp MDPI 50 mcg | Fp MDPI 100 mcg | Placebo MDPI | Flovent Diskus 100mcg | Fp MDPI 12.5 mcg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 42.4 years STANDARD_DEVIATION 16.02 | 39.1 years STANDARD_DEVIATION 16.06 | 36.9 years STANDARD_DEVIATION 15.34 | 39.7 years STANDARD_DEVIATION 15.28 | 40.0 years STANDARD_DEVIATION 15.34 | 41.0 years STANDARD_DEVIATION 16.94 | 39.9 years STANDARD_DEVIATION 15.87 |
| Age, Customized 12-17 years | 7 Participants | 14 Participants | 9 Participants | 5 Participants | 7 Participants | 10 Participants | 52 Participants |
| Age, Customized Adults (18-64 years) | 90 Participants | 86 Participants | 88 Participants | 93 Participants | 93 Participants | 85 Participants | 535 Participants |
| Age, Customized Adults (65+ years) | 7 Participants | 4 Participants | 6 Participants | 6 Participants | 4 Participants | 8 Participants | 35 Participants |
| Body Mass Index | 28.1 kg/m^2 STANDARD_DEVIATION 6.47 | 27.5 kg/m^2 STANDARD_DEVIATION 6.78 | 29.6 kg/m^2 STANDARD_DEVIATION 7.54 | 28.0 kg/m^2 STANDARD_DEVIATION 6.61 | 28.4 kg/m^2 STANDARD_DEVIATION 7.31 | 28.7 kg/m^2 STANDARD_DEVIATION 7.43 | 28.4 kg/m^2 STANDARD_DEVIATION 7.04 |
| Forced Expiratory Volume in 1 Second (FEV1) | 2.2 liters STANDARD_DEVIATION 0.59 | 2.2 liters STANDARD_DEVIATION 0.63 | 2.3 liters STANDARD_DEVIATION 0.66 | 2.3 liters STANDARD_DEVIATION 0.62 | 2.2 liters STANDARD_DEVIATION 0.66 | 2.3 liters STANDARD_DEVIATION 0.69 | 2.2 liters STANDARD_DEVIATION 0.64 |
| Height | 169.2 cm STANDARD_DEVIATION 8.89 | 168.6 cm STANDARD_DEVIATION 10.33 | 168.7 cm STANDARD_DEVIATION 10.94 | 169.5 cm STANDARD_DEVIATION 9.25 | 169.0 cm STANDARD_DEVIATION 9.39 | 168.8 cm STANDARD_DEVIATION 10.54 | 169.0 cm STANDARD_DEVIATION 9.88 |
| % Predicted Expiratory Volume In 1 Second | 67.5 percent predicted FEV1 STANDARD_DEVIATION 10.5 | 66.3 percent predicted FEV1 STANDARD_DEVIATION 11.15 | 66.4 percent predicted FEV1 STANDARD_DEVIATION 11.61 | 66.4 percent predicted FEV1 STANDARD_DEVIATION 11.14 | 65.3 percent predicted FEV1 STANDARD_DEVIATION 11.74 | 66.6 percent predicted FEV1 STANDARD_DEVIATION 11.8 | 66.4 percent predicted FEV1 STANDARD_DEVIATION 11.3 |
| Qualifying Airway Reversibility | 26.0 percentage increase in FEV1 STANDARD_DEVIATION 11.86 | 24.3 percentage increase in FEV1 STANDARD_DEVIATION 10.63 | 27.6 percentage increase in FEV1 STANDARD_DEVIATION 12.92 | 30.6 percentage increase in FEV1 STANDARD_DEVIATION 17.84 | 26.2 percentage increase in FEV1 STANDARD_DEVIATION 12.5 | 26.7 percentage increase in FEV1 STANDARD_DEVIATION 12.01 | 26.9 percentage increase in FEV1 STANDARD_DEVIATION 13.25 |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 4 Participants | 0 Participants | 1 Participants | 1 Participants | 10 Participants |
| Race/Ethnicity, Customized Black | 11 Participants | 12 Participants | 14 Participants | 17 Participants | 17 Participants | 10 Participants | 81 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 7 Participants | 13 Participants | 11 Participants | 6 Participants | 9 Participants | 50 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 100 Participants | 97 Participants | 90 Participants | 93 Participants | 98 Participants | 94 Participants | 572 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 91 Participants | 90 Participants | 85 Participants | 85 Participants | 85 Participants | 91 Participants | 527 Participants |
| Sex: Female, Male Female | 63 Participants | 60 Participants | 60 Participants | 55 Participants | 63 Participants | 57 Participants | 358 Participants |
| Sex: Female, Male Male | 41 Participants | 44 Participants | 43 Participants | 49 Participants | 41 Participants | 46 Participants | 264 Participants |
| Weight | 80.4 kg STANDARD_DEVIATION 19.62 | 78.7 kg STANDARD_DEVIATION 23.08 | 84.6 kg STANDARD_DEVIATION 23.51 | 80.5 kg STANDARD_DEVIATION 20 | 81.5 kg STANDARD_DEVIATION 23.53 | 82.0 kg STANDARD_DEVIATION 23.29 | 81.3 kg STANDARD_DEVIATION 22.22 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 104 | 8 / 103 | 10 / 103 | 7 / 104 | 10 / 104 | 8 / 104 |
