Efficacy and Safety Study of FP MDPI Compared With FS MDPI in Adolescent and Adult Patients With Persistent Asthma

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02141854
• Collaborator: (none)
• Enrollment: 882
• Locations: 154
• Arms: 5
• Duration (Months): 15
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: FS MDPI; Drug: Fp MDPI; Drug: Placebo MDPI; Drug: Albuterol/salmeterol HFA MDI	Phase 3

Detailed Description

Study drug and placebo were supplied in Teva multidose dry powder inhaler (MDPI) devices and provided for participants to use at home. Participants performed spirometry at every visit. Each participant was given a diary at each visit for use until the next visit. Rescue medication (albuterol/salbutamol) was dispensed at each visit, if needed, as determined by the investigational center personnel.

Study Design

• Study Type: Interventional
• Actual Enrollment: 882 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 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 200 / 12.5 mcg Participants took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either fluticasone propionate/salmeterol MDPI 200/12.5 mcg or fluticasone propionate/salmeterol MDPI 100/12.5 mcg twice a day for a total daily dose of 200/25 mcg or 400/25 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.; Other Names: fluticasone propionate inhaled corticosteroid salmeterol xinafoate β2 adrenoceptor agonist ; Drug: Albuterol/salmeterol HFA MDI; Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.; Other Names: short-acting β2-adrenergic agonists
Experimental: FS MDPI 100 / 12.5 mcg Participants 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.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either fluticasone propionate/salmeterol MDPI 200/12.5 mcg or fluticasone propionate/salmeterol MDPI 100/12.5 mcg twice a day for a total daily dose of 200/25 mcg or 400/25 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.; Other Names: fluticasone propionate inhaled corticosteroid salmeterol xinafoate β2 adrenoceptor agonist ; Drug: Albuterol/salmeterol HFA MDI; Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.; Other Names: short-acting β2-adrenergic agonists
Experimental: Fp MDPI 200 mcg Participants took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks.	Drug: Fp MDPI; Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either 200 mcg or 100 mcg of Fp one inhalation twice a day for a total daily dose of 400 mcg or 200 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.; Other Names: fluticasone propionate inhaled corticosteroid ; Drug: Albuterol/salmeterol HFA MDI; Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.; Other Names: short-acting β2-adrenergic agonists
Experimental: Fp MDPI 100 mcg Participants took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks.	Drug: Fp MDPI; Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate (Fp) dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. During the treatment period, participants were randomized to either 200 mcg or 100 mcg of Fp one inhalation twice a day for a total daily dose of 400 mcg or 200 mcg. Participants were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.; Other Names: fluticasone propionate inhaled corticosteroid ; Drug: Albuterol/salmeterol HFA MDI; Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.; Other Names: short-acting β2-adrenergic agonists
Placebo Comparator: Placebo MDPI Participants took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks.	Drug: Placebo MDPI; The placebo multidose dry powder inhaler (MDPI) was identical to the devices used to deliver active drug, and indistinguishable from the active treatments. Patients took one inhalation twice a day (approximately 12 hours apart). Patients were instructed to rinse their mouth and expectorate (not swallow) after study drug administration.; Other Names: inert powder ; Drug: Albuterol/salmeterol HFA MDI; Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.; Other Names: short-acting β2-adrenergic agonists

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 AUEC0-12) at Week 12 [Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours]

   A subset of patients performed postdose serial spirometry. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.

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 is a morning spirometry taken predose and pre-rescue bronchodilator. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).

Secondary 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, baseline), Day 1 (postdose) daily until Week 12]

   Morning PEF tests were performed before administration of study drug or rescue medications (data were excluded if the time of PEF measurement was more than 5 minutes after the dose time). The patient recorded the highest value of 3 measurements obtained in the patient diary. The baseline PEF was the average value of recorded (nonmissing) morning assessments over the 7 days prior to randomization on Day 1. For efficacy analyses of weekly average morning PEF measurements, values were the averages based on available data for that week.

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. Daytime Symptom Score: 0=No symptoms 1=Symptoms for 1 short period 2=Symptoms for 2+ short periods 3=Symptoms for most of the day - did not affect normal daily activities 4=Symptoms for most of the day - did affect normal daily activities 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): 0=No symptoms 1=Symptoms causing me to wake once (or wake early) 2=Symptoms causing me to wake twice or more (including waking early) 3=Symptoms causing me to be awake for most of the night 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).

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 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)]

   The baseline forced expiratory volume in 1 second (FEV1) was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, the baseline trough FEV1 was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of NA indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.

