MGR001 / Advair Diskus Local Equivalence Study in Asthma

• Sponsor: Mylan Pharma UK Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02245672
• Collaborator: (none)
• Enrollment: 1,128
• Locations: 101
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 11.2
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether MGR001 is equivalent to Advair Diskus when administered by inhalation in adult asthma patients

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate); Drug: Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate); Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Double Dummy, Parallel Group Study to Determine the Local Equivalence of Multiple Doses of MGR001 to Advair Diskus Administered Via Oral Inhalation in Adult Asthma Patients
• Study Start Date: Oct 1, 2014
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MGR001 MGR001 administered two times per day by inhalation throughout the study	Drug: MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate); Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device
Active Comparator: Advair Diskus Advair Diskus administered two times per day by inhalation throughout the study	Drug: Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate); Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device
Placebo Comparator: Placebo Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study	Drug: Placebo; Placebo administered via the CRC749 and Diskus devices

Outcome Measures

Primary Outcome Measures

1. Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity) [0-12 hours after dosing on Day 1]

   The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo

2. Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence) [0-12 hours after dosing on Day 1]

   The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures

3. FEV1 Trough Value (Assay Sensitivity) [Day 1 and Day 29]

   Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of [prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1]. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo.

4. FEV1 Trough Value (Bioequivalence) [Day 1 and Day 29]

   Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of [prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key inclusion criteria include:

• Male or female subjects aged ≥18 years. Females may be of either childbearing or non-childbearing potential

• Physician diagnosed history of asthma for at least 12 weeks prior to screening

• pre-bronchodilator FEV1 60-85% at screening and other specified visits

• Post-bronchodilator reversibility >/=12%

• Non-smokers and prior smokers with no history of smoking within the past 12 months prior to screening and a total smoking history of ≤10 pack-years

• Subjects able to discontinue asthma medications for the duration of the study and be maintained using albuterol as required

• Body mass index between 18-40 kg/m2 inclusive

Key exclusion criteria include:

• Presence or recent history of any other active, severe, progressive, and/or uncontrolled clinical disease, eg, poorly controlled Type 1 or 2 diabetes, seizure disorder or epilepsy, cerebrovascular accident, significant cardiac conduction abnormalities

• Respiratory conditions other than asthma and allergic rhinitis, including but not limited to: severe nasal polyposis or chronic rhinosinusitis, chronic obstructive pulmonary disease, bronchiectasis, Churg-Strauss Disease, lung resection, pulmonary fibrosis (primary or secondary), pulmonary hypertension, cystic fibrosis, sarcoidosis

• History of life-threatening asthma, defined as a history of asthma episode(s) requiring intubation, and/or associated with hypercapnia; respiratory arrest or hypoxic seizures, asthma related syncopal episode(s)

• In patient hospitalization (not including ER visits) for an asthma exacerbation within the past year or during the run in period

• An asthma exacerbation requiring change in asthma therapy or oral/IV corticosteroids in the 3 months prior to screening

• History of seasonally unstable asthma where the season will coincide with the subject's participation in the study

• Use of prescription or non-prescription drugs, including beta blockers, tricyclic antidepressants, oral decongestants, benzodiazepines, digitalis, phenothiazines, monoamine oxidase inhibitors, etc

• Suspected hypersensitivity to the study drugs (including lactose) or severe milk protein allergy

