Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02980133
• Collaborator: (none)
• Enrollment: 841
• Locations: 118
• Arms: 4
• Actual Duration (Months): 27.5
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study is to evaluate the safety and efficacy of fluticasone propionate and fluticasone propionate salmeterol in pediatric participants with a documented history of persistent asthma.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Fluticasone Propionate; Drug: Fluticasone Propionate/Salmeterol; Drug: Placebo MDPI	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 841 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Efficacy and Safety Study of Fluticasone Propionate Multidose Dry Powder Inhaler Compared With Fluticasone Propionate/Salmeterol Multidose Dry Powder Inhaler in Patients Aged 4 Through 11 Years With Persistent Asthma
• Actual Study Start Date: Dec 28, 2016
• Actual Primary Completion Date: Apr 7, 2019
• Actual Study Completion Date: Apr 13, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo MDPI Participants received matching placebo via multidose dry powder inhaler (MDPI) for 12 weeks.	Drug: Placebo MDPI; Matching placebo was administered via MDPI per the schedule specified in the arm.
Experimental: Fp MDPI 25 mcg BID Participants received 1 inhalation of 25 mcg fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 mcg) for 12 weeks.	Drug: Fluticasone Propionate; Fluticasone propionate was administered via MDPI per the dose and schedule specified in the arm.
Experimental: Fp MDPI 50 mcg BID Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Drug: Fluticasone Propionate; Fluticasone propionate was administered via MDPI per the dose and schedule specified in the arm.
Experimental: FS MDPI 50/12.5 mcg BID Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.	Drug: Fluticasone Propionate/Salmeterol; Fluticasone propionate/salmeterol was administered via MDPI per the dose and schedule specified in the arm.

Outcome Measures

Primary Outcome Measures

1. For FS MDPI Versus Fp MDPI: Change From Baseline in 1-Hour Postdose Percent Predicted Morning Forced Expiratory Volume in 1 Second (FEV1) at Week 12 [Baseline, Week 12]

   FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. The baseline 1-hour trough morning percent predicted FEV1 was defined as the predose trough morning percent predicted FEV1 measurement at the randomization visit (Baseline [Day 1]) at the investigational center. The IMP dose was administered right after the predose FEV1 measurement (within a 10 minute window). Participant then performed 1-hour (±10 minutes) postdose lung function assessments on Week 12 at the investigational center.

2. For Fp MDPI Versus Placebo: Change From Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 at Week 12 [Baseline, Week 12]

   FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Baseline trough morning percent predicted FEV1 was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. The first day before randomization consisted of the electronic patient diary entry at home on the morning of the randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of the electronic patient diary entry at home on the morning of the day after the randomization visit (Baseline [Day 1]). For postdose weekly average of trough morning percent predicted FEV1 measurements, the values were the averages based on the available data for that week. The averages were calculated as the sum of morning FEV1 values divided by the number of nonmissing assessments.

Secondary Outcome Measures

1. Change From Baseline in the Weekly Average of Daily Trough Morning (Predose and Pre-Rescue Bronchodilator) Peak Expiratory Flow (PEF) Over the 12 Week Treatment Period [Baseline, Week 1 to 12]

   PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Morning PEF was determined in the morning, before administration of IMP or rescue medications. Baseline trough morning PEF was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. The first day before randomization consisted of the electronic patient diary entry at home on the morning of the randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of the electronic patient diary entry at home on the morning of the day after the randomization visit (Baseline [Day 1]). For postdose weekly average of trough morning PEF measurements, the values were the averages based on the available data for that week. The averages were calculated as the sum of morning PEF values divided by the number of nonmissing assessments.