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. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

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 qualifying dose of an inhaled corticosteroid (ICS). The ICS may be either as ICS monotherapy or as an ICS/long-acting beta agonist (LABA) combination. The ICS component of the patient's asthma therapy should be stable for a minimum of 1 month before providing consent.

3. Reversibility of Disease: Patients must have at least 15% reversibility (all patients) and at least a 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol at the SV. Note: Patients who do not qualify for the study due to failure to meet reversibility will be permitted to perform a retest once within 7 days.

4. Patients must provide written informed consent/assent.. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written ICF must be signed and dated by the parent/legal guardian and the written assent form must be signed and dated by the patient (if applicable). Note: Age requirements are as specified by local regulations.

5. Outpatient >= 12 years of age on the date of consent/assent. In countries where the local regulations permit enrollment of adult patients only, patients must be 18 years of age and older.

6. Asthma diagnosis: The patient has a diagnosis of asthma as defined by the National Institute of Health (NIH). The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in asthma medication) for at least 30 days.

7. The patient is able to perform acceptable and repeatable spirometry.

8. The patient is able to perform peak expiratory flow (PEF) with a handheld peak flow meter.

9. The patient is able to use a metered dose inhaler (MDI) device without a spacer device and a multidose dry powder inhaler (MDPI) device.

10. The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before the screening visit (SV) and before all treatment visits.

11. The patient/parent/legal guardian/caregiver is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements.

12. SABAs: All patients must be able to replace their current SABA with albuterol/salbutamol HFA MDI inhalation aerosol for the duration of the study.

13. Female patients may not be pregnant, breastfeeding, or attempting to become pregnant.

• other criteria may apply, please contact the investigator for more information

Exclusion Criteria:

1. A history of a life-threatening asthma exacerbation (an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, or hypoxic seizures).

2. The patient is pregnant or lactating, or plans to become pregnant during the study period or for 30 days after the study.

3. The patient has participated as a randomized patient in any investigational drug study within 30 days of the SV.

4. The patient has previously participated as a randomized patient in a study of Fp MDPI or FS MDPI.

5. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the study drug or rescue medication formulation (ie, lactose).

6. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, or clarithromycin) within 30 days before the SV.

7. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before the SV.

8. The patient currently smokes or has a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). The patient must not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).

9. The patient has a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before the SV.

10. The patient has a history of alcohol or drug abuse within 2 years preceding the SV.

11. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV, or has had any hospitalization for asthma within 2 months before the SV.

12. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients on stable immunotherapy may be considered for inclusion.

13. The patient has used immunosuppressive medications within 4 weeks before the SV.

14. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications.

15. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study.

16. The patient has a history of a positive test for human immunodeficiency virus (HIV), active hepatitis B virus, or hepatitis C infection.

