Asthma
Conditions
Brief summary
The primary objective of this study was to evaluate the efficacy of fluticasone propionate (Fp) multidose dry powder inhaler (MDPI) and fluticasone propionate/salmeterol xinafoate (FS) MDPI when administered over 12 weeks in patients 12 years of age and older with persistent asthma.
Detailed description
Study drug and placebo were supplied in Teva multidose dry powder inhaler (MDPI) devices and provided for participants to use at home. Participants performed spirometry at every visit. Each participant was given a diary at each visit for use until the next visit. Rescue medication (albuterol/salbutamol) was dispensed at each visit, if needed, as determined by the investigational center personnel.
Interventions
DRUGAlbuterol/salmeterol HFA MDI
Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
DRUGFS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate 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 either fluticasone propionate/salmeterol MDPI 200/12.5 mcg or fluticasone propionate/salmeterol MDPI 100/12.5 mcg twice a day for a total daily dose of 200/25 mcg or 400/25 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
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 either 200 mcg or 100 mcg of Fp one inhalation twice a day for a total daily dose of 400 mcg or 200 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
DRUGPlacebo MDPI
The placebo multidose dry powder inhaler (MDPI) was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart). Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
Sponsors
Teva Branded Pharmaceutical Products R&D, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Best pre-bronchodilator forced expiratory volume in 1 second (FEV1) of 40 to 85% of their predicted normal value. 2. Current Asthma Therapy: Patients must have a short-acting β2-agonist (for rescue use) for a minimum of 8 weeks before the Screening Visit (SV) and a qualifying dose of an inhaled corticosteroid (ICS). The ICS may be either as ICS monotherapy or as an ICS/long-acting beta agonist (LABA) combination. The ICS component of the patient's asthma therapy should be stable for a minimum of 1 month before providing consent. 3. Reversibility of Disease: Patients must have at least 15% reversibility (all patients) and at least a 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol at the SV. Note: Patients who do not qualify for the study due to failure to meet reversibility will be permitted to perform a retest once within 7 days. 4. Patients must provide written informed consent/assent.. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written assent form must be signed and dated by the patient (if applicable). Note: Age requirements are as specified by local regulations. 5. Outpatient \>= 12 years of age on the date of consent/assent. In countries where the local regulations permit enrollment of adult patients only, patients must be 18 years of age and older. 6. Asthma diagnosis: The patient has a diagnosis of asthma as defined by the National Institute of Health (NIH). The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in asthma medication) for at least 30 days. 7. The patient is able to perform acceptable and repeatable spirometry. 8. The patient is able to perform peak expiratory flow (PEF) with a handheld peak flow meter. 9. The patient is able to use a metered dose inhaler (MDI) device without a spacer device and a multidose dry powder inhaler (MDPI) device. 10. The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before the screening visit (SV) and before all treatment visits. 11. The patient/parent/legal guardian/caregiver is 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. 12. SABAs: All patients must be able to replace their current SABA with albuterol/salbutamol HFA MDI inhalation aerosol for the duration of the study. 13. Female patients may not be pregnant, breastfeeding, or attempting to become pregnant. * other criteria may apply, please contact the investigator for more information
Exclusion criteria
1. A history of a life-threatening asthma exacerbation (an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, or hypoxic seizures). 2. The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the study. 3. The patient has participated as a randomized patient in any investigational drug study within 30 days of the SV. 4. The patient has previously participated as a randomized patient in a study of Fp MDPI or FS MDPI. 5. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the study drug or rescue medication formulation (ie, lactose). 6. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, or clarithromycin) within 30 days before the SV. 7. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before the SV. 8. The patient currently smokes or has a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient must not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco). 9. The patient has a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV. 10. The patient has a history of alcohol or drug abuse within 2 years preceding the SV. 11. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV, or has had any hospitalization for asthma within 2 months before the SV. 12. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients on stable immunotherapy may be considered for inclusion. 13. The patient has used immunosuppressive medications within 4 weeks before the SV. 14. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications. 15. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study. 16. The patient has a history of a positive test for human immunodeficiency virus (HIV), active hepatitis B virus, or hepatitis C infection. 17. The patient is either an employee or an immediate relative of an employee of the clinical investigational center. 18. A member of the patient's household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened. 19. The patient has a disease/condition that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study. * other criteria may apply, please contact the investigator for more information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours | A subset of patients performed postdose serial spirometry. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value. |
| Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | Day 1 (predose, baseline), Week 12 | Trough FEV1 is a morning spirometry taken predose and pre-rescue bronchodilator. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | Days -6 to Day 1 (predose, baseline), up to week 12 | Patients recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each AM and PM in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value. The weekly average was based on the available data for the 7 days before each analysis week. The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using a mixed model for repeated measures. |
| Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | up to Week 12 of the Treatment Period | The analysis of probability of remaining in the study at Week 12 used the time to patient withdrawal for worsening asthma, defined as the number of days elapsed from the date of randomization to the date of withdrawal due to worsening asthma. Patients who were lost to follow-up, who had not withdrawn due to worsening asthma by week 12, or who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment. |
| Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | Days -6 to Day 1 (predose, baseline), Day 1 (postdose) daily until Week 12 | Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week. |
| Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | Day 1 of the Treatment Period (predose and postdose) | The baseline forced expiratory volume in 1 second (FEV1) was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, the baseline trough FEV1 was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of NA indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%. |
| Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | Day 1 to Week 12 of 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. Relation 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. |
| Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | Day 1 (predose, baseline), end of trial (up to week 12) | The AQLQ(S) (September 2010 version; patients aged ≥18 years) was self administered by the patients at the investigational center at the randomization visit and at Week 12 or end of trial. The questionnaire is a tool to measure the impact of asthma on a patient's quality of life (physical, emotional, social, and occupational) with a recall period of 2 weeks. The AQLQ(S) was administered only to patients 18 years and older. The 32 individual questions in the AQLQ were equally weighted. The overall AQLQ score was the mean of the responses to each of the 32 questions, and ranged from 1 to 7. A score 7.0 indicated that the patient had no impairments due to asthma and a score of 1.0 indicated severe impairment. Positive change from baseline scores indicate improved quality of life. |
| Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | Days -6 to Day 1 (predose, baseline), to Week 12 | The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary. Daytime Symptom Score: * 0=No symptoms * 1=Symptoms for 1 short period * 2=Symptoms for 2+ short periods * 3=Symptoms for most of the day - did not affect normal daily activities * 4=Symptoms for most of the day - did affect normal daily activities * 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): * 0=No symptoms * 1=Symptoms causing me to wake once (or wake early) * 2=Symptoms causing me to wake twice or more (including waking early) * 3=Symptoms causing me to be awake for most of the night * 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM). |
Countries
Canada, Czechia, Hungary, Poland, Russia, South Africa, Thailand, Ukraine, United States
Participant flow
Pre-assignment details
A total of 1661 patients with persistent asthma were screened and 882 patients enrolled. 154 patients were not randomized, most commonly (76 patients) because of not meeting randomization criteria.
Participants by arm
| Arm | Count |
|---|---|
| FS MDPI 200 / 12.5 mcg Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.
Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. | 146 |
| FS MDPI 100 / 12.5 mcg Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.
Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. | 145 |
| Fp MDPI 200 mcg Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks.
Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. | 146 |
| Fp MDPI 100 mcg Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks.
Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. | 146 |
| Placebo MDPI Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks.
Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. | 145 |
| Total | 728 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Run-In Period (Pre-assignment) | Adverse Event | 10 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Exclusion criteria met | 14 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Inclusion criteria not met | 25 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Lost to Follow-up | 6 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Other | 14 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Randomization criteria not met | 76 | 0 | 0 | 0 | 0 | 0 |
| Run-In Period (Pre-assignment) | Withdrawal by Subject | 9 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period | Adverse Event | 0 | 2 | 2 | 0 | 2 | 2 |
| Treatment Period | Disease progression | 0 | 2 | 1 | 3 | 0 | 18 |
| Treatment Period | Lack of Efficacy | 0 | 0 | 0 | 1 | 1 | 7 |
| Treatment Period | Lost to Follow-up | 0 | 1 | 1 | 1 | 0 | 1 |
| Treatment Period | Noncompliance | 0 | 0 | 0 | 1 | 0 | 0 |
| Treatment Period | Other | 0 | 1 | 2 | 0 | 1 | 2 |
| Treatment Period | Pregnancy | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period | Protocol Violation | 0 | 1 | 0 | 2 | 2 | 1 |
| Treatment Period | Withdrawal by Subject | 0 | 2 | 3 | 3 | 4 | 7 |
Baseline characteristics
| Characteristic | FS MDPI 100 / 12.5 mcg | Fp MDPI 200 mcg | Fp MDPI 100 mcg | FS MDPI 200 / 12.5 mcg | Placebo MDPI | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 44.3 years STANDARD_DEVIATION 14.88 | 44.4 years STANDARD_DEVIATION 16.36 | 45.7 years STANDARD_DEVIATION 15.64 | 44.7 years STANDARD_DEVIATION 16.93 | 44.5 years STANDARD_DEVIATION 16.05 | 44.7 years STANDARD_DEVIATION 15.95 |
| Age, Customized Adolescents (12-17 years) | 8 Participants | 10 Participants | 9 Participants | 12 Participants | 6 Participants | 45 Participants |
| Age, Customized Adults (18-64 years) | 125 Participants | 119 Participants | 124 Participants | 115 Participants | 125 Participants | 608 Participants |
| Age, Customized Adults (65-84 years) | 12 Participants | 17 Participants | 13 Participants | 19 Participants | 14 Participants | 75 Participants |
| Body Mass Index | 30.2 kg/m^2 STANDARD_DEVIATION 7.6 | 29.9 kg/m^2 STANDARD_DEVIATION 7.27 | 29.9 kg/m^2 STANDARD_DEVIATION 7.62 | 29.4 kg/m^2 STANDARD_DEVIATION 7.35 | 29.3 kg/m^2 STANDARD_DEVIATION 7.41 | 29.7 kg/m^2 STANDARD_DEVIATION 7.44 |
| Forced Expiratory Volume in 1 second (FEV1) | 2.157 liters STANDARD_DEVIATION 0.6402 | 2.075 liters STANDARD_DEVIATION 0.5696 | 2.069 liters STANDARD_DEVIATION 0.6017 | 2.083 liters STANDARD_DEVIATION 0.6532 | 2.141 liters STANDARD_DEVIATION 0.6849 | 2.105 liters STANDARD_DEVIATION 0.6303 |
| History of Smoking No tobacco use | 117 Participants | 125 Participants | 118 Participants | 126 Participants | 122 Participants | 608 Participants |
| History of Smoking Prior Smoker | 28 Participants | 21 Participants | 28 Participants | 20 Participants | 23 Participants | 120 Participants |
| Previous Asthma Therapy Inhaled corticosteroid | 67 Participants | 63 Participants | 58 Participants | 73 Participants | 68 Participants | 329 Participants |
| Previous Asthma Therapy Inhaled corticosteroid/long-acting beta2-agonist | 78 Participants | 83 Participants | 88 Participants | 73 Participants | 77 Participants | 399 Participants |
| Race/Ethnicity, Customized American Indian or Alaskan Native | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 28 Participants | 23 Participants | 31 Participants | 20 Participants | 18 Participants | 120 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 10 Participants | 10 Participants | 11 Participants | 10 Participants | 8 Participants | 49 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 135 Participants | 136 Participants | 134 Participants | 136 Participants | 136 Participants | 677 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 3 Participants | 4 Participants | 1 Participants | 1 Participants | 14 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 112 Participants | 116 Participants | 111 Participants | 125 Participants | 124 Participants | 588 Participants |
| Sex: Female, Male Female | 79 Participants | 88 Participants | 94 Participants | 87 Participants | 91 Participants | 439 Participants |
| Sex: Female, Male Male | 66 Participants | 58 Participants | 52 Participants | 59 Participants | 54 Participants | 289 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 21 / 143 | 20 / 145 | 26 / 145 | 20 / 146 | 20 / 144 |
| serious Total, serious adverse events | 2 / 143 | 2 / 145 | 1 / 145 | 1 / 146 | 1 / 144 |
Outcome results
Primary
Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
Trough FEV1 is a morning spirometry taken predose and pre-rescue bronchodilator. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).
