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Study of Fluticasone Propionate MDPI Compared With Fluticasone/Salmeterol MDPI in Adolescent and Adult Patients With Persistent Asthma

Sponsor
Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02139644
Collaborator
(none)
787
Enrollment
140
Locations
5
Arms
15
Duration (Months)
5.6
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study was to evaluate the efficacy of fluticasone propionate multidose dry powder inhaler (Fp MDPI) and fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) when administered over 12 weeks in patients 12 years of age and older with persistent asthma.

Study drug and placebo was 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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
787 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A 12-Week, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone/Salmeterol Multidose Dry Powder Inhaler in Adolescent and Adult Patients With Persistent Asthma Symptomatic Despite Low-dose or or Mid-dose Inhaled Corticosteroid Therapy
Study Start Date :
Jun 1, 2014
Actual Primary Completion Date :
Sep 1, 2015
Actual Study Completion Date :
Sep 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: FS MDPI 100 / 12.5 mcg

Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.

Drug: FS MDPI
FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) and salmeterol xinafoate (Sx) 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 100/12.5 mcg Fp/Sx or 50/12.5 mcg Fp/Sx in the morning and evening for a total daily dose of 200/25 mcg or 100/25 mcg Fp/Sx. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • salmeterol xinafoate
  • β2 adrenoceptor agonist

    • Drug: albuterol/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).
    Other Names:
  • short-acting β2-adrenergic agonists

    • Drug: Beclomethasone dipropionate
    QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.
    Other Names:
  • QVAR

    		•
    Experimental: FS MDPI 50 / 12.5 mcg

    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.

    Drug: FS MDPI
    FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) and salmeterol xinafoate (Sx) 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 100/12.5 mcg Fp/Sx or 50/12.5 mcg Fp/Sx in the morning and evening for a total daily dose of 200/25 mcg or 100/25 mcg Fp/Sx. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
    Other Names:
  • fluticasone propionate
  • inhaled corticosteroid
  • salmeterol xinafoate
  • β2 adrenoceptor agonist

    • Drug: albuterol/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).
    Other Names:
  • short-acting β2-adrenergic agonists

    • Drug: Beclomethasone dipropionate
    QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.
    Other Names:
  • QVAR

    		•
    Experimental: Fp MDPI 100 mcg

    Patients 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 for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.

    Drug: Fp MDPI
    Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate 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 100 mcg or 50 mcg of Fp one inhalation twice a day for a total daily dose of 200 mcg or 100 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
    Other Names:
  • fluticasone propionate
  • inhaled corticosteroid

    • Drug: albuterol/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).
    Other Names:
  • short-acting β2-adrenergic agonists

    • Drug: Beclomethasone dipropionate
    QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.
    Other Names:
  • QVAR

    		•
    Experimental: Fp MDPI 50 mcg

    Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.

    Drug: Fp MDPI
    Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate 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 100 mcg or 50 mcg of Fp one inhalation twice a day for a total daily dose of 200 mcg or 100 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.
    Other Names:
  • fluticasone propionate
  • inhaled corticosteroid

    • Drug: albuterol/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).
    Other Names:
  • short-acting β2-adrenergic agonists

    • Drug: Beclomethasone dipropionate
    QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.
    Other Names:
  • QVAR

    		•
    Placebo Comparator: Placebo MDPI

    The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.

    Drug: Placebo MDPI
    Placebo administered via a multidose dry powder inhaler (MDPI) one puff in the morning and one puff in the evening for 12 weeks.
    Other Names:
  • inert powder

    • Drug: albuterol/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).
    Other Names:
  • short-acting β2-adrenergic agonists

    • Drug: Beclomethasone dipropionate
    QVAR (beclomethasone dipropionate) 40 mcg inhalation aerosol is a pressurized MDI that contains a Food and Drug Administration (FDA)-approved formulation of beclomethasone dipropionate. Patients took 1 puff twice a day from open-label QVAR 40 mcg hydrofluoroalkane (specifically, HFA-134a) metered-dose inhaler (MDI) for the duration of the Run-in Period (14-21 days) and prior to randomization. A clinically equivalent dose of inhaled corticosteroid (ICS) was substituted in countries where QVAR 40 mcg was not available.
    Other Names:
  • QVAR

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours Postdose (FEV1 AUEC0-12h) 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 approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. 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.