• Clinically significant abnormalities in the screening ECG

• Evidence of alcohol or drug abuse or dependency within 6 months prior to screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mylan Investigative Site #1	Birmingham	Alabama	United States	35209
2	Mylan Investigative Site #2	Little Rock	Arkansas	United States	72205
3	Mylan Investigative Site #3	Anaheim	California	United States	92801
4	Mylan Investigative Site #4	Bakersfield	California	United States	93301
5	Mylan Investigative Site #5	Burbank	California	United States	91505
6	Mylan Investigative Site #6	Costa Mesa	California	United States	92626
7	Mylan Investigative Site #7	Encinitas	California	United States	92024
8	Mylan Investigative Site #8	Fresno	California	United States	93720
9	Mylan Investigative Site #9	Fullerton	California	United States	92835
10	Mylan Investigative Site #10	Huntington Beach	California	United States	92647
11	Mylan Investigative Site #11	Huntington Beach	California	United States	92647
12	Mylan Investigative Site #12	Los Angeles	California	United States	90025
13	Mylan Investigative Site #13	Los Angeles	California	United States	90025
14	Mylan Investigative Site #14	Los Angeles	California	United States	90048
15	Mylan Investigative Site #15	Mission Viejo	California	United States	92691
16	Mylan Investigative Site #16	Napa	California	United States	94558
17	Mylan Investigative Site #17	Orange	California	United States	92868
18	Mylan Investigative Site #18	Riverside	California	United States	92506
19	Mylan Investigational Site #27	Rolling Hills Estates	California	United States	90274
20	Mylan Investigative Site #19	Sacramento	California	United States	95842
21	Mylan Investigative Site #20	San Diego	California	United States	92123
22	Mylan Investigative Site #21	San Jose	California	United States	95117
23	Mylan Investigative Site #101	Centennial	Colorado	United States	80112
24	Mylan Investigative Site #22	Centennial	Colorado	United States	80112
25	Mylan Investigative Site #23	Colorado Springs	Colorado	United States	80907
26	Mylan Investigative Site #24	Colorado Springs	Colorado	United States	80907
27	Mylan Investigative Site #25	Denver	Colorado	United States	80230
28	Mylan Investigative Site #26	Wheat Ridge	Colorado	United States	80033
29	Mylan Investigative Site #28	Coral Gables	Florida	United States	33134
30	Mylan Investigative Site #29	Gainesville	Florida	United States	32607
31	Mylan Investigative Site #30	Hialeah	Florida	United States	33012
32	Mylan Investigative Site #31	Largo	Florida	United States	33770
33	Mylan Investigative Site #32	Miami	Florida	United States	33015
34	Mylan Investigative Site #34	Miami	Florida	United States	33133
35	Mylan Investigative Site #33	Miami	Florida	United States	33134
36	Mylan Investigative Site #35	Miami	Florida	United States	33155
37	Mylan Investigative Site #36	New Port Richey	Florida	United States	34653
38	Mylan Investigative Site #37	Tallahassee	Florida	United States	32308
39	Mylan Investigative Site #38	Lawrenceville	Georgia	United States	30046
40	Mylan Investigative Site #39	River Forest	Illinois	United States	60305
41	Mylan Investigative Site #40	Shiloh	Illinois	United States	62269
42	Mylan Investigative Site #41	Lenexa	Kansas	United States	66219
43	Mylan Investigative Site #42	Bangor	Maine	United States	04401
44	Mylan Investigative Site #43	Baltimore	Maryland	United States	21236
45	Mylan Investigative Site #44	Bethesda	Maryland	United States	20814
46	Mylan Investigative Site #45	Wheaton	Maryland	United States	20902
47	Mylan Investigative Site #46	White Marsh	Maryland	United States	21162
48	Mylan Investigative Site #47	Fall River	Massachusetts	United States	02720
49	Mylan Investigative Site #48	North Dartmouth	Massachusetts	United States	02747