2. Change From Baseline in the Weekly Average of Total Daily (24 Hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1 Through 12 [Baseline, Week 1 to 12]

   Participants recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each morning and evening in the electronic patient diary. An entry of 0 inhalations indicated no rescue medication was needed. To calculate the total daily use of albuterol/salbutamol inhalation aerosol (number of inhalations), the electronic patient diary entry on randomization visit (Baseline [Day 1]) was defined as the first day of analysis. The weekly average of the total daily inhalations was the average based on the available data for that week. The average was calculated as the sum of total daily inhalations over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and standard error (SE) were obtained using mixed model for repeated measures (MMRM).

3. Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1 Through 12 [Baseline, Week 1 to 12]

   Asthma symptom scores were recorded in the patient diary. Each participant assessed the symptoms of cough, wheeze, shortness of breath, and chest tightness and entered a single score that was inclusive of all symptoms. Daytime Symptom Score (determined in the evening) ranged from 0=No symptoms during the day to 5=Symptoms so severe that I could not go to work or perform normal daily activities. Nighttime Symptom Score (determined in the morning) ranged from 0=No symptoms during the night to 4=Symptoms so severe that I did not sleep at all. The total daily asthma symptom score was the average of the daytime and nighttime scores. The total daily asthma symptom score ranged from 0 - 9 with 0=no symptoms during the day or night and 9=severe symptoms both day and night. The weekly average was calculated as the sum of total daily asthma symptom scores over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and SE were obtained using MMRM.

4. Change From Baseline in Asthma Control (Measured by Childhood Asthma Control Test [C-ACT] Score) Over the 12 Week Treatment Period [Baseline, Week 1 to 12]

   C-ACT was a simple, participant-completed tool used for the assessment of overall asthma control. The first 4 items of the test were completed by the participant, while the last 3 items were completed by the participant's parents/legal guardians/caregivers. A total sum score based upon responses to all items was calculated to provide an overall measure of asthma control. The derived C-ACT score ranging from 0 to 27. These scores spanned the continuum of poor control of asthma (score ≤5) to complete control of asthma (score ≥25), with a cut off score of 19 indicating participants with poorly controlled asthma. LS mean and SE were obtained using MMRM.

5. Time to First Onset of Effect [Baseline up to Week 12]

   The time to first onset of effect, defined as the first decrease from baseline in daily rescue medication use, was calculated based on the number of inhalations of rescue medication (albuterol/salbutamol hydrofluoroalkane metered-dose inhaler [HFA MDI] [90 mcg ex actuator] or equivalent) recorded by the participant each morning and evening in the patient diary built into the handheld device.

6. Percentage of Participants Who Discontinued From Investigational Medicinal Product (IMP) for Asthma Exacerbation During the 12 Week Treatment Period [Baseline up to Week 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 11 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The participant has a diagnosis of asthma as defined by the National Institutes of Health (NIH).

• The participant has persistent asthma with a FEV1 ≥50% and ≤90% of the value predicted for age, height, sex, and race at the screening visit (SV).

• The participant's persistent asthma is stable and is currently being treated with stable asthma therapy for at least 30 days before the SV. Participants currently on a short-acting β2-agonist (SABA) only, regimen or as needed (PRN), are not eligible.

• The participant has demonstrated ≥10% response to a bronchodilator from screening FEV1 within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol.

• The participant (with assistance from parents/legal guardians/caregivers, as needed) is able to perform technically acceptable lung function assessments by handheld device.

• All participants must be able to replace their current SABA with albuterol/salbutamol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) inhalation aerosol at the SV for use as needed for the duration of the study.

• Additional criteria apply, please contact the investigator for more information

Exclusion Criteria:

• The participant has a history of life-threatening asthma exacerbation that is defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, or hypoxic seizures.

• The participant is pregnant or lactating or plans to become pregnant during the study period or within 30 days after the participant's last study-related visit.

• The participant has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the investigational medicinal product (IMP) or rescue medication formulation (that is, lactose).

• The participant has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (for example, ketoconazole, ritonavir, clarithromycin) within 30 days before the SV or plans to be treated with any strong CYP3A4 inhibitor during the study.