| serious Total, serious adverse events | 2 / 104 | 2 / 103 | 0 / 103 | 0 / 104 | 1 / 104 | 2 / 104 |
Outcome results
Primary
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), During Study (Days 7, 14, 28, 56 and 84 pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints (see outcome #11).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.170 liters | Standard Error 0.03 |
| Fp MDPI 25 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.229 liters | Standard Error 0.0295 |
| Fp MDPI 50 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.243 liters | Standard Error 0.0288 |
| Fp MDPI 100 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.267 liters | Standard Error 0.03 |
| Placebo MDPI | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period | 0.118 liters | Standard Error 0.0302 |
Comparison: A linear in log-dose trend contrast evaluated the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo). A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 0.05 level. Specifically, the 2-sided linear in log-dose time-averaged trend test was first performed followed by pairwise comparisons of each Fp MDPI dose versus placebo.p-value: 0.0001Regression, Linear
Comparison: This is the second analysis in the fixed-sequence testing procedure employed to control the overall Type I error rate at the 0.05 level.p-value: 0.000595% CI: [0.066, 0.233]mixed model for repeated measures
Comparison: This is the third analysis in the fixed-sequence testing procedure employed to control the overall Type I error rate at the 0.05 level.p-value: 0.002795% CI: [0.044, 0.208]mixed model for repeated measures
Comparison: This is the fourth analysis in the fixed-sequence testing procedure employed to control the overall Type I error rate at the 0.05 level.p-value: 0.008695% CI: [0.028, 0.194]mixed model for repeated measures
Comparison: This is the fifth analysis in the fixed-sequence testing procedure employed to control the overall Type I error rate at the 0.05 level.p-value: 0.222795% CI: [-0.032, 0.136]mixed model for repeated measures
Secondary
Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp
Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments.
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
Population: Pharmacokinetics analysis set. Placebo samples not included in these results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 21.6 pg*hr/mL | Standard Deviation 27.09 |
| Fp MDPI 25 mcg | Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 42.0 pg*hr/mL | Standard Deviation 23.21 |
| Fp MDPI 50 mcg | Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 63.2 pg*hr/mL | Standard Deviation 22.64 |
| Fp MDPI 100 mcg | Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 153.8 pg*hr/mL | Standard Deviation 91.42 |
| Flovent Diskus 100mcg | Area Under The Curve From Time 0 Until The Last Measurable Concentration (AUC0-t) of Fp | 10.4 pg*hr/mL | Standard Deviation 45.65 |
Secondary
Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period
The number of inhalations of rescue medication used each day and each night was recorded in the subject's diary device. Change from baseline in the percentage of rescue-free 24-hour periods was analyzed with a marginal (also called population averaged) logistic model. The model included 2 time points of measurement for each subject: the baseline and the treatment period. The model contained covariates for sex, age, and treatment. The model for the 2 time points was considered as an incomplete randomized block model, with each subject as a block, receiving the baseline level in 1 sub-block and either active treatment or placebo in the other sub-block. The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. Measure type are estimated mean and measure of dispersion is the standard error of the estimated mean.