Time frame: Day 1 (predose, baseline), Week 12
Population: If the patient inadvertently administered asthma medication/study drug at home on the AM of the visit, or if the patient took rescue medication within 6 hours of testing, the visit was rescheduled.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.272 liters | Standard Error 0.0307 |
| FS MDPI 100 / 12.5 mcg | Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.271 liters | Standard Error 0.0311 |
| Fp MDPI 200 mcg | Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.179 liters | Standard Error 0.0308 |
| Fp MDPI 100 mcg | Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | 0.119 liters | Standard Error 0.0311 |
| Placebo MDPI | Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 | -0.004 liters | Standard Error 0.0312 |
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fifth in the sequence.p-value: 095% CI: [0.191, 0.361]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the sixth in the sequence.p-value: 095% CI: [0.189, 0.36]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the seventh in the sequence.p-value: 095% CI: [0.098, 0.268]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the eighth in the sequence.p-value: 0.004795% CI: [0.038, 0.208]ANCOVA
Primary
Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12
A subset of patients performed postdose serial spirometry. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.
Time frame: Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours
Population: A subset of patients who performed postdose serial spirometry at the baseline visit and week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | 0.446 liters | Standard Error 0.0463 |
| FS MDPI 100 / 12.5 mcg | Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | 0.442 liters | Standard Error 0.0496 |
| Fp MDPI 200 mcg | Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | 0.267 liters | Standard Error 0.0466 |
| Fp MDPI 100 mcg | Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | 0.260 liters | Standard Error 0.0463 |
| Placebo MDPI | Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours PostDose (FEV1 AUEC0-12) at Week 12 | 0.121 liters | Standard Error 0.0472 |
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the first in the sequence.p-value: 0.000995% CI: [0.074, 0.285]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the second in the sequence.p-value: 0.00195% CI: [0.074, 0.291]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the third in the sequence.p-value: 095% CI: [0.221, 0.431]ANCOVA
Comparison: A fixed-sequence multiple testing procedure was used to control the overall Type I error rate at the 0.05 level (2-sided) for the primary endpoints analyses. Analyses appear in the defined sequence. This is the fourth in the sequence.p-value: 095% CI: [0.212, 0.432]ANCOVA
Secondary
Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old
The AQLQ(S) (September 2010 version; patients aged ≥18 years) was self administered by the patients at the investigational center at the randomization visit and at Week 12 or end of trial. The questionnaire is a tool to measure the impact of asthma on a patient's quality of life (physical, emotional, social, and occupational) with a recall period of 2 weeks. The AQLQ(S) was administered only to patients 18 years and older. The 32 individual questions in the AQLQ were equally weighted. The overall AQLQ score was the mean of the responses to each of the 32 questions, and ranged from 1 to 7. A score 7.0 indicated that the patient had no impairments due to asthma and a score of 1.0 indicated severe impairment. Positive change from baseline scores indicate improved quality of life.
Time frame: Day 1 (predose, baseline), end of trial (up to week 12)
Population: Full analysis set of participants who contributed at least once to analysis and were \>= 18 years old
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | 0.534 units on a scale | Standard Error 0.0741 |
| FS MDPI 100 / 12.5 mcg | Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | 0.592 units on a scale | Standard Error 0.0725 |
| Fp MDPI 200 mcg | Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | 0.384 units on a scale | Standard Error 0.0742 |
| Fp MDPI 100 mcg | Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | 0.340 units on a scale | Standard Error 0.074 |
| Placebo MDPI | Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old | -0.089 units on a scale | Standard Error 0.0747 |
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 095% CI: [0.269, 0.677]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 095% CI: [0.224, 0.632]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 095% CI: [0.418, 0.828]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 095% CI: [0.478, 0.885]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 0.14995% CI: [-0.054, 0.354]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 0.014395% CI: [0.051, 0.455]ANCOVA
Comparison: The change from baseline in AQLQ(S) score (patients ≥18 years of age) at endpoint (ie, last postbaseline observation) was analyzed using an ANCOVA model with effects due to baseline AQLQ(S) score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment, imputing missing data via last observation carried forward (LOCF).p-value: 0.043595% CI: [0.006, 0.411]ANCOVA
Secondary
Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment
Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week.