• The participant currently smokes or has a smoking history. The participant must not have used tobacco products within the past year (for example, cigarettes, cigars, chewing tobacco, or pipe tobacco).

• The participant 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.

• The participant has used immunosuppressive medications within 30 days before the SV.

• The participant has untreated oral candidiasis at the SV. Participants with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the run-in period.

• The participant has a history of a positive test for human immunodeficiency virus, active hepatitis B virus, or hepatitis C infection.

• The participant is an immediate relative of an employee of the clinical investigational center.

• A member of the participant's household is participating in the study at the same time.

• Vulnerable participants (that is, people kept in detention) are excluded from participation.

• Additional criteria apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 13881	Birmingham	Alabama	United States	35209
2	Teva Investigational Site 13883	Little Rock	Arkansas	United States	72205
3	Teva Investigational Site 13906	Bakersfield	California	United States	93301
4	Teva Investigational Site 14615	Corona	California	United States	92883
5	Teva Investigational Site 13892	Downey	California	United States	90241
6	Teva Investigational Site 13875	Fountain Valley	California	United States	92708
7	Teva Investigational Site 13904	Huntington Beach	California	United States	92647 6818
8	Teva Investigational Site 13877	Huntington Beach	California	United States	92648
9	Teva Investigational Site 14668	Long Beach	California	United States	90806
10	Teva Investigational Site 13914	Napa	California	United States	94558
11	Teva Investigational Site 13918	Paramount	California	United States	90723
12	Teva Investigational Site 14618	Rolling Hills Estates	California	United States	90274
13	Teva Investigational Site 13912	Roseville	California	United States	95661
14	Teva Investigational Site 13847	Stockton	California	United States	95207
15	Teva Investigational Site 13848	Thousand Oaks	California	United States	91360
16	Teva Investigational Site 13856	Centennial	Colorado	United States	80112
17	Teva Investigational Site 13910	Colorado Springs	Colorado	United States	80907
18	Teva Investigational Site 13868	Longmont	Colorado	United States	80501
19	Teva Investigational Site 13913	Chiefland	Florida	United States	32626
20	Teva Investigational Site 14616	DeLand	Florida	United States	32720
21	Teva Investigational Site 13909	Homestead	Florida	United States	33030
22	Teva Investigational Site 13857	Loxahatchee Groves	Florida	United States	33470
23	Teva Investigational Site 13870	Miami Lakes	Florida	United States	33014
24	Teva Investigational Site 14617	Miami Lakes	Florida	United States	33015
25	Teva Investigational Site 13916	Miami Springs	Florida	United States	33185
26	Teva Investigational Site 13872	Miami	Florida	United States	33134
27	Teva Investigational Site 13907	Miami	Florida	United States	33134
28	Teva Investigational Site 13893	Miami	Florida	United States	33142
29	Teva Investigational Site 13886	Miami	Florida	United States	33155
30	Teva Investigational Site 13899	Miami	Florida	United States	33175
31	Teva Investigational Site 13864	Miami	Florida	United States	33176
32	Teva Investigational Site 13880	Miami	Florida	United States	33176
33	Teva Investigational Site 13911	Ocala	Florida	United States	34471
34	Teva Investigational Site 13876	Palmetto Bay	Florida	United States	33157
35	Teva Investigational Site 13844	Winter Park	Florida	United States	32789
36	Teva Investigational Site 13866	Gainesville	Georgia	United States	30501
37	Teva Investigational Site 13858	Savannah	Georgia	United States	31406
38	Teva Investigational Site 13896	Eagle	Idaho	United States	83616
39	Teva Investigational Site 13903	Idaho Falls	Idaho	United States	83402
40	Teva Investigational Site 13882	Springfield	Illinois	United States	62704
41	Teva Investigational Site 13887	Overland Park	Kansas	United States	66210
42	Teva Investigational Site 13851	Owensboro	Kentucky	United States	42301
43	Teva Investigational Site 13849	Rockville	Maryland	United States	20850
44	Teva Investigational Site 13865	Columbia	Missouri	United States	65203
45	Teva Investigational Site 13885	Columbia	Missouri	United States	65203
46	Teva Investigational Site 13891	Missoula	Montana	United States	59808
47	Teva Investigational Site 13897	Ocean City	New Jersey	United States	07712
48	Teva Investigational Site 13854	Verona	New Jersey	United States	07044
49	Teva Investigational Site 13908	Watertown	New York	United States	13601