17. The patient is either an employee or an immediate relative of an employee of the clinical investigational center.

18. A member of the patient's household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened.

19. The patient has a disease/condition that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study.

• other criteria may apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 12429	Birmingham	Alabama	United States
2	Teva Investigational Site 12599	Little Rock	Alaska	United States
3	Teva Investigational Site 12609	Phoenix	Arizona	United States
4	Teva Investigational Site 12445	Costa Mesa	California	United States
5	Teva Investigational Site 12454	Encinitas	California	United States
6	Teva Investigational Site 12456	Fresno	California	United States
7	Teva Investigational Site 12461	Fullerton	California	United States
8	Teva Investigational Site 12410	Huntington Beach	California	United States
9	Teva Investigational Site 12452	Huntington Beach	California	United States
10	Teva Investigational Site 12417	Long Beach	California	United States
11	Teva Investigational Site 13017	Mission Viejo	California	United States
12	Teva Investigational Site 12462	Rancho Mirage	California	United States
13	Teva Investigational Site 12411	Rolling Hills Estates	California	United States
14	Teva Investigational Site 13018	San Diego	California	United States
15	Teva Investigational Site 12413	San Jose	California	United States
16	Teva Investigational Site 12403	Stockton	California	United States
17	Teva Investigational Site 12444	Upland	California	United States
18	Teva Investigational Site 12999	Vista	California	United States
19	Teva Investigational Site 12405	Centennial	Colorado	United States
20	Teva Investigational Site 12419	Centennial	Colorado	United States
21	Teva Investigational Site 13000	Colorado Springs	Colorado	United States
22	Teva Investigational Site 12459	Waterbury	Connecticut	United States
23	Teva Investigational Site 13004	Largo	Florida	United States
24	Teva Investigational Site 12414	Miami	Florida	United States
25	Teva Investigational Site 12437	Miami	Florida	United States
26	Teva Investigational Site 12427	Orlando	Florida	United States
27	Teva Investigational Site 12423	Ormond Beach	Florida	United States
28	Teva Investigational Site 12604	Panama City	Florida	United States
29	Teva Investigational Site 13316	Tamarac	Florida	United States
30	Teva Investigational Site 12606	Winter Park	Florida	United States
31	Teva Investigational Site 12435	Savannah	Georgia	United States
32	Teva Investigational Site 13315	Eagle	Idaho	United States
33	Teva Investigational Site 12439	River Forest	Illinois	United States
34	Teva Investigational Site 12449	Shiloh	Illinois	United States
35	Teva Investigational Site 12457	South Bend	Indiana	United States
36	Teva Investigational Site 12446	Bangor	Maine	United States
37	Teva Investigational Site 12602	Columbia	Maryland	United States
38	Teva Investigational Site 12432	Fall River	Massachusetts	United States
39	Teva Investigational Site 12441	North Dartmouth	Massachusetts	United States
40	Teva Investigational Site 12466	North Dartmouth	Massachusetts	United States
41	Teva Investigational Site 13001	Royal Oak	Michigan	United States
42	Teva Investigational Site 12428	Ypsilanti	Michigan	United States
43	Teva Investigational Site 13020	Minneapolis	Minnesota	United States
44	Teva Investigational Site 12451	Columbia	Missouri	United States
45	Teva Investigational Site 12421	Rolla	Missouri	United States
46	Teva Investigational Site 12412	Saint Louis	Missouri	United States
47	Teva Investigational Site 12453	Saint Louis	Missouri	United States
48	Teva Investigational Site 12610	Missoula	Montana	United States
49	Teva Investigational Site 13021	Las Vegas	Nevada	United States
50	Teva Investigational Site 12409	Skillman	New Jersey	United States
51	Teva Investigational Site 12603	Bronx	New York	United States
52	Teva Investigational Site 12464	Brooklyn	New York	United States
53	Teva Investigational Site 12430	Charlotte	North Carolina	United States
54	Teva Investigational Site 12407	Raleigh	North Carolina	United States
55	Teva Investigational Site 12415	Canton	Ohio	United States
56	Teva Investigational Site 12455	Cincinnati	Ohio	United States
57	Teva Investigational Site 12463	Cincinnati	Ohio	United States
58	Teva Investigational Site 12460	Middleburg Heights	Ohio	United States
59	Teva Investigational Site 12426	Edmond	Oklahoma	United States
60	Teva Investigational Site 13008	Oklahoma City	Oklahoma	United States
61	Teva Investigational Site 12406	Medford	Oregon	United States
62	Teva Investigational Site 12442	Portland	Oregon	United States
63	Teva Investigational Site 12563	Normal	Pennsylvania	United States
64	Teva Investigational Site 12443	Pittsburgh	Pennsylvania	United States
65	Teva Investigational Site 12438	Upland	Pennsylvania	United States
66	Teva Investigational Site 12408	Charleston	South Carolina	United States
67	Teva Investigational Site 12431	Greenville	South Carolina	United States
68	Teva Investigational Site 12465	Mount Pleasant	South Carolina	United States
69	Teva Investigational Site 12467	Mount Pleasant	South Carolina	United States