    2. Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12 [Day 1 (predose, baseline), Week 12]

      Trough FEV1 was a morning spirometry taken predose and pre-rescue bronchodilator. 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. 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 Outcome Measures

    1. 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), 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.

    2. 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 (range 0-9). Daytime Symptom Score: 0=No symptoms Symptoms for 1 short period Symptoms for 2+ short periods Symptoms for most of the day - did not affect normal daily activities Symptoms for most of the day - did affect normal daily activities 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 Symptoms causing me to wake once (or wake early) Symptoms causing me to wake twice or more (including waking early) Symptoms causing me to be awake for most of the night 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).

    3. 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.

    4. 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.

    5. 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 of 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.

    6. 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)]

      A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Baseline FEV1 was the average of 2 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, baseline 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 9999 indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.

    7. 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. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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 low-dose inhaled corticosteroid (ICS). The low-dose 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 months 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 Institutes 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 MDI device without a spacer device and a 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 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 hypercapnea, 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Teva Investigational Site 12397 Birmingham Alabama United States
    2 Teva Investigational Site 12375 Glendale Arizona United States
    3 Teva Investigational Site 12395 Cypress California United States
    4 Teva Investigational Site 12476 Encinitas California United States
    5 Teva Investigational Site 12586 Fountain Valley California United States
    6 Teva Investigational Site 12591 Fresno California United States
    7 Teva Investigational Site 12372 Huntington Beach California United States
    8 Teva Investigational Site 12365 Los Angeles California United States
    9 Teva Investigational Site 12381 Los Angeles California United States
    10 Teva Investigational Site 12401 Los Angeles California United States
    11 Teva Investigational Site 12394 Mission Viejo California United States
    12 Teva Investigational Site 12490 Rancho Mirage California United States
    13 Teva Investigational Site 12393 Riverside California United States
    14 Teva Investigational Site 12366 Rolling Hills Estates California United States
    15 Teva Investigational Site 12383 San Diego California United States
    16 Teva Investigational Site 12370 San Jose California United States
    17 Teva Investigational Site 12371 Stockton California United States
    18 Teva Investigational Site 12579 Upland California United States
    19 Teva Investigational Site 12379 Centennial Colorado United States
    20 Teva Investigational Site 12386 Centennial Colorado United States
    21 Teva Investigational Site 12596 Colorado Springs Colorado United States
    22 Teva Investigational Site 12584 Longmont Colorado United States
    23 Teva Investigational Site 12484 Waterbury Connecticut United States
    24 Teva Investigational Site 12590 Waterbury Connecticut United States
    25 Teva Investigational Site 12493 Clearwater Florida United States
    26 Teva Investigational Site 12992 Largo Florida United States
    27 Teva Investigational Site 12376 Miami Florida United States
    28 Teva Investigational Site 12390 Miami Florida United States
    29 Teva Investigational Site 12583 Orlando Florida United States
    30 Teva Investigational Site 12481 Tallahassee Florida United States
    31 Teva Investigational Site 12491 Winter Park Florida United States
    32 Teva Investigational Site 12997 Decatur Georgia United States
    33 Teva Investigational Site 12392 Savannah Georgia United States
    34 Teva Investigational Site 12592 Shiloh Illinois United States
    35 Teva Investigational Site 12483 Lenexa Kansas United States
    36 Teva Investigational Site 12399 Baltimore Maryland United States
    37 Teva Investigational Site 12391 Bethesda Maryland United States
    38 Teva Investigational Site 12589 Columbia Maryland United States
    39 Teva Investigational Site 12369 Rockville Maryland United States
    40 Teva Investigational Site 12396 Fall River Massachusetts United States
    41 Teva Investigational Site 12384 North Dartmouth Massachusetts United States
    42 Teva Investigational Site 12585 North Dartmouth Massachusetts United States
    43 Teva Investigational Site 12588 Ypsilanti Michigan United States
    44 Teva Investigational Site 12494 Saint Louis Missouri United States
    45 Teva Investigational Site 12595 Saint Louis Missouri United States
    46 Teva Investigational Site 12594 Missoula Montana United States
    47 Teva Investigational Site 12385 Ocean City New Jersey United States
    48 Teva Investigational Site 12380 Skillman New Jersey United States