50	Teva Investigational Site 13890	Charlotte	North Carolina	United States	28277
51	Teva Investigational Site 13863	Raleigh	North Carolina	United States	27607
52	Teva Investigational Site 13855	Canton	Ohio	United States	44718
53	Teva Investigational Site 13905	Milford	Ohio	United States	45150
54	Teva Investigational Site 13852	Oklahoma City	Oklahoma	United States	73112
55	Teva Investigational Site 13879	Oklahoma City	Oklahoma	United States	73112
56	Teva Investigational Site 13884	Oklahoma City	Oklahoma	United States	73120
57	Teva Investigational Site 13860	Tulsa	Oklahoma	United States	74136
58	Teva Investigational Site 13894	Tulsa	Oklahoma	United States	74136
59	Teva Investigational Site 13861	Medford	Oregon	United States	97504
60	Teva Investigational Site 13874	Pittsburgh	Pennsylvania	United States	15241
61	Teva Investigational Site 13895	Scottdale	Pennsylvania	United States	15683
62	Teva Investigational Site 13888	Providence	Rhode Island	United States	02909
63	Teva Investigational Site 13871	Charleston	South Carolina	United States	29407
64	Teva Investigational Site 13889	Charleston	South Carolina	United States	29414
65	Teva Investigational Site 13853	Spartanburg	South Carolina	United States	29303
66	Teva Investigational Site 14671	Summerville	South Carolina	United States	29483
67	Teva Investigational Site 13898	Baytown	Texas	United States	77521
68	Teva Investigational Site 14673	Boerne	Texas	United States	78006
69	Teva Investigational Site 13867	El Paso	Texas	United States	79903
70	Teva Investigational Site 13902	Killeen	Texas	United States	76542-0969
71	Teva Investigational Site 13846	Live Oak	Texas	United States	78233
72	Teva Investigational Site 13878	San Antonio	Texas	United States	78229
73	Teva Investigational Site 14672	San Antonio	Texas	United States	78229
74	Teva Investigational Site 13917	San Antonio	Texas	United States	78251
75	Teva Investigational Site 13845	Waco	Texas	United States	76712
76	Teva Investigational Site 13850	Richmond	Virginia	United States	23223
77	Teva Investigational Site 13915	Bellingham	Washington	United States	98225
78	Teva Investigational Site 81041	Kutaisi		Georgia	4600
79	Teva Investigational Site 81047	Tbilisi		Georgia	0119
80	Teva Investigational Site 81046	Tbilisi		Georgia	0141
81	Teva Investigational Site 81044	Tbilisi		Georgia	0159
82	Teva Investigational Site 81040	Tbilisi		Georgia	0160
83	Teva Investigational Site 81045	Tbilisi		Georgia	0171
84	Teva Investigational Site 81042	Tbilisi		Georgia	0179
85	Teva Investigational Site 81043	Tbilisi		Georgia	0186
86	Teva Investigational Site 51277	Budapest		Hungary	1083
87	Teva Investigational Site 51278	Budapest		Hungary	1094
88	Teva Investigational Site 51272	Budapest		Hungary	H-1021
89	Teva Investigational Site 51279	Debrecen		Hungary	4032
90	Teva Investigational Site 51271	Dombovar		Hungary	7200
91	Teva Investigational Site 51269	Gyor		Hungary	9023
92	Teva Investigational Site 51274	Kaposvar		Hungary	7400
93	Teva Investigational Site 51270	Miskolc		Hungary	3526
94	Teva Investigational Site 51276	Szeged		Hungary	6720
95	Teva Investigational Site 51273	Szigetvar		Hungary	7900
96	Teva Investigational Site 50444	Moscow		Russian Federation	125412
97	Teva Investigational Site 50446	Perm		Russian Federation	614066
98	Teva Investigational Site 50445	Saint Petersburg		Russian Federation	196240
99	Teva Investigational Site 50443	Saint Petersburg		Russian Federation	196657
100	Teva Investigational Site 50442	Saint-Petersburg		Russian Federation	191144
101	Teva Investigational Site 50447	Saint-Petersburg		Russian Federation	192071
102	Teva Investigational Site 50441	Saint-Petersburg		Russian Federation	192148
103	Teva Investigational Site 50448	Saint-Petersburg		Russian Federation	196191
104	Teva Investigational Site 50440	Tomsk		Russian Federation	634050
105	Teva Investigational Site 58261	Chernivtsi		Ukraine	58023
106	Teva Investigational Site 58262	Dnipropetrovsk		Ukraine	49101
107	Teva Investigational Site 58269	Ivano-Frankivsk		Ukraine	76014
108	Teva Investigational Site 58270	Kharkiv		Ukraine	61093
109	Teva Investigational Site 58265	Kryvyi Rih		Ukraine	50082
110	Teva Investigational Site 58271	Kyiv		Ukraine	03115
111	Teva Investigational Site 58268	Kyiv		Ukraine	03680
112	Teva Investigational Site 58264	Kyiv		Ukraine	04050
113	Teva Investigational Site 58260	Lviv		Ukraine	79059
114	Teva Investigational Site 58259	Odesa		Ukraine	65000
115	Teva Investigational Site 58272	Odessa		Ukraine	65000
116	Teva Investigational Site 58263	Vinnytsya		Ukraine	21021
117	Teva Investigational Site 58267	Zaporizhzhia		Ukraine	69063
118	Teva Investigational Site 58266	Zaporizhzhya		Ukraine	69038