Time frame: Days -6 to Day 1 (predose, baseline), Day 1 (postdose) daily until Week 12
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | 20.235 liters/minute | Standard Error 2.3845 |
| FS MDPI 100 / 12.5 mcg | Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | 18.610 liters/minute | Standard Error 2.4137 |
| Fp MDPI 200 mcg | Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | 7.464 liters/minute | Standard Error 2.3887 |
| Fp MDPI 100 mcg | Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | 5.731 liters/minute | Standard Error 2.4102 |
| Placebo MDPI | Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment | -10.987 liters/minute | Standard Error 2.4784 |
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [11.751, 25.15]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [9.988, 23.449]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [24.513, 37.93]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [22.839, 36.354]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.000295% CI: [6.179, 19.363]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.000295% CI: [6.216, 19.541]mixed model for repeated measures
Comparison: The analysis of change from baseline in weekly average of daily (AM predose and pre rescue bronchodilator) PEF over the 12-week treatment period was performed using an mixed model for repeated measures (MMRM) with an unstructured covariance matrix and with effects due to baseline weekly average of daily AM PEF, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.00195% CI: [4.511, 17.782]mixed model for repeated measures
Secondary
Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period
Patients recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each AM and PM in the diary. The average number of daily inhalations over the 7 days before the randomization visit was the baseline value. The weekly average was based on the available data for the 7 days before each analysis week. The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using a mixed model for repeated measures.
Time frame: Days -6 to Day 1 (predose, baseline), up to week 12
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | -0.898 puffs | Standard Error 0.1069 |
| FS MDPI 100 / 12.5 mcg | Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | -0.821 puffs | Standard Error 0.108 |
| Fp MDPI 200 mcg | Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | -0.534 puffs | Standard Error 0.107 |
| Fp MDPI 100 mcg | Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | -0.439 puffs | Standard Error 0.1081 |
| Placebo MDPI | Change From Baseline in the Weekly Average of the Total Daily (24-hour) Use of Albuterol/Salbutamol Inhalation Aerosol Over the 12-Week Treatment Period | 0.168 puffs | Standard Error 0.1102 |
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-1.001, -0.403]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.000195% CI: [-0.908, -0.307]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-1.365, -0.766]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-1.291, -0.686]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.01695% CI: [-0.659, -0.068]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.012495% CI: [-0.681, -0.083]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of total daily (24-hour) use of albuterol/ salbutamol inhalation aerosol (number of inhalations) over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline value, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.058895% CI: [-0.584, 0.011]Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period
The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary. Daytime Symptom Score: * 0=No symptoms * 1=Symptoms for 1 short period * 2=Symptoms for 2+ short periods * 3=Symptoms for most of the day - did not affect normal daily activities * 4=Symptoms for most of the day - did affect normal daily activities * 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): * 0=No symptoms * 1=Symptoms causing me to wake once (or wake early) * 2=Symptoms causing me to wake twice or more (including waking early) * 3=Symptoms causing me to be awake for most of the night * 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).