    49 Teva Investigational Site 12587 Brooklyn New York United States
    50 Teva Investigational Site 12485 Rockville Centre New York United States
    51 Teva Investigational Site 12475 Huntersville North Carolina United States
    52 Teva Investigational Site 12364 Raleigh North Carolina United States
    53 Teva Investigational Site 12374 Canton Ohio United States
    54 Teva Investigational Site 12480 Cincinnati Ohio United States
    55 Teva Investigational Site 12492 Cincinnati Ohio United States
    56 Teva Investigational Site 12487 Middleburg Heights Ohio United States
    57 Teva Investigational Site 12488 Sylvania Ohio United States
    58 Teva Investigational Site 12377 Edmond Oklahoma United States
    59 Teva Investigational Site 12368 Medford Oregon United States
    60 Teva Investigational Site 12382 Portland Oregon United States
    61 Teva Investigational Site 12400 Pittsburgh Pennsylvania United States
    62 Teva Investigational Site 12473 Upland Pennsylvania United States
    63 Teva Investigational Site 12389 Greenville South Carolina United States
    64 Teva Investigational Site 12580 Mount Pleasant South Carolina United States
    65 Teva Investigational Site 12398 Orangeburg South Carolina United States
    66 Teva Investigational Site 12991 Knoxville Tennessee United States
    67 Teva Investigational Site 12990 Cypress Texas United States
    68 Teva Investigational Site 12373 Dallas Texas United States
    69 Teva Investigational Site 12402 El Paso Texas United States
    70 Teva Investigational Site 12582 New Braunfels Texas United States
    71 Teva Investigational Site 12363 San Antonio Texas United States
    72 Teva Investigational Site 12482 San Antonio Texas United States
    73 Teva Investigational Site 12477 Waco Texas United States
    74 Teva Investigational Site 12478 Murray Utah United States
    75 Teva Investigational Site 12388 South Burlington Vermont United States
    76 Teva Investigational Site 12378 Milwaukee Wisconsin United States
    77 Teva Investigational Site 11065 Toronto Ontario Canada
    78 Teva Investigational Site 11067 Montreal Quebec Canada
    79 Teva Investigational Site 11068 Vancouver Quebec Canada
    80 Teva Investigational Site 54084 Neratovice Czechia
    81 Teva Investigational Site 54088 Praha Czechia
    82 Teva Investigational Site 54087 Rokycany Czechia
    83 Teva Investigational Site 51134 Budapest Hungary
    84 Teva Investigational Site 51143 Budapest Hungary
    85 Teva Investigational Site 51144 Budapest Hungary
    86 Teva Investigational Site 51140 Debrecen Hungary
    87 Teva Investigational Site 51142 Deszk Hungary
    88 Teva Investigational Site 51165 Dombovar Hungary
    89 Teva Investigational Site 51145 Kiskunhalas Hungary
    90 Teva Investigational Site 51141 Miskolc Hungary
    91 Teva Investigational Site 51133 Mosdós Hungary
    92 Teva Investigational Site 51136 Nyíregyháza Hungary
    93 Teva Investigational Site 51139 Nyíregyháza Hungary
    94 Teva Investigational Site 51163 Sopron Hungary
    95 Teva Investigational Site 51137 Szeged Hungary
    96 Teva Investigational Site 51164 Szigetvár Hungary
    97 Teva Investigational Site 51138 Szombathely Hungary
    98 Teva Investigational Site 53182 Bialystok Poland
    99 Teva Investigational Site 53183 Bialystok Poland
    100 Teva Investigational Site 53185 Bialystok Poland
    101 Teva Investigational Site 53191 Bialystok Poland
    102 Teva Investigational Site 53187 Bienkówka Poland
    103 Teva Investigational Site 53219 Bydgoszcz Poland
    104 Teva Investigational Site 53217 Debica Poland
    105 Teva Investigational Site 53188 Krakow Poland
    106 Teva Investigational Site 53178 Kraków Poland
    107 Teva Investigational Site 53180 Kraków Poland
    108 Teva Investigational Site 53220 Lodz Poland
    109 Teva Investigational Site 53235 Lodz Poland
    110 Teva Investigational Site 53237 Lublin Poland
    111 Teva Investigational Site 53221 Lódz Poland
    112 Teva Investigational Site 53194 Poznan Poland
    113 Teva Investigational Site 53234 Poznan Poland
    114 Teva Investigational Site 53233 Strzelce Opolskie Poland
    115 Teva Investigational Site 53179 Tarnów Poland
    116 Teva Investigational Site 53218 Tarnów Poland
    117 Teva Investigational Site 53193 Warszawa Poland
    118 Teva Investigational Site 53181 Wroclaw Poland
    119 Teva Investigational Site 53189 Wroclaw Poland
    120 Teva Investigational Site 50236 Chelyabinsk Russian Federation
    121 Teva Investigational Site 50226 Ekaterinburg Russian Federation
    122 Teva Investigational Site 50227 Kazan Russian Federation
    123 Teva Investigational Site 50234 Moscow Russian Federation
    124 Teva Investigational Site 50238 Moscow Russian Federation
    125 Teva Investigational Site 50230 Novosibirsk Russian Federation
    126 Teva Investigational Site 50231 Saint Petersburg Russian Federation
    127 Teva Investigational Site 50224 St. Petersburg Russian Federation
    128 Teva Investigational Site 50233 Voronezh Russian Federation
    129 Teva Investigational Site 50237 Yaroslavl Russian Federation
    130 Teva Investigational Site 90002 Cape Town South Africa
    131 Teva Investigational Site 90008 Cape Town South Africa
    132 Teva Investigational Site 90005 Centurion South Africa
    133 Teva Investigational Site 90001 Johannesburg South Africa
    134 Teva Investigational Site 90003 Middelburg South Africa
    135 Teva Investigational Site 90007 Pretoria South Africa
    136 Teva Investigational Site 58125 Kharkiv Ukraine
    137 Teva Investigational Site 58126 Kharkiv Ukraine
    138 Teva Investigational Site 58127 Kyiv Ukraine
    139 Teva Investigational Site 58128 Kyiv Ukraine
    140 Teva Investigational Site 58129 Vinnytsya Ukraine