Time frame: Baseline (Days -7 to -1), During Study (Days 1-84)
Population: Full analysis set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 34.08 percentage of total 24 hour periods | Standard Error 3.909 |
| Fp MDPI 25 mcg | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 31.76 percentage of total 24 hour periods | Standard Error 4.229 |
| Fp MDPI 50 mcg | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 28.06 percentage of total 24 hour periods | Standard Error 3.799 |
| Fp MDPI 100 mcg | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 24.07 percentage of total 24 hour periods | Standard Error 4.283 |
| Placebo MDPI | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 21.30 percentage of total 24 hour periods | Standard Error 4.668 |
| Flovent Diskus 100mcg | Change From Baseline in the Percentage of Rescue-Free 24-hour Periods During the 12-Week Treatment Period | 29.82 percentage of total 24 hour periods | Standard Error 4.191 |
Comparison: The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. This model was used to obtain 2-sided 95% confidence limits for the difference in treatment effects of Fp MDPI versus placebo.p-value: 0.6668595% CI: [-10.07, 15.6]GEE
Comparison: The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. This model was used to obtain 2-sided 95% confidence limits for the difference in treatment effects of Fp MDPI versus placebo.p-value: 0.2674195% CI: [-5.43, 18.94]GEE
Comparison: The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. This model was used to obtain 2-sided 95% confidence limits for the difference in treatment effects of Fp MDPI versus placebo.p-value: 0.0996495% CI: [-2.24, 23.15]GEE
Comparison: The generalized estimating equation (GEE) algorithm was used to fit the model, using a robust estimator for the variance which provided a proper adjustment for possible correlation between the 2 measurements on each subject. This model was used to obtain 2-sided 95% confidence limits for the difference in treatment effects of Fp MDPI versus placebo.p-value: 0.0382595% CI: [0.44, 25.11]GEE
Secondary
Change From Baseline In Weekly Average Of Daily 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 -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints (see outcome #13).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 27.65 liters/minute | Standard Error 4.474 |
| Fp MDPI 25 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 18.69 liters/minute | Standard Error 4.347 |
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 22.20 liters/minute | Standard Error 4.237 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 20.48 liters/minute | Standard Error 4.49 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period | 9.42 liters/minute | Standard Error 4.588 |
Comparison: A linear in log-dose trend contrast evaluated the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo).p-value: 0.0434Regression, Linear
p-value: 0.085295% CI: [-1.54, 23.66]mixed model for repeated measures
p-value: 0.041195% CI: [0.52, 25.04]mixed model for repeated measures
p-value: 0.142895% CI: [-3.14, 21.69]mixed model for repeated measures
p-value: 0.004695% CI: [5.64, 30.82]mixed model for repeated measures
Secondary
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 -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns. Flovent Diskus data was used for confirmatory and exploratory endpoints (see outcome #12).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | 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 | 30.99 liters/minute | Standard Error 4.6 |
| Fp MDPI 25 mcg | 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 | 21.01 liters/minute | Standard Error 4.521 |
| Fp MDPI 50 mcg | 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 | 29.58 liters/minute | Standard Error 4.396 |
| Fp MDPI 100 mcg | 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 | 27.55 liters/minute | Standard Error 4.61 |
| Placebo MDPI | 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 | 9.26 liters/minute | Standard Error 4.755 |
Comparison: A linear in log-dose trend contrast evaluated the time-averaged dose-response trend, where the logarithm of dose was defined as log(dose+1) to accommodate the case of a zero dose (placebo).p-value: 0.0017Regression, Linear
p-value: 0.00695% CI: [5.28, 31.29]mixed model for repeated measures
p-value: 0.001895% CI: [7.61, 33.03]mixed model for repeated measures
p-value: 0.074195% CI: [-1.15, 24.64]mixed model for repeated measures
p-value: 0.001195% CI: [8.73, 34.72]mixed model for repeated measures
Secondary
Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12
The time to withdrawal due to stopping criteria was compared between the treatment groups with the log rank test. The Kaplan-Meier estimate of the probability of remaining in the study at week 12 with 95% CI was presented by treatment group. Subjects who completed the study were censored at the date of completion, subjects who withdrew for reasons other than stopping criteria were censored at the time of withdrawal. Stopping criteria were based on day subject first met stopping criteria, using subject's diary data and asthma exacerbations recorded in CRF.
Time frame: Day 1 to Day 84
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fp MDPI 12.5 mcg | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.8041 probability |
| Fp MDPI 25 mcg | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.7895 probability |
| Fp MDPI 50 mcg | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.9077 probability |
| Fp MDPI 100 mcg | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.7657 probability |
| Placebo MDPI | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.5655 probability |
| Flovent Diskus 100mcg | Kaplan-Meier Estimate of Probability of Remaining in the Study at Week 12 | 0.8272 probability |
Comparison: Comparison of survival curve to placebop-value: 0.2841Log Rank
Comparison: Comparison of survival curve to placebop-value: <0.0001Log Rank
Comparison: Comparison of survival curve to placebop-value: 0.0008Log Rank
Comparison: Comparison of survival curve to placebop-value: 0.001Log Rank
Secondary
Maximum Observed Plasma Concentration (Cmax) of Fp
Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments.