70	Teva Investigational Site 12420	Orangeburg	South Carolina	United States
71	Teva Investigational Site 12433	Rock Hill	South Carolina	United States
72	Teva Investigational Site 13003	Knoxville	Tennessee	United States
73	Teva Investigational Site 12425	Arlington	Texas	United States
74	Teva Investigational Site 12416	Dallas	Texas	United States
75	Teva Investigational Site 12418	Dallas	Texas	United States
76	Teva Investigational Site 12440	El Paso	Texas	United States
77	Teva Investigational Site 12447	Killeen	Texas	United States
78	Teva Investigational Site 13318	San Antonio	Texas	United States
79	Teva Investigational Site 13002	Sugar Land	Texas	United States
80	Teva Investigational Site 12424	Waco	Texas	United States
81	Teva Investigational Site 12422	South Burlington	Vermont	United States
82	Teva Investigational Site 12605	Richmond	Virginia	United States
83	Teva Investigational Site 12436	Spokane	Washington	United States
84	Teva Investigational Site 12564	Tacoma	Washington	United States
85	Teva Investigational Site 12448	Greenfield	Wisconsin	United States
86	Teva Investigational Site 11072	Toronto	Ontario	Canada
87	Teva Investigational Site 11075	Vancouver	Quebec	Canada
88	Teva Investigational Site 54096	Jindrichuv Hradec		Czechia
89	Teva Investigational Site 54098	Praha		Czechia
90	Teva Investigational Site 54095	Rokycany		Czechia
91	Teva Investigational Site 54094	Strakonice		Czechia
92	Teva Investigational Site 51149	Budapest		Hungary
93	Teva Investigational Site 51155	Budapest		Hungary
94	Teva Investigational Site 51157	Budapest		Hungary
95	Teva Investigational Site 51161	Budapest		Hungary
96	Teva Investigational Site 51154	Debrecen		Hungary
97	Teva Investigational Site 51152	Deszk		Hungary
98	Teva Investigational Site 51170	Dombovar		Hungary
99	Teva Investigational Site 51158	Kiskunhalas		Hungary
100	Teva Investigational Site 51153	Miskolc		Hungary
101	Teva Investigational Site 51156	Mosdós		Hungary
102	Teva Investigational Site 51150	Nyíregyháza		Hungary
103	Teva Investigational Site 51151	Nyíregyháza		Hungary
104	Teva Investigational Site 51146	Szeged		Hungary
105	Teva Investigational Site 51162	Szigetvár		Hungary
106	Teva Investigational Site 51147	Szombathely		Hungary
107	Teva Investigational Site 51148	Százhalombatta		Hungary
108	Teva Investigational Site 51176	Tatabánya		Hungary
109	Teva Investigational Site 51177	Törökbálint		Hungary
110	Teva Investigational Site 53199	Bialystok		Poland
111	Teva Investigational Site 53200	Bialystok		Poland
112	Teva Investigational Site 53202	Bialystok		Poland
113	Teva Investigational Site 53208	Bialystok		Poland
114	Teva Investigational Site 53210	Bydgoszcz		Poland
115	Teva Investigational Site 53227	Bydgoszcz		Poland
116	Teva Investigational Site 53225	Debica		Poland
117	Teva Investigational Site 53203	Gdansk		Poland
118	Teva Investigational Site 53205	Krakow		Poland
119	Teva Investigational Site 53195	Kraków		Poland
120	Teva Investigational Site 53197	Kraków		Poland
121	Teva Investigational Site 53228	Lodz		Poland
122	Teva Investigational Site 53240	Lodz		Poland
123	Teva Investigational Site 53241	Lublin		Poland
124	Teva Investigational Site 53201	Lódz		Poland
125	Teva Investigational Site 53229	Lódz		Poland
126	Teva Investigational Site 53206	Poznan		Poland
127	Teva Investigational Site 53211	Poznan		Poland
128	Teva Investigational Site 53230	Strzelce Opolskie		Poland
129	Teva Investigational Site 53196	Tarnów		Poland
130	Teva Investigational Site 53222	Warszawa		Poland
131	Teva Investigational Site 53198	Wroclaw		Poland
132	Teva Investigational Site 53224	Wroclaw		Poland
133	Teva Investigational Site 50255	Chelyabinsk		Russian Federation
134	Teva Investigational Site 50243	Ekaterinburg		Russian Federation
135	Teva Investigational Site 50241	Kazan		Russian Federation
136	Teva Investigational Site 50250	Moscow		Russian Federation
137	Teva Investigational Site 50252	Moscow		Russian Federation
138	Teva Investigational Site 50246	Saint Petersburg		Russian Federation
139	Teva Investigational Site 50242	Saint-Petersburg		Russian Federation
140	Teva Investigational Site 50254	Saratov		Russian Federation
141	Teva Investigational Site 50245	St. Petersburg		Russian Federation
142	Teva Investigational Site 50244	Tomsk		Russian Federation
143	Teva Investigational Site 50251	Voronezh		Russian Federation
144	Teva Investigational Site 50275	Yaroslavl		Russian Federation
145	Teva Investigational Site 90011	Berea		South Africa
146	Teva Investigational Site 90015	Bloemfontein		South Africa
147	Teva Investigational Site 90012	Cape Town		South Africa
148	Teva Investigational Site 90013	Centurion		South Africa
149	Teva Investigational Site 90016	Middelburg		South Africa
150	Teva Investigational Site 90014	Pretoria		South Africa
151	Teva Investigational Site 12404	Papillion	NE	Thailand
152	Teva Investigational Site 58133	Kharkiv		Ukraine
153	Teva Investigational Site 58135	Kharkiv		Ukraine
154	Teva Investigational Site 58132	Kyiv		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: NCT02141854
• Other Study ID Numbers: FSS-AS-30017; 2014-000923-25
• First Posted: May 20, 2014
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Albuterol; Salmeterol Xinafoate; Adrenergic Agonists