    Sponsors and Collaborators

    • Teva Branded Pharmaceutical Products R&D, Inc.

    Investigators

    • Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Teva Branded Pharmaceutical Products R&D, Inc.
    ClinicalTrials.gov Identifier:
    NCT02139644
    Other Study ID Numbers:
    • FSS-AS-301
    • 2014-001149-25
    First Posted:
    May 15, 2014
    Last Update Posted:
    Nov 12, 2021
    Last Verified:
    Nov 1, 2021
    Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.
    fluticasone propionate
    multidose dry powder inhaler
    Additional relevant MeSH terms:
    Asthma
    Fluticasone
    Xhance
    Beclomethasone
    Albuterol
    Salmeterol Xinafoate
    Adrenergic Agonists

    Study Results

    Participant Flow

    Recruitment Details A total of 1363 patients with persistent asthma were screened for enrollment into this study. 787 patients at 129 investigational centers in the US and elsewhere internationally met entry criteria and were considered eligible for enrollment into the study.
    Pre-assignment Detail Patients were randomized 1:1:1:1:1 to one of the five treatment arms during the Treatment Period.
    Arm/Group Title Enrolled Patients FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description During the run-in period (from the screening visit to the randomization visit), all patients replaced their current rescue medication with study-specific rescue medication (albuterol/salbutamol HFA MDI) for use on an as-needed basis for the immediate relief of asthma symptoms throughout the period. All patients discontinued their current ICS or ICS/LABA, and took 1 inhalation twice a day from a single-blinded placebo MDPI device and 1 puff twice a day from open-label QVAR 40 mcg HFA MDI (or equivalent). Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Period Title: Run-In Period (Pre-assignment)
    STARTED 787 0 0 0 0 0
    COMPLETED 647 0 0 0 0 0
    NOT COMPLETED 140 0 0 0 0 0
    Period Title: Run-In Period (Pre-assignment)
    STARTED 0 129 129 130 129 130
    COMPLETED 0 126 121 121 121 113
    NOT COMPLETED 0 3 8 9 8 17