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
Population: Pharmacokinetics analysis set. Placebo samples not included in these results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Maximum Observed Plasma Concentration (Cmax) of Fp | 5.4 pg/mL | Standard Deviation 4.23 |
| Fp MDPI 25 mcg | Maximum Observed Plasma Concentration (Cmax) of Fp | 10.0 pg/mL | Standard Deviation 5.35 |
| Fp MDPI 50 mcg | Maximum Observed Plasma Concentration (Cmax) of Fp | 12.9 pg/mL | Standard Deviation 5.13 |
| Fp MDPI 100 mcg | Maximum Observed Plasma Concentration (Cmax) of Fp | 33.6 pg/mL | Standard Deviation 15.49 |
| Flovent Diskus 100mcg | Maximum Observed Plasma Concentration (Cmax) of Fp | 23.4 pg/mL | Standard Deviation 10.73 |
Secondary
Oropharyngeal Exam Findings at Each Study Visit
Oropharyngeal examinations for visual evidence of oral candidiasis were conducted at all study visits. If the visual oropharyngeal examination was abnormal at the screening visit, the subject was excluded from entering the study and subjects with an abnormal oropharyngeal exam on Day 1 were not eligible for randomization. Any visual evidence of oral candidiasis during the treatment period of the study was evaluated by obtaining and analyzing a swab of the suspect area. 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. If a subject required a protocol-prohibited medication for therapy, the subject was to be discontinued from the study. Data format: Time frame, \<signs of oral candidiasis?\> yes or no
Time frame: Screening (week -3 to -2), Baseline (Week 0), Weeks 1, 2, 4, 8, 12
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 103 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 90 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 102 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 103 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 93 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 84 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 88 Participants |
| Fp MDPI 12.5 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 104 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 104 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 98 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 93 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 1 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 89 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 85 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Fp MDPI 25 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 102 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 104 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 99 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 97 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 104 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 100 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 92 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 0 Participants |
| Fp MDPI 50 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 103 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 84 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 95 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 100 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 91 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 103 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 100 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
| Fp MDPI 100 mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 103 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 94 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 104 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 75 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 66 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 83 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 97 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 104 Participants |
| Placebo MDPI | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - No | 104 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - No | 101 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - No | 90 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - No | 93 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 0 - No | 104 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 2 - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 4 - Yes (positive culture) | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - No | 98 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - No | 83 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 1 - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 12 - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Screening - Yes | 0 Participants |
| Flovent Diskus 100mcg | Oropharyngeal Exam Findings at Each Study Visit | Week 8 - Yes | 0 Participants |
Secondary
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 -84
Population: Safety analysis set
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 0 Participants |
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 0 Participants |
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 31 Participants |
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 6 Participants |
| Fp MDPI 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 0 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 0 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 32 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 0 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 3 Participants |
| Fp MDPI 25 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 0 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 3 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 1 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 36 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 3 Participants |
| Fp MDPI 50 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 0 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 2 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 2 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 1 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 37 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 2 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 3 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 31 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 2 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 1 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 2 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Withdrawn from treatment due to AE | 2 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Severe AE | 3 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Any adverse event (AE) | 32 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Other serious AE | 2 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Deaths | 0 Participants |
| Flovent Diskus 100mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Treatment-related AE | 1 Participants |
Secondary
Time of Maximum Concentration (Tmax) of Fp
Approximately 20% of subjects randomized to the study and distributed across preselected study sites were to participate in fluticasone propionate pharmacokinetic assessments (the pharmacokinetic cohort). Subjects who had received fluticasone propionate in any form (orally, inhaled, or nasal) within 14 days of Day 1 were not permitted to participate in pharmacokinetic assessments.