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)

• Study Protocol - Jun 5, 2018
• Statistical Analysis Plan - Apr 16, 2019

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02980133
• Other Study ID Numbers: FSS-AS-30003; 2016-003835-39
• First Posted: Dec 2, 2016
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Salmeterol Xinafoate

Study Results

Participant Flow

Pre-assignment Detail	A total of 841 participants with persistent asthma were randomized in a 1:1:1:1 ratio to receive Fp MDPI 25 mcg, Fp MDPI 50 mcg, FS MDPI 50/12.5 mcg, or placebo MDPI. Randomization was stratified by previous therapy (inhaled corticosteroid [ICS] or non-corticosteroid [NCS]).

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via multidose dry powder inhaler (MDPI) for 12 weeks.	Participants received 1 inhalation of 25 micrograms (mcg) fluticasone propionate (Fp) via MDPI twice daily (BID) (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol (FS) via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Period Title: Overall Study
STARTED	209	211	210	211
Received at Least 1 Dose of Study Drug	209	211	208	211
COMPLETED	202	206	203	205
NOT COMPLETED	7	5	7	6

Baseline Characteristics

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID	Total
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.	Total of all reporting groups
Overall Participants	209	211	210	211	841
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.5 (1.98)	8.7 (1.83)	8.5 (1.94)	8.4 (2.05)	8.5 (1.95)
Sex: Female, Male (Count of Participants)
Female	79 37.8%	74 35.1%	80 38.1%	91 43.1%	324 38.5%
Male	130 62.2%	137 64.9%	130 61.9%	120 56.9%	517 61.5%
Race/Ethnicity, Customized (Count of Participants)
White	172 82.3%	168 79.6%	171 81.4%	172 81.5%	683 81.2%
Black or African American	33 15.8%	41 19.4%	32 15.2%	29 13.7%	135 16.1%
Asian	1 0.5%	0 0%	2 1%	3 1.4%	6 0.7%
American Indian or Alaska Native	0 0%	1 0.5%	2 1%	0 0%	3 0.4%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	0 0%	0 0%	1 0.1%
Other	2 1%	1 0.5%	3 1.4%	7 3.3%	13 1.5%
At-Home Baseline Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) (percent predicted of FEV1) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted of FEV1]	68.8 (9.70)	69.6 (9.68)	69.6 (9.47)	69.9 (9.15)	69.5 (9.49)
In-Clinic Baseline Percent Predicted FEV1 (percent predicted of FEV1) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent predicted of FEV1]	74.9 (14.58)	73.0 (13.43)	72.9 (13.00)	74.1 (15.02)	73.7 (14.03)

Outcome Measures

1. Primary Outcome

Title	For FS MDPI Versus Fp MDPI: Change From Baseline in 1-Hour Postdose Percent Predicted Morning Forced Expiratory Volume in 1 Second (FEV1) at Week 12
Description	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. The baseline 1-hour trough morning percent predicted FEV1 was defined as the predose trough morning percent predicted FEV1 measurement at the randomization visit (Baseline [Day 1]) at the investigational center. The IMP dose was administered right after the predose FEV1 measurement (within a 10 minute window). Participant then performed 1-hour (±10 minutes) postdose lung function assessments on Week 12 at the investigational center.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. Missing data was imputed using MNAR methodology for prematurely discontinue participants or MAR for completers with implausible data.

Arm/Group Title	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	211	209	211
Least Squares Mean (Standard Error) [percent predicted of FEV1]	16.8 (1.32)	16.4 (1.32)	18.2 (1.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 50 mcg BID, FS MDPI 50/12.5 mcg BID