    Baseline Characteristics

    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI Total
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Total of all reporting groups
    Overall Participants 129 129 130 129 130 647
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    41.0
    (17.00)
    41.4
    (18.61)
    40.6
    (17.16)
    43.3
    (17.96)
    40.9
    (17.35)
    41.5
    (17.60)
    Age, Customized (Count of Participants)
    Adolescents (12-17 years)
    19
    14.7%
    19
    14.7%
    18
    13.8%
    13
    10.1%
    17
    13.1%
    86
    13.3%
    Adults (18-64 years)
    100
    77.5%
    97
    75.2%
    102
    78.5%
    93
    72.1%
    102
    78.5%
    494
    76.4%
    Adults (65+ years)
    10
    7.8%
    13
    10.1%
    10
    7.7%
    23
    17.8%
    11
    8.5%
    67
    10.4%
    Sex: Female, Male (Count of Participants)
    Female
    72
    55.8%
    71
    55%
    76
    58.5%
    75
    58.1%
    70
    53.8%
    364
    56.3%
    Male
    57
    44.2%
    58
    45%
    54
    41.5%
    54
    41.9%
    60
    46.2%
    283
    43.7%
    Race/Ethnicity, Customized (Count of Participants)
    White
    105
    81.4%
    109
    84.5%
    93
    71.5%
    107
    82.9%
    101
    77.7%
    515
    79.6%
    Black or African American
    20
    15.5%
    19
    14.7%
    30
    23.1%
    18
    14%
    26
    20%
    113
    17.5%
    Asian
    4
    3.1%
    1
    0.8%
    4
    3.1%
    1
    0.8%
    1
    0.8%
    11
    1.7%
    American Indian or Alaskan Native
    0
    0%
    0
    0%
    1
    0.8%
    0
    0%
    0
    0%
    1
    0.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    1
    0.8%
    0
    0%
    1
    0.2%
    Other
    0
    0%
    0
    0%
    2
    1.5%
    2
    1.6%
    2
    1.5%
    6
    0.9%
    Race/Ethnicity, Customized (Count of Participants)
    Not Hispanic or Latino
    119
    92.2%
    121
    93.8%
    114
    87.7%
    121
    93.8%
    122
    93.8%
    597
    92.3%
    Hispanic or Latino
    10
    7.8%
    8
    6.2%
    16
    12.3%
    8
    6.2%
    7
    5.4%
    49
    7.6%
    Unknown
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.8%
    1
    0.2%
    Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg/m^2]
    27.94
    (6.686)
    28.00
    (7.166)
    27.63
    (6.603)
    27.94
    (7.259)
    27.99
    (6.849)
    27.90
    (6.897)
    History of Smoking (Count of Participants)
    Prior smoker
    18
    14%
    13
    10.1%
    15
    11.5%
    14
    10.9%
    12
    9.2%
    72
    11.1%
    No tobacco use
    111
    86%
    116
    89.9%
    115
    88.5%
    115
    89.1%
    118
    90.8%
    575
    88.9%
    Previous Asthma Therapy (Count of Participants)
    Inhaled corticosteroid
    97
    75.2%
    90
    69.8%
    83
    63.8%
    89
    69%
    102
    78.5%
    461
    71.3%
    Inhaled corticosteroid/long-acting beta2-agonist
    32
    24.8%
    39
    30.2%
    47
    36.2%
    40
    31%
    28
    21.5%
    186
    28.7%
    Forced Expiratory Volume in 1 second (FEV1) (liters) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [liters]
    2.162
    (0.5522)
    2.302
    (0.6526)
    2.166
    (0.5725)
    2.134
    (0.6362)
    2.188
    (0.5628)
    2.190
    (0.5977)

    Outcome Measures

    1. Primary Outcome
    Title Standardized Baseline-Adjusted Forced Expiratory Volume in 1 Second (FEV1) Area Under the Effect Curve From Time Zero to 12 Hours Postdose (FEV1 AUEC0-12h) at Week 12
    Description A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. 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