Time frame: Days -6 to Day 1 (predose, baseline), to Week 12
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | -0.391 units on a scale | Standard Error 0.0328 |
| FS MDPI 100 / 12.5 mcg | Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | -0.364 units on a scale | Standard Error 0.0332 |
| Fp MDPI 200 mcg | Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | -0.242 units on a scale | Standard Error 0.0329 |
| Fp MDPI 100 mcg | Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | -0.282 units on a scale | Standard Error 0.0333 |
| Placebo MDPI | Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period | -0.087 units on a scale | Standard Error 0.0342 |
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.00195% CI: [-0.248, -0.063]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-0.288, -0.102]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-0.397, -0.212]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 095% CI: [-0.37, -0.184]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.001495% CI: [-0.239, -0.058]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.081895% CI: [-0.174, 0.01]mixed model for repeated measures
Comparison: The change from baseline in the weekly average of the total daily asthma symptom scores over weeks 1 to 12 was analyzed using an MMRM with an unstructured covariance matrix and with effects due to baseline score, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), week, treatment, and week-by-treatment interaction.p-value: 0.009495% CI: [-0.213, -0.03]mixed model for repeated measures
Secondary
Kaplan-Meier Estimate of Probability of Remaining in 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, defined as the number of days elapsed from the date of randomization to the date of withdrawal due to worsening asthma. Patients who were lost to follow-up, who had not withdrawn due to worsening asthma by week 12, or who had withdrawn due to reasons other than worsening asthma were right-censored at the date of last assessment.
Time frame: up to Week 12 of the Treatment Period
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FS MDPI 200 / 12.5 mcg | Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | 0.9719 probability |
| FS MDPI 100 / 12.5 mcg | Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | 0.9929 probability |
| Fp MDPI 200 mcg | Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | 0.9786 probability |
| Fp MDPI 100 mcg | Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | 0.9930 probability |
| Placebo MDPI | Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12 | 0.8528 probability |
p-value: 0.0001Log Rank
p-value: <0.0001Log Rank
p-value: 0.0003Log Rank
p-value: <0.0001Log Rank
p-value: 0.7203Log Rank
p-value: 0.996Log Rank
p-value: 0.325Log Rank
Secondary
Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1
The baseline forced expiratory volume in 1 second (FEV1) was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, the baseline trough FEV1 was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of NA indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.
Time frame: Day 1 of the Treatment Period (predose and postdose)
Population: Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 15% improvement | 0.8 hours |
| FS MDPI 200 / 12.5 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 12% improvement | 0.4 hours |
| FS MDPI 100 / 12.5 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 15% improvement | 0.9 hours |
| FS MDPI 100 / 12.5 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 12% improvement | 0.4 hours |
| Fp MDPI 200 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 15% improvement | NA hours |
| Fp MDPI 200 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 12% improvement | 6.9 hours |
| Fp MDPI 100 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 12% improvement | NA hours |
| Fp MDPI 100 mcg | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 15% improvement | NA hours |
| Placebo MDPI | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 15% improvement | NA hours |
| Placebo MDPI | Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1 | 12% improvement | NA hours |
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. Relation 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 of the Treatment Period
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE resulting in death | 0 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 nonserious TEAE | 61 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe TEAE | 3 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 serious TEAE | 2 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe treatment-related TEAE | 1 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 treatment-related TEAE | 8 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE leading to withdrawal | 2 Participants |
| FS MDPI 200 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE | 61 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 serious TEAE | 2 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE | 59 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE leading to withdrawal | 2 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe TEAE | 2 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 nonserious TEAE | 58 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE resulting in death | 1 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 treatment-related TEAE | 4 Participants |
| FS MDPI 100 / 12.5 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe treatment-related TEAE | 0 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 serious TEAE | 1 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE resulting in death | 0 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE leading to withdrawal | 0 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe TEAE | 0 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe treatment-related TEAE | 0 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 nonserious TEAE | 60 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE | 60 Participants |
| Fp MDPI 200 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 treatment-related TEAE | 9 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe treatment-related TEAE | 0 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 serious TEAE | 1 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE leading to withdrawal | 2 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE | 53 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 treatment-related TEAE | 6 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE resulting in death | 0 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe TEAE | 1 Participants |
| Fp MDPI 100 mcg | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 nonserious TEAE | 52 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE leading to withdrawal | 2 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 nonserious TEAE | 52 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE resulting in death | 0 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe TEAE | 1 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 serious TEAE | 1 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 severe treatment-related TEAE | 0 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 treatment-related TEAE | 5 Participants |
| Placebo MDPI | Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period | >=1 TEAE | 52 Participants |