	Comments	Analysis was performed using an ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.285
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -1.6 to 5.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	For Fp MDPI Versus Placebo: Change From Baseline in Weekly Average of the Percent Predicted Trough Morning FEV1 at Week 12
Description	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. Baseline trough morning percent predicted FEV1 was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. The first day before randomization consisted of the electronic patient diary entry at home on the morning of the randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of the electronic patient diary entry at home on the morning of the day after the randomization visit (Baseline [Day 1]). For postdose weekly average of trough morning percent predicted FEV1 measurements, the values were the averages based on the available data for that week. The averages were calculated as the sum of morning FEV1 values divided by the number of nonmissing assessments.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure. Missing data was imputed using missing not at random (MNAR) methodology for prematurely discontinue participants or missing at random (MAR) for completers with implausible data.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.
Measure Participants	209	211	209
Least Squares Mean (Standard Error) [percent predicted of FEV1]	7.3 (1.10)	13.3 (1.09)	14.2 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 25 mcg BID, Fp MDPI 50 mcg BID
	Comments	Analysis was performed using an analysis of covariance (ANCOVA) model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (inhaled corticosteroid [ICS] or noncorticosteroid [NCS]), and investigational medicinal product (IMP) treatment group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	6.0
	Confidence Interval	(2-Sided) 95%; 3.2 to 8.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 25 mcg BID, FS MDPI 50/12.5 mcg BID
	Comments	Analysis was performed using an ANCOVA model with effects due to baseline trough morning percent predicted FEV1, sex, age, (pooled) investigational center, previous therapy (ICS or NCS), and IMP treatment group.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	7.0
	Confidence Interval	(2-Sided) 95%; 4.1 to 9.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in the Weekly Average of Daily Trough Morning (Predose and Pre-Rescue Bronchodilator) Peak Expiratory Flow (PEF) Over the 12 Week Treatment Period
Description	PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. Morning PEF was determined in the morning, before administration of IMP or rescue medications. Baseline trough morning PEF was defined as the average value of recorded (nonmissing) morning assessments 5 out of the last 7 days prior to randomization. The first day before randomization consisted of the electronic patient diary entry at home on the morning of the randomization visit (Baseline [Day 1]) and the first day postrandomization consisted of the electronic patient diary entry at home on the morning of the day after the randomization visit (Baseline [Day 1]). For postdose weekly average of trough morning PEF measurements, the values were the averages based on the available data for that week. The averages were calculated as the sum of morning PEF values divided by the number of nonmissing assessments.
Time Frame	Baseline, Week 1 to 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	208	210	208	211
Least Squares Mean (Standard Error) [liters/minute]	12.3 (2.65)	28.9 (2.62)	26.3 (2.64)	32.0 (2.61)