    Outcome Measure Data

    Analysis Population Description
    Full analysis set: a subset of patients who performed postdose serial spirometry at the baseline visit and week 12
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 61 56 72 63 60
    Least Squares Mean (Standard Error) [liters]
    0.408
    (0.0465)
    0.399
    (0.0479)
    0.254
    (0.0434)
    0.268
    (0.0457)
    0.074
    (0.0487)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0076
    Comments
    Method ANCOVA
    Comments Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.154
    Confidence Interval (2-Sided) 95%
    0.041 to 0.267
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0322
    Comments
    Method ANCOVA
    Comments Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.131
    Confidence Interval (2-Sided) 95%
    0.011 to 0.250
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments
    Method ANCOVA
    Comments Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.335
    Confidence Interval (2-Sided) 95%
    0.216 to 0.453
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments
    Method ANCOVA
    Comments Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.325
    Confidence Interval (2-Sided) 95%
    0.203 to 0.447
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) at Week 12
    Description Trough FEV1 was a morning spirometry taken predose and pre-rescue bronchodilator. 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. 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

    Outcome Measure Data

    Analysis Population Description
    Full analysis set
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 126 128 129 128 129
    Least Squares Mean (Standard Error) [liters]
    0.315
    (0.0352)
    0.319
    (0.0350)
    0.204
    (0.0340)
    0.172
    (0.0347)
    0.053
    (0.0350)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments
    Method ANCOVA
    Comments Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.262
    Confidence Interval (2-Sided) 95%
    0.168 to 0.356
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments
    Method ANCOVA
    Comments Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.266
    Confidence Interval (2-Sided) 95%
    0.172 to 0.360
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments
    Method ANCOVA
    Comments Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.151
    Confidence Interval (2-Sided) 95%
    0.057 to 0.244
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0132
    Comments
    Method ANCOVA
    Comments Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.119
    Confidence Interval (2-Sided) 95%
    0.025 to 0.212
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline in the Weekly Average of the Daily Morning Trough Peak Expiratory Flow (PEF) Over the 12 Week Treatment
    Description 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), Day 1 (postdose) daily until Week 12

    Outcome Measure Data

    Analysis Population Description
    Full analysis set of patients who contributed at least once to the analysis.
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 125 128 129 128 128
    Least Squares Mean (Standard Error) [liters/minute]
    24.415
    (3.1530)
    24.864
    (3.1182)
    14.517
    (3.0778)
    10.609
    (3.1176)
    3.591
    (3.1474)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0123
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 10.926
    Confidence Interval (2-Sided) 95%
    2.380 to 19.471
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1074
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 7.018
    Confidence Interval (2-Sided) 95%
    -1.531 to 15.567
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 20.824
    Confidence Interval (2-Sided) 95%
    12.253 to 29.395
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 21.273
    Confidence Interval (2-Sided) 95%
    12.728 to 29.818
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0233
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 9.898
    Confidence Interval (2-Sided) 95%
    1.349 to 18.447
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0011
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 14.255
    Confidence Interval (2-Sided) 95%
    5.732 to 22.778
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0175
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 10.347
    Confidence Interval (2-Sided) 95%
    1.822 to 18.872
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over the 12-Week Treatment Period
    Description The total daily asthma symptom score is the average of the daytime and nighttime scores as recorded in the patient diary (range 0-9). Daytime Symptom Score: 0=No symptoms Symptoms for 1 short period Symptoms for 2+ short periods Symptoms for most of the day - did not affect normal daily activities Symptoms for most of the day - did affect normal daily activities 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 Symptoms causing me to wake once (or wake early) Symptoms causing me to wake twice or more (including waking early) Symptoms causing me to be awake for most of the night 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

    Outcome Measure Data

    Analysis Population Description
    Full analysis set of patients who contributed at least once to the analysis.
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 125 128 129 128 128
    Least Squares Mean (Standard Error) [units on a scale]
    -0.364
    (0.0318)
    -0.329
    (0.0314)
    -0.300
    (0.0308)
    -0.278
    (0.0314)
    -0.135
    (0.0318)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.165
    Confidence Interval (2-Sided) 95%
    -0.251 to -0.080
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0010
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.143
    Confidence Interval (2-Sided) 95%
    -0.229 to -0.058
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.230
    Confidence Interval (2-Sided) 95%
    -0.315 to -0.144
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.194
    Confidence Interval (2-Sided) 95%
    -0.279 to -0.109
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1381
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.064
    Confidence Interval (2-Sided) 95%
    -0.150 to 0.021
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.2438
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.051
    Confidence Interval (2-Sided) 95%
    -0.136 to 0.035
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.5095
    Comments Significance level of 0.05.
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.029
    Confidence Interval (2-Sided) 95%
    -0.114 to 0.057
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title 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
    Description 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