50	Mylan Investigative Site #49	North Dartmouth	Massachusetts	United States	02747
51	Mylan Investigative Site #50	Minneapolis	Minnesota	United States	55402
52	Mylan Investigative Site #51	Columbia	Missouri	United States	65203
53	Mylan Investigative Site #52	Rolla	Missouri	United States	65401
54	Mylan Investigative Site #53	Saint Louis	Missouri	United States	63141
55	Mylan Investigative Site #54	Warrensburg	Missouri	United States	64093
56	Mylan Investigative Site #55	Bozeman	Montana	United States	59718
57	Mylan Investigative Site #56	Missoula	Montana	United States	59808
58	Mylan Investigative Site #57	Bellevue	Nebraska	United States	68123-4303
59	Mylan Investigative Site #58	Brick	New Jersey	United States	08724
60	Mylan Investigative Site #59	Ocean City	New Jersey	United States	07712
61	Mylan Investigative Site #60	Skillman	New Jersey	United States	08558
62	Mylan Investigative Site #61	New York	New York	United States	11570
63	Mylan Investigative Site #62	Asheville	North Carolina	United States	28801
64	Mylan Investigative Site #63	Charlotte	North Carolina	United States	28207
65	Mylan Investigative Site #64	Raleigh	North Carolina	United States	27607
66	Mylan Investigative Site #65	Canton	Ohio	United States	44718
67	Mylan Investigative Site #66	Cincinnati	Ohio	United States	45231
68	Mylan Investigative Site #67	Cincinnati	Ohio	United States	45242
69	Mylan Investigative Site #68	Sylvania	Ohio	United States	43560
70	Mylan Investigative Site #69	Toledo	Ohio	United States	43617
71	Mylan Investigative Site #70	Oklahoma City	Oklahoma	United States	73112
72	Mylan Investigative Site #71	Tulsa	Oklahoma	United States	74136-8303
73	Mylan Investigative Site #72	Eugene	Oregon	United States	97401
74	Mylan Investigative Site #73	Lake Oswego	Oregon	United States	97035
75	Mylan Investigative Site #74	Medford	Oregon	United States	97504
76	Mylan Investigative Site #75	Portland	Oregon	United States	97202
77	Mylan Investigative Site #76	Jenkintown	Pennsylvania	United States	19046
78	Mylan Investigative Site #77	Pittsburgh	Pennsylvania	United States	15243
79	Mylan Investigative Site #78	Smithfield	Pennsylvania	United States	15478
80	Mylan Investigative Site #79	Providence	Rhode Island	United States	02906
81	Mylan Investigative Site #80	Warwick	Rhode Island	United States	02886
82	Mylan Investigative Site #81	North Charleston	South Carolina	United States	29420
83	Mylan Investigative Site #82	Spartanburg	South Carolina	United States	29303
84	Mylan Investigative Site #83	Spartanburg	South Carolina	United States	29303
85	Mylan Investigative Site #84	Boerne	Texas	United States	78006
86	Mylan Investigative Site #85	Dallas	Texas	United States	75231
87	Mylan Investigative Site #86	Dallas	Texas	United States	75231
88	Mylan Investigative Site #87	Dickinson	Texas	United States	77539
89	Mylan Investigative Site #88	El Paso	Texas	United States	79903
90	Mylan Investigative Site #89	New Braunfels	Texas	United States	78130
91	Mylan Investigative Site #90	San Antonio	Texas	United States	78229
92	Mylan Investigative Site #91	San Antonio	Texas	United States	78229
93	Mylan Investigative Site #92	Waco	Texas	United States	76712
94	Mylan Investigative Site #93	Provo	Utah	United States	84604
95	Mylan Investigative Site #94	South Burlington	Vermont	United States	05403
96	Mylan Investigative Site #95	Henrico	Virginia	United States	23233
97	Mylan Investigative Site #96	Seattle	Washington	United States	98115
98	Mylan Investigative Site #97	Spokane	Washington	United States	99204
99	Mylan Investigative Site #98	Tacoma	Washington	United States	98405
100	Mylan Investigative Site #99	Tacoma	Washington	United States	98405
101	Mylan Investigative Site #100	Greenfield	Wisconsin	United States	53228