Study Results

Participant Flow

Pre-assignment Detail	A total of 1661 patients with persistent asthma were screened and 882 patients enrolled. 154 patients were not randomized, most commonly (76 patients) because of not meeting randomization criteria.

Arm/Group Title	Fluticasone Propionate 50 mcg BID	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	All enrolled participants used single-blind fluticasone propionate multidose dry powder inhaler twice a day for a total daily dose of 100 mcg during the Run-In Period (14-21 days).	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Period Title: Run-In Period (Pre-assignment)
STARTED	882	0	0	0	0	0
COMPLETED	728	0	0	0	0	0
NOT COMPLETED	154	0	0	0	0	0
Period Title: Run-In Period (Pre-assignment)
STARTED	0	146	145	146	146	145
Intent to Treat Population	0	146	145	146	146	145
Safety Population	0	145	143	146	145	144
Full Analysis Set	0	145	141	146	145	143
COMPLETED	0	136	136	135	136	107
NOT COMPLETED	0	10	9	11	10	38

Baseline Characteristics

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI	Total
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Total of all reporting groups
Overall Participants	146	145	146	146	145	728
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.7 (16.93)	44.3 (14.88)	44.4 (16.36)	45.7 (15.64)	44.5 (16.05)	44.7 (15.95)
Age, Customized (Count of Participants)
Adolescents (12-17 years)	12 8.2%	8 5.5%	10 6.8%	9 6.2%	6 4.1%	45 6.2%
Adults (18-64 years)	115 78.8%	125 86.2%	119 81.5%	124 84.9%	125 86.2%	608 83.5%
Adults (65-84 years)	19 13%	12 8.3%	17 11.6%	13 8.9%	14 9.7%	75 10.3%
Sex: Female, Male (Count of Participants)
Female	87 59.6%	79 54.5%	88 60.3%	94 64.4%	91 62.8%	439 60.3%
Male	59 40.4%	66 45.5%	58 39.7%	52 35.6%	54 37.2%	289 39.7%
Race/Ethnicity, Customized (Count of Participants)
White	125 85.6%	112 77.2%	116 79.5%	111 76%	124 85.5%	588 80.8%
Black or African American	20 13.7%	28 19.3%	23 15.8%	31 21.2%	18 12.4%	120 16.5%
Asian	0 0%	0 0%	2 1.4%	0 0%	2 1.4%	4 0.5%
American Indian or Alaskan Native	0 0%	0 0%	2 1.4%	0 0%	0 0%	2 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Other	1 0.7%	5 3.4%	3 2.1%	4 2.7%	1 0.7%	14 1.9%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	136 93.2%	135 93.1%	136 93.2%	134 91.8%	136 93.8%	677 93%
Hispanic or Latino	10 6.8%	10 6.9%	10 6.8%	11 7.5%	8 5.5%	49 6.7%
Unknown	0 0%	0 0%	0 0%	1 0.7%	1 0.7%	2 0.3%
History of Smoking (Count of Participants)
Prior Smoker	20 13.7%	28 19.3%	21 14.4%	28 19.2%	23 15.9%	120 16.5%
No tobacco use	126 86.3%	117 80.7%	125 85.6%	118 80.8%	122 84.1%	608 83.5%
Previous Asthma Therapy (Count of Participants)
Inhaled corticosteroid	73 50%	67 46.2%	63 43.2%	58 39.7%	68 46.9%	329 45.2%
Inhaled corticosteroid/long-acting beta2-agonist	73 50%	78 53.8%	83 56.8%	88 60.3%	77 53.1%	399 54.8%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.4 (7.35)	30.2 (7.60)	29.9 (7.27)	29.9 (7.62)	29.3 (7.41)	29.7 (7.44)
Forced Expiratory Volume in 1 second (FEV1) (liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [liters]	2.083 (0.6532)	2.157 (0.6402)	2.075 (0.5696)	2.069 (0.6017)	2.141 (0.6849)	2.105 (0.6303)

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 AUEC0-12) at Week 12
Description	A subset of patients performed postdose serial spirometry. Data from these assessments were used to analyze the primary endpoint of baseline-adjusted FEV1 AUEC0-12h at week 12 using the trapezoidal rule based on actual time of measurement. It was standardized by dividing it by the number of hours between the start time of dose administration and the end time of the last nonmissing FEV1 measurement. The baseline FEV1 was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose). If 1 of these was missing, the nonmissing value was used; if both were missing, baseline was treated as missing. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting the baseline FEV1 value.
Time Frame	Day 1 (predose, baseline), Week 12 and was performed at the following times relative to the administration of study drug (±5 minutes): 15 and 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours

Outcome Measure Data

Analysis Population Description

A subset of patients who performed postdose serial spirometry at the baseline visit and week 12.