    Outcome Measure Data

    Analysis Population Description
    FAS of patients who contributed at least once to the analysis
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 126 128 129 128 129
    Least Squares Mean (Standard Error) [puffs]
    -0.677
    (0.0937)
    -0.706
    (0.0930)
    -0.466
    (0.0915)
    -0.467
    (0.0928)
    -0.003
    (0.0937)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.463
    Confidence Interval (2-Sided) 95%
    -0.716 to -0.209
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0003
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.464
    Confidence Interval (2-Sided) 95%
    -0.718 to -0.211
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.675
    Confidence Interval (2-Sided) 95%
    -0.928 to -0.421
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.704
    Confidence Interval (2-Sided) 95%
    -0.957 to -0.450
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1014
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.212
    Confidence Interval (2-Sided) 95%
    -0.465 to 0.042
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0640
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.239
    Confidence Interval (2-Sided) 95%
    -0.492 to 0.014
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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.
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0626
    Comments Significance level of 0.05
    Method mixed model for repeated measures
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.241
    Confidence Interval (2-Sided) 95%
    -0.494 to 0.013
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title Kaplan-Meier Estimate of Probability of Remaining in Study At Week 12
    Description 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

    Outcome Measure Data

    Analysis Population Description
    FAS
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 126 128 129 128 129
    Number (95% Confidence Interval) [probability]
    1.0000
    0.9917
    0.9919
    0.9919
    0.9681
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1679
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1701
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0437
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.1718
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.3134
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.9930
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 100 mcg
    Comments
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.9999
    Comments Significance level of 0.05
    Method Log Rank
    Comments
    7. Secondary Outcome
    Title Change From Baseline in the Asthma Quality of Life Questionnaire With Standardized Activities (AQLQ(S)) Score at Endpoint for Patients >=18 Years Old
    Description 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 of 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)

    Outcome Measure Data

    Analysis Population Description
    FAS patients who contributed at least once to analysis and were >= 18 years old
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 109 102 103 108 97
    Least Squares Mean (Standard Error) [units on a scale]
    0.808
    (0.0728)
    0.565
    (0.0752)
    0.636
    (0.0736)
    0.588
    (0.0733)
    0.335
    (0.0777)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 100 mcg, Placebo MDPI
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0044
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.301
    Confidence Interval (2-Sided) 95%
    0.094 to 0.508
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Fp MDPI 50 mcg, Placebo MDPI
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0155
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.253
    Confidence Interval (2-Sided) 95%
    0.048 to 0.458
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Placebo MDPI
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0000
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.473
    Confidence Interval (2-Sided) 95%
    0.270 to 0.676
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Placebo MDPI
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0293
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.230
    Confidence Interval (2-Sided) 95%
    0.023 to 0.437
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection FS MDPI 100 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.0913
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value 0.172
    Confidence Interval (2-Sided) 95%
    -0.028 to 0.372
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 50 mcg
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.8216
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.023
    Confidence Interval (2-Sided) 95%
    -0.223 to 0.177
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection FS MDPI 50 / 12.5 mcg, Fp MDPI 100 mcg
    Comments 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).
    Type of Statistical Test Superiority or Other (legacy)
    Comments
    Statistical Test of Hypothesis p-Value 0.4934
    Comments Significance level of 0.05
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LSM difference
    Estimated Value -0.071
    Confidence Interval (2-Sided) 95%
    -0.275 to 0.133
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Kaplan-Meier Estimates for Time to 15% and 12% Improvement From Baseline in FEV1 Postdose on Day 1
    Description A subset of approximately 300 patients who performed postdose serial spirometry is based on sample size calculation. Baseline FEV1 was the average of 2 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, baseline 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 9999 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)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set: a subset of patients who performed postdose serial spirometry on Day 1
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 61 56 72 63 60
    15% improvement
    4.3
    1.3
    NA
    NA
    NA
    12% improvement
    1.0
    0.5
    NA
    NA
    NA
    9. Secondary Outcome
    Title Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period
    Description An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
    Time Frame Day 1 to Week 12 of the Treatment Period