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
Population: Pharmacokinetics analysis set. Placebo samples not included in these results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Time of Maximum Concentration (Tmax) of Fp | 1.2 hours | Standard Deviation 0.97 |
| Fp MDPI 25 mcg | Time of Maximum Concentration (Tmax) of Fp | 1.4 hours | Standard Deviation 2.43 |
| Fp MDPI 50 mcg | Time of Maximum Concentration (Tmax) of Fp | 1.7 hours | Standard Deviation 2.55 |
| Fp MDPI 100 mcg | Time of Maximum Concentration (Tmax) of Fp | 1.1 hours | Standard Deviation 0.95 |
| Flovent Diskus 100mcg | Time of Maximum Concentration (Tmax) of Fp | 1.7 hours | Standard Deviation 2.61 |
Other Pre-specified
Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data
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 including data from all treatments: change from baseline = baseline FEV1 + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Day 1, pre-dose), During Study (Days 7, 14, 28, 56 and 84 pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.172 liters | Standard Error 0.0293 |
| Fp MDPI 25 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.232 liters | Standard Error 0.0288 |
| Fp MDPI 50 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.245 liters | Standard Error 0.028 |
| Fp MDPI 100 mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.268 liters | Standard Error 0.0292 |
| Placebo MDPI | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.120 liters | Standard Error 0.0294 |
| Flovent Diskus 100mcg | Change From Baseline In Trough (Morning Predose And Pre-Rescue Bronchodilator) Forced Expiratory Volume In 1 Second (FEV1) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 0.234 liters | Standard Error 0.0288 |
p-value: 0.005895% CI: [-0.195, -0.033]mixed model for repeated measures
p-value: 0.408395% CI: [-0.046, 0.114]mixed model for repeated measures
p-value: 0.788295% CI: [-0.068, 0.089]mixed model for repeated measures
p-value: 0.958695% CI: [-0.082, 0.078]mixed model for repeated measures
p-value: 0.130695% CI: [-0.143, 0.018]mixed model for repeated measures
Other Pre-specified
Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data
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 including all treatment groups: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 28.00 liters/minute | Standard Error 4.442 |
| Fp MDPI 25 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 18.97 liters/minute | Standard Error 4.315 |
| Fp MDPI 50 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 22.27 liters/minute | Standard Error 4.206 |
| Fp MDPI 100 mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 20.47 liters/minute | Standard Error 4.453 |
| Placebo MDPI | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 9.70 liters/minute | Standard Error 4.557 |
| Flovent Diskus 100mcg | Change From Baseline In Weekly Average Of Daily Evening Peak Expiratory Flow (PEF) Over The 12-Week Treatment Period Inclusive of Flovent Diskus Data | 24.95 liters/minute | Standard Error 4.356 |
p-value: 0.015895% CI: [-27.63, -2.88]mixed model for repeated measures
p-value: 0.470995% CI: [-16.69, 7.721]mixed model for repeated measures
p-value: 0.657295% CI: [-14.55, 9.19]mixed model for repeated measures
p-value: 0.329295% CI: [-18.01, 6.05]mixed model for repeated measures
p-value: 0.623795% CI: [-9.16, 15.26]mixed model for repeated measures
Other Pre-specified
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 Inclusive of Flovent Diskus Data
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 including all treatments: change from baseline = baseline PEF + sex + age + treatment + visit + treatment\*visit with an unstructured covariance matrix assumed.
Time frame: Baseline (Days -7 to 1, am pre-dose), During Study (Days 2-84 am pre-dose)
Population: Full analysis set, (participants who contributed \>=1 to the analysis). Data from one site omitted due to GCP concerns.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Fp MDPI 12.5 mcg | 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 Inclusive of Flovent Diskus Data | 31.20 liters/minute | Standard Error 4.544 |
| Fp MDPI 25 mcg | 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 Inclusive of Flovent Diskus Data | 21.27 liters/minute | Standard Error 4.465 |
| Fp MDPI 50 mcg | 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 Inclusive of Flovent Diskus Data | 29.63 liters/minute | Standard Error 4.339 |
| Fp MDPI 100 mcg | 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 Inclusive of Flovent Diskus Data | 27.66 liters/minute | Standard Error 4.55 |
| Placebo MDPI | 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 Inclusive of Flovent Diskus Data | 9.30 liters/minute | Standard Error 4.7 |
| Flovent Diskus 100mcg | 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 Inclusive of Flovent Diskus Data | 26.96 liters/minute | Standard Error 4.496 |
p-value: 0.006895% CI: [-30.43, -4.89]mixed model for repeated measures
p-value: 0.913595% CI: [-11.84, 13.23]mixed model for repeated measures
p-value: 0.668995% CI: [-9.58, 14.92]mixed model for repeated measures
p-value: 0.369195% CI: [-18.12, 6.74]mixed model for repeated measures
p-value: 0.507295% CI: [-8.31, 16.78]mixed model for repeated measures