4. Secondary Outcome

Title	Change From Baseline in the Weekly Average of Total Daily (24 Hour) Use of Albuterol/Salbutamol Inhalation Aerosol (Number of Inhalations) Over Weeks 1 Through 12
Description	Participants recorded the number of inhalations of rescue medication (albuterol/salbutamol HFA MDI) each morning and evening in the electronic patient diary. An entry of 0 inhalations indicated no rescue medication was needed. To calculate the total daily use of albuterol/salbutamol inhalation aerosol (number of inhalations), the electronic patient diary entry on randomization visit (Baseline [Day 1]) was defined as the first day of analysis. The weekly average of the total daily inhalations was the average based on the available data for that week. The average was calculated as the sum of total daily inhalations over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and standard error (SE) were obtained using mixed model for repeated measures (MMRM).
Time Frame	Baseline, Week 1 to 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	208	210	209	211
Least Squares Mean (Standard Error) [inhalations]	-0.2 (0.05)	-0.4 (0.05)	-0.5 (0.05)	-0.4 (0.05)

5. Secondary Outcome

Title	Change From Baseline in the Weekly Average of the Total Daily Asthma Symptom Score Over Weeks 1 Through 12
Description	Asthma symptom scores were recorded in the patient diary. Each participant assessed the symptoms of cough, wheeze, shortness of breath, and chest tightness and entered a single score that was inclusive of all symptoms. Daytime Symptom Score (determined in the evening) ranged from 0=No symptoms during the day to 5=Symptoms so severe that I could not go to work or perform normal daily activities. Nighttime Symptom Score (determined in the morning) ranged from 0=No symptoms during the night to 4=Symptoms so severe that I did not sleep at all. The total daily asthma symptom score was the average of the daytime and nighttime scores. The total daily asthma symptom score ranged from 0 - 9 with 0=no symptoms during the day or night and 9=severe symptoms both day and night. The weekly average was calculated as the sum of total daily asthma symptom scores over the 7 days for each analysis week divided by the number of nonmissing assessments. LS mean and SE were obtained using MMRM.
Time Frame	Baseline, Week 1 to 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	208	210	209	211
Least Squares Mean (Standard Error) [units on a scale]	-0.1 (0.02)	-0.2 (0.02)	-0.2 (0.02)	-0.2 (0.02)

6. Secondary Outcome

Title	Change From Baseline in Asthma Control (Measured by Childhood Asthma Control Test [C-ACT] Score) Over the 12 Week Treatment Period
Description	C-ACT was a simple, participant-completed tool used for the assessment of overall asthma control. The first 4 items of the test were completed by the participant, while the last 3 items were completed by the participant's parents/legal guardians/caregivers. A total sum score based upon responses to all items was calculated to provide an overall measure of asthma control. The derived C-ACT score ranging from 0 to 27. These scores spanned the continuum of poor control of asthma (score ≤5) to complete control of asthma (score ≥25), with a cut off score of 19 indicating participants with poorly controlled asthma. LS mean and SE were obtained using MMRM.
Time Frame	Baseline, Week 1 to 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	204	208	205	209
Least Squares Mean (Standard Error) [units on a scale]	4.5 (0.21)	5.1 (0.21)	5.5 (0.21)	5.4 (0.21)