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	68	58	61	64	61
Least Squares Mean (Standard Error) [liters]	0.446 (0.0463)	0.442 (0.0496)	0.267 (0.0466)	0.260 (0.0463)	0.121 (0.0472)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 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	0.0009
	Comments	Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.179
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.285
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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 second in the sequence.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.182
	Confidence Interval	(2-Sided) 95%; 0.074 to 0.291
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.326
	Confidence Interval	(2-Sided) 95%; 0.221 to 0.431
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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 fourth in the sequence.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments	Fixed effects of treatment, sex, (pooled) center, previous therapy (ICS or ICS/LABA), and covariates of age and baseline FEV1.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.322
	Confidence Interval	(2-Sided) 95%; 0.212 to 0.432
	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 is a morning spirometry taken predose and pre-rescue bronchodilator. The baseline for predose FEV1 was defined as the average of the 30-minute and 10-minute predose measurements obtained at the randomization visit (Day 1).
Time Frame	Day 1 (predose, baseline), Week 12

Outcome Measure Data

Analysis Population Description

If the patient inadvertently administered asthma medication/study drug at home on the AM of the visit, or if the patient took rescue medication within 6 hours of testing, the visit was rescheduled.

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	143	140	145	144	143
Least Squares Mean (Standard Error) [liters]	0.272 (0.0307)	0.271 (0.0311)	0.179 (0.0308)	0.119 (0.0311)	-0.004 (0.0312)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.276
	Confidence Interval	(2-Sided) 95%; 0.191 to 0.361
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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 sixth in the sequence.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0000
	Comments	Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.274
	Confidence Interval	(2-Sided) 95%; 0.189 to 0.360
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 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	0.0000
	Comments	Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.183
	Confidence Interval	(2-Sided) 95%; 0.098 to 0.268
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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 eighth in the sequence.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0047
	Comments	Effects due to baseline trough AM FEV1, sex, age, (pooled) center, previous therapy (ICS or ICS/LABA), and treatment.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.123
	Confidence Interval	(2-Sided) 95%; 0.038 to 0.208
	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, baseline), Day 1 (postdose) daily until Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	145	141	146	145	142
Least Squares Mean (Standard Error) [liters/minute]	20.235 (2.3845)	18.610 (2.4137)	7.464 (2.3887)	5.731 (2.4102)	-10.987 (2.4784)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 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	18.450
	Confidence Interval	(2-Sided) 95%; 11.751 to 25.150
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	0.0000
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	16.718
	Confidence Interval	(2-Sided) 95%; 9.988 to 23.449
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	31.221
	Confidence Interval	(2-Sided) 95%; 24.513 to 37.930
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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	29.597
	Confidence Interval	(2-Sided) 95%; 22.839 to 36.354
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 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	0.0002
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	12.771
	Confidence Interval	(2-Sided) 95%; 6.179 to 19.363
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

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	0.0002
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	12.879
	Confidence Interval	(2-Sided) 95%; 6.216 to 19.541
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100 / 12.5 mcg, Fp MDPI 200 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	0.0010
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	11.146
	Confidence Interval	(2-Sided) 95%; 4.511 to 17.782
	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. Daytime Symptom Score: 0=No symptoms 1=Symptoms for 1 short period 2=Symptoms for 2+ short periods 3=Symptoms for most of the day - did not affect normal daily activities 4=Symptoms for most of the day - did affect normal daily activities 5=Symptoms so severe that I could not go to work or perform normal daily activities Nighttime Symptom Score (determined in the AM): 0=No symptoms 1=Symptoms causing me to wake once (or wake early) 2=Symptoms causing me to wake twice or more (including waking early) 3=Symptoms causing me to be awake for most of the night 4=Symptoms so severe that I did not sleep Baseline was the average of recorded scores over the 7 days before randomization. The change from baseline in the weekly average over weeks 1 to 12 was analyzed using an mixed model for repeated measures (MMRM).
Time Frame	Days -6 to Day 1 (predose, baseline), to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	145	141	146	145	142
Least Squares Mean (Standard Error) [units on a scale]	-0.391 (0.0328)	-0.364 (0.0332)	-0.242 (0.0329)	-0.282 (0.0333)	-0.087 (0.0342)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 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	-0.156
	Confidence Interval	(2-Sided) 95%; -0.248 to -0.063
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	0.0000
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.195
	Confidence Interval	(2-Sided) 95%; -0.288 to -0.102
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	-0.304
	Confidence Interval	(2-Sided) 95%; -0.397 to -0.212
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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	-0.277
	Confidence Interval	(2-Sided) 95%; -0.370 to -0.184
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 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	0.0014
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.149
	Confidence Interval	(2-Sided) 95%; -0.239 to -0.058
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