    Outcome Measure Data

    Analysis Population Description
    Safety population
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    Measure Participants 126 128 129 129 129
    >=1 TEAE
    37
    28.7%
    46
    35.7%
    40
    30.8%
    44
    34.1%
    47
    36.2%
    >=1 severe TEAE
    2
    1.6%
    0
    0%
    1
    0.8%
    1
    0.8%
    0
    0%
    >=1 treatment-related TEAE
    4
    3.1%
    4
    3.1%
    5
    3.8%
    7
    5.4%
    5
    3.8%
    >=1 severe treatment-related TEAE
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    >=1 serious TEAE
    1
    0.8%
    0
    0%
    1
    0.8%
    0
    0%
    2
    1.5%
    >=1 TEAE leading to withdrawal
    0
    0%
    3
    2.3%
    2
    1.5%
    1
    0.8%
    6
    4.6%
    >=1 nonserious TEAE
    36
    27.9%
    46
    35.7%
    39
    30%
    44
    34.1%
    45
    34.6%
    >=1 TEAE resulting in death
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%

    Adverse Events

    Time Frame Day 1 up to Week 12
    Adverse Event Reporting Description
    Arm/Group Title FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Arm/Group Description Patients 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/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 50 mcg (for a total daily dose of 100 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 200 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. Patients took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate for a total daily dose of 100 mcg for 12 weeks. Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication. The placebo multidose dry powder inhaler 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). Albuterol/salbutamol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
    All Cause Mortality
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/126 (0.8%) 0/128 (0%) 1/129 (0.8%) 0/129 (0%) 2/129 (1.6%)
    Gastrointestinal disorders
    Pancreatitis 1/126 (0.8%) 1 0/128 (0%) 0 0/129 (0%) 0 0/129 (0%) 0 0/129 (0%) 0
    Hepatobiliary disorders
    Cholecystitis 1/126 (0.8%) 1 0/128 (0%) 0 0/129 (0%) 0 0/129 (0%) 0 0/129 (0%) 0
    Cholelithiasis 1/126 (0.8%) 1 0/128 (0%) 0 0/129 (0%) 0 0/129 (0%) 0 0/129 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma 0/126 (0%) 0 0/128 (0%) 0 1/129 (0.8%) 1 0/129 (0%) 0 0/129 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous 0/126 (0%) 0 0/128 (0%) 0 0/129 (0%) 0 0/129 (0%) 0 1/129 (0.8%) 1
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/126 (0%) 0 0/128 (0%) 0 0/129 (0%) 0 0/129 (0%) 0 1/129 (0.8%) 1
    Other (Not Including Serious) Adverse Events
    FS MDPI 100 / 12.5 mcg FS MDPI 50 / 12.5 mcg Fp MDPI 100 mcg Fp MDPI 50 mcg Placebo MDPI
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/126 (9.5%) 22/128 (17.2%) 21/129 (16.3%) 15/129 (11.6%) 15/129 (11.6%)
    Infections and infestations
    Nasopharyngitis 3/126 (2.4%) 3 11/128 (8.6%) 11 9/129 (7%) 10 7/129 (5.4%) 8 4/129 (3.1%) 5
    Upper respiratory tract infection 2/126 (1.6%) 2 6/128 (4.7%) 6 4/129 (3.1%) 4 7/129 (5.4%) 8 6/129 (4.7%) 6
    Nervous system disorders
    Headache 7/126 (5.6%) 10 7/128 (5.5%) 8 9/129 (7%) 11 2/129 (1.6%) 4 5/129 (3.9%) 7

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.

    Results Point of Contact

    Name/Title Director, Clinical Research
    Organization Teva Branded Pharmaceutical Products, R&D Inc.
    Phone 215-591-3000
    Email ustevatrials@tevapharm.com
    Responsible Party:
    Teva Branded Pharmaceutical Products R&D, Inc.
    ClinicalTrials.gov Identifier:
    NCT02139644
    Other Study ID Numbers:
    • FSS-AS-301
    • 2014-001149-25
    First Posted:
    May 15, 2014
    Last Update Posted:
    Nov 12, 2021
    Last Verified:
    Nov 1, 2021