7. Secondary Outcome

Title	Time to First Onset of Effect
Description	The time to first onset of effect, defined as the first decrease from baseline in daily rescue medication use, was calculated based on the number of inhalations of rescue medication (albuterol/salbutamol hydrofluoroalkane metered-dose inhaler [HFA MDI] [90 mcg ex actuator] or equivalent) recorded by the participant each morning and evening in the patient diary built into the handheld device.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	208	210	208	211
Median (95% Confidence Interval) [days]	20.0	NA	2.0	6.0

8. Secondary Outcome

Title	Percentage of Participants Who Discontinued From Investigational Medicinal Product (IMP) for Asthma Exacerbation During the 12 Week Treatment Period
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Placebo MDPI	Fp MDPI 25 mcg BID	Fp MDPI 50 mcg BID	FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.	Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.	Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.	Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
Measure Participants	208	210	208	211
Number [percentage of participants]	6 2.9%	2 0.9%	1 0.5%	2 0.9%

Adverse Events

Time Frame	Baseline up to Week 13
Adverse Event Reporting Description	Safety analysis set included all randomized participants who received at least 1 dose of IMP.
Arm/Group Title	Placebo MDPI		Fp MDPI 25 mcg BID		Fp MDPI 50 mcg BID		FS MDPI 50/12.5 mcg BID
Arm/Group Description	Participants received matching placebo via MDPI for 12 weeks.		Participants received 1 inhalation of 25 mcg fluticasone propionate via MDPI BID (total daily dose: 50 mcg) for 12 weeks.		Participants received 1 inhalation of 50 mcg fluticasone propionate via MDPI BID (total daily dose: 100 mcg) for 12 weeks.		Participants received 1 inhalation of 50/12.5 mcg fluticasone propionate/salmeterol via MDPI BID (total daily dose: 100/25 mcg) for 12 weeks.
All Cause Mortality
	Placebo MDPI		Fp MDPI 25 mcg BID		Fp MDPI 50 mcg BID		FS MDPI 50/12.5 mcg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/209 (0%)		0/211 (0%)		0/208 (0%)		0/211 (0%)
Serious Adverse Events
	Placebo MDPI		Fp MDPI 25 mcg BID		Fp MDPI 50 mcg BID		FS MDPI 50/12.5 mcg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/209 (0.5%)		2/211 (0.9%)		1/208 (0.5%)		4/211 (1.9%)
Blood and lymphatic system disorders
Lymphadenitis	0/209 (0%)	0	0/211 (0%)	0	0/208 (0%)	0	1/211 (0.5%)	1
General disorders
Pyrexia	0/209 (0%)	0	0/211 (0%)	0	0/208 (0%)	0	1/211 (0.5%)	1
Infections and infestations
Pneumonia mycoplasmal	0/209 (0%)	0	1/211 (0.5%)	1	0/208 (0%)	0	0/211 (0%)	0
Respiratory tract infection viral	1/209 (0.5%)	1	0/211 (0%)	0	0/208 (0%)	0	0/211 (0%)	0
Nervous system disorders
Headache	0/209 (0%)	0	0/211 (0%)	0	0/208 (0%)	0	1/211 (0.5%)	1
Partial seizures	0/209 (0%)	0	0/211 (0%)	0	0/208 (0%)	0	1/211 (0.5%)	1
Psychiatric disorders
Disruptive mood dysregulation disorder	0/209 (0%)	0	0/211 (0%)	0	1/208 (0.5%)	1	0/211 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	1/209 (0.5%)	1	1/211 (0.5%)	1	0/208 (0%)	0	0/211 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo MDPI		Fp MDPI 25 mcg BID		Fp MDPI 50 mcg BID		FS MDPI 50/12.5 mcg BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/209 (5.3%)		8/211 (3.8%)		11/208 (5.3%)		9/211 (4.3%)
Infections and infestations
Nasopharyngitis	11/209 (5.3%)	12	8/211 (3.8%)	9	11/208 (5.3%)	11	9/211 (4.3%)	9

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.