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	0.0818
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.082
	Confidence Interval	(2-Sided) 95%; -0.174 to 0.010
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100 / 12.5 mcg, Fp MDPI 200 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	0.0094
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.121
	Confidence Interval	(2-Sided) 95%; -0.213 to -0.030
	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

Full analysis set

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	145	141	146	145	143
Least Squares Mean (Standard Error) [puffs]	-0.898 (0.1069)	-0.821 (0.1080)	-0.534 (0.1070)	-0.439 (0.1081)	0.168 (0.1102)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 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	-0.702
	Confidence Interval	(2-Sided) 95%; -1.001 to -0.403
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	0.0001
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.607
	Confidence Interval	(2-Sided) 95%; -0.908 to -0.307
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	-1.066
	Confidence Interval	(2-Sided) 95%; -1.365 to -0.766
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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	-0.989
	Confidence Interval	(2-Sided) 95%; -1.291 to -0.686
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 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	0.0160
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.364
	Confidence Interval	(2-Sided) 95%; -0.659 to -0.068
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

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	0.0124
	Comments	Significance level of 0.05.
	Method	mixed model for repeated measures
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.382
	Confidence Interval	(2-Sided) 95%; -0.681 to -0.083
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100 / 12.5 mcg, Fp MDPI 200 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	0.0588
	Comments	Significance level of 0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.287
	Confidence Interval	(2-Sided) 95%; -0.584 to 0.011
	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

Full analysis set

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	145	141	146	145	143
Number (95% Confidence Interval) [probability]	0.9719	0.9929	0.9786	0.9930	0.8528

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 mcg, Placebo MDPI
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 2

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	<.0001
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Placebo MDPI
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 4

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	<.0001
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 mcg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7203
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 6

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	0.9960
	Comments	Significance level of 0.05.
	Method	Log Rank
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100 / 12.5 mcg, Fp MDPI 200 mcg
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3250
	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 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

Full analysis set of participants who contributed at least once to analysis and were >= 18 years old

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	131	135	132	133	129
Least Squares Mean (Standard Error) [units on a scale]	0.534 (0.0741)	0.592 (0.0725)	0.384 (0.0742)	0.340 (0.0740)	-0.089 (0.0747)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 200 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%; 0.269 to 0.677
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

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	0.0000
	Comments	Significance level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.428
	Confidence Interval	(2-Sided) 95%; 0.224 to 0.632
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 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	0.623
	Confidence Interval	(2-Sided) 95%; 0.418 to 0.828
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

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	Slope
	Estimated Value	0.681
	Confidence Interval	(2-Sided) 95%; 0.478 to 0.885
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 200 / 12.5 mcg, Fp MDPI 200 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	0.1490
	Comments	Significance level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.150
	Confidence Interval	(2-Sided) 95%; -0.054 to 0.354
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

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	0.0143
	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%; 0.051 to 0.455
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100 / 12.5 mcg, Fp MDPI 200 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	0.0435
	Comments	Significance level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.209
	Confidence Interval	(2-Sided) 95%; 0.006 to 0.411
	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	The baseline forced expiratory volume in 1 second (FEV1) was the average of the 2 predose FEV1 measurements (30 and 10 minutes predose) on Day 1. If one of these was missing, the other measurement was used as baseline value. If both were missing, the baseline trough FEV1 was treated as missing. Time to target improvement (15% or 12%) was defined as the time elapsed from the time of first dose to the first time the target improvement in FEV1 was achieved. If an exact target increase was not achieved at a measured timepoint, then the time was estimated by linear interpolation between the timepoint when target was reached and the timepoint immediately before. Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment. Values of NA indicate the values could not be estimated which happened when the estimated probability of not achieving target is more than 50%.
Time Frame	Day 1 of the Treatment Period (predose and postdose)

Outcome Measure Data

Analysis Population Description

Patients who did not achieve the target improvement were censored at the time of last serial spirometry assessment.

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	68	58	61	64	61
15% improvement	0.8	0.9	NA	NA	NA
12% improvement	0.4	0.4	6.9	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. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame	Day 1 to Week 12 of the Treatment Period

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	FS MDPI 200 / 12.5 mcg	FS MDPI 100 / 12.5 mcg	Fp MDPI 200 mcg	Fp MDPI 100 mcg	Placebo MDPI
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
Measure Participants	145	143	146	145	144
>=1 TEAE	61 41.8%	59 40.7%	60 41.1%	53 36.3%	52 35.9%
>=1 severe TEAE	3 2.1%	2 1.4%	0 0%	1 0.7%	1 0.7%
>=1 treatment-related TEAE	8 5.5%	4 2.8%	9 6.2%	6 4.1%	5 3.4%
>=1 severe treatment-related TEAE	1 0.7%	0 0%	0 0%	0 0%	0 0%
>=1 serious TEAE	2 1.4%	2 1.4%	1 0.7%	1 0.7%	1 0.7%
>=1 TEAE leading to withdrawal	2 1.4%	2 1.4%	0 0%	2 1.4%	2 1.4%
>=1 nonserious TEAE	61 41.8%	58 40%	60 41.1%	52 35.6%	52 35.9%
>=1 TEAE resulting in death	0 0%	1 0.7%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Day 1 up to Week 14
Arm/Group Title	FS MDPI 100/12.5 mcg		FS MDPI 200/12.5 mcg		Fp MDPI 100 mcg		Fp MDPI 200 mcg		Placebo
Arm/Group Description	Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate 100 mcg (for a total daily dose of 200 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.		Following randomization, participants in this treatment arm took 1 inhalation twice a day using a multidose dry powder inhaler (MDPI) of fluticasone propionate 200 mcg (for a total daily dose of 400 mcg) and salmeterol 12.5 mcg (for a total daily dose of 25 mcg) for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.		Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 200 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.		Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of fluticasone propionate (Fp) for a total daily dose of 400 mcg for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.		Following randomization, participants in this treatment arm took 1 inhalation using a multidose dry powder inhaler (MDPI) twice a day of placebo for 12 weeks. Albuterol/salmeterol HFA MDI: Albuterol/salmeterol hydrofluoroalkane (HFA) metered dose inhaler (MDI) was supplied to participants throughout the study to be used as needed as a rescue medication.
All Cause Mortality
	FS MDPI 100/12.5 mcg		FS MDPI 200/12.5 mcg		Fp MDPI 100 mcg		Fp MDPI 200 mcg		Placebo
	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 200/12.5 mcg		Fp MDPI 100 mcg		Fp MDPI 200 mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/143 (1.4%)		2/145 (1.4%)		1/145 (0.7%)		1/146 (0.7%)		1/144 (0.7%)
General disorders
Pyrexia	0/143 (0%)	0	0/145 (0%)	0	0/145 (0%)	0	1/146 (0.7%)	1	0/144 (0%)	0
Hepatobiliary disorders
Jaundice	1/143 (0.7%)	1	0/145 (0%)	0	0/145 (0%)	0	0/146 (0%)	0	0/144 (0%)	0
Infections and infestations
Pneumonia	0/143 (0%)	0	1/145 (0.7%)	1	0/145 (0%)	0	0/146 (0%)	0	0/144 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/143 (0.7%)	1	0/145 (0%)	0	0/145 (0%)	0	0/146 (0%)	0	0/144 (0%)	0
Nervous system disorders
Grand mal convulsion	0/143 (0%)	0	0/145 (0%)	0	1/145 (0.7%)	1	0/146 (0%)	0	0/144 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/143 (0%)	0	1/145 (0.7%)	1	0/145 (0%)	0	0/146 (0%)	0	1/144 (0.7%)	1
Other (Not Including Serious) Adverse Events
	FS MDPI 100/12.5 mcg		FS MDPI 200/12.5 mcg		Fp MDPI 100 mcg		Fp MDPI 200 mcg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/143 (14.7%)		20/145 (13.8%)		26/145 (17.9%)		20/146 (13.7%)		20/144 (13.9%)
Infections and infestations
Nasopharyngitis	10/143 (7%)	10	10/145 (6.9%)	12	7/145 (4.8%)	7	7/146 (4.8%)	8	8/144 (5.6%)	9
Upper respiratory tract infection	6/143 (4.2%)	6	6/145 (4.1%)	6	9/145 (6.2%)	11	8/146 (5.5%)	9	7/144 (4.9%)	7
Nervous system disorders
Headache	6/143 (4.2%)	21	4/145 (2.8%)	5	11/145 (7.6%)	18	7/146 (4.8%)	7	7/144 (4.9%)	10

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.