Sponsors and Collaborators

• Mylan Pharma UK Ltd.

Investigators

• Study Director: Dik WH Ng, PhD, Mylan Pharma UK Ltd.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mylan Pharma UK Ltd.
• ClinicalTrials.gov Identifier: NCT02245672
• Other Study ID Numbers: MGR001-3001
• First Posted: Sep 19, 2014
• Last Update Posted: Feb 24, 2022
• Last Verified: Feb 1, 2022

• Keywords provided by Mylan Pharma UK Ltd.: Asthma; fluticasone; salmeterol; CRC749; Diskus; Advair; FEV1; MGR001
• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Salmeterol Xinafoate

Study Results

Participant Flow

Arm/Group Title	MGR001	Advair Diskus	Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
Period Title: Overall Study
STARTED	512	513	103
COMPLETED	499	500	98
NOT COMPLETED	13	13	5

Baseline Characteristics

Arm/Group Title	MGR001	Advair Diskus	Placebo	Total
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices	Total of all reporting groups
Overall Participants	512	512	103	1127
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.6 (14.08)	42.5 (14.21)	43.5 (13.85)	42.6 (14.11)
Sex: Female, Male (Count of Participants)
Female	306 59.8%	309 60.4%	64 62.1%	679 60.2%
Male	206 40.2%	203 39.6%	39 37.9%	448 39.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	102 19.9%	92 18%	24 23.3%	218 19.3%
Not Hispanic or Latino	410 80.1%	420 82%	79 76.7%	909 80.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	11 2.1%	11 2.1%	1 1%	23 2%
Native Hawaiian or Other Pacific Islander	1 0.2%	0 0%	1 1%	2 0.2%
Black or African American	92 18%	98 19.1%	22 21.4%	212 18.8%
White	378 73.8%	372 72.7%	73 70.9%	823 73%
More than one race	30 5.9%	31 6.1%	6 5.8%	67 5.9%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	512 100%	512 100%	103 100%	1127 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.38 (6.026)	29.12 (5.886)	29.37 (5.890)	29.26 (5.947)

Outcome Measures

1. Primary Outcome

Title	Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity)
Description	The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo
Time Frame	0-12 hours after dosing on Day 1

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	MGR001	Advair Diskus	Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
Measure Participants	508	510	102
Least Squares Mean (Standard Error) [L*hr]	3.9534 (0.1609)	3.4964 (0.1595)	0.8191 (0.3477)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MGR001, Placebo
	Comments	MGR001 (Test) vs Placebo
	Type of Statistical Test	Superiority
	Comments	In order for the bioequivalence results to be valid, assay sensitivity had to be established. For assay sensitivity, the following comparisons were performed using the Full Analysis Set for each co-primary endpoint: MGR001 versus placebo, and Advair Diskus versus placebo. Assay sensitivity was demonstrated if the p-values for active treatment versus placebo were less than 0.05
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Advair Diskus, Placebo
	Comments	Advair Diskus (Reference) vs Placebo
	Type of Statistical Test	Superiority
	Comments	In order for the bioequivalence results to be valid, assay sensitivity had to be established.For assay sensitivity, the following comparisons were performed using the Full Analysis Set for each co-primary endpoint: MGR001 versus placebo, and Advair Diskus versus placebo. Assay sensitivity was demonstrated if the p-values for active treatment versus placebo were less than 0.05
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

2. Primary Outcome

Title	Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence)
Description	The FEV1 AUEC(0-12) on Day 1 was calculated from FEV1 measurements collected 30 minutes prior to morning dose, 0 minutes prior to morning dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours following completion of dosing on Day 1 (Visit 3). The baseline for the FEV1 AUEC(0-12) endpoint was the mean of the 2 predose FEV1 measures
Time Frame	0-12 hours after dosing on Day 1

Outcome Measure Data

Analysis Population Description

Per Protocol Set

Arm/Group Title	MGR001	Advair Diskus	Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
Measure Participants	497	494	94
Least Squares Mean (Standard Error) [L*hr]	3.9734 (0.1704)	3.5411 (0.1593)	0.8400 (0.2983)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MGR001, Advair Diskus
	Comments	Equivalence of MGR001 and Advair Diskus is established if the ratio of the LS means and 90% confidence interval are wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).
	Type of Statistical Test	Equivalence
	Comments	A linear analysis of covariance (ANCOVA) model was fitted for the endpoint and least-squares (LS) means were derived for each treatment. To assess equivalence, LS means (one for Test and one for Reference) from the ANCOVA models were used to generate Test/Reference ratios and 90% CIs were calculated by using Fieller's theorem. To demonstrate equivalence, the 90% CIs were each required to be wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (MGR001/Advair Diskus)
	Estimated Value	1.120
	Confidence Interval	(2-Sided) 90%; 1.016 to 1.237
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence was established between active treatments (MGR001 and Advair Diskus) for the FEV1 AUEC0-12 clinical endpoint

3. Primary Outcome

Title	FEV1 Trough Value (Assay Sensitivity)
Description	Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of [prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1]. To confirm assay sensitivity, both active treatments (MGR001 and Advair Diskus) had to be significantly superior to placebo.
Time Frame	Day 1 and Day 29

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	MGR001	Advair Diskus	Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
Measure Participants	504	505	100
Least Squares Mean (Standard Error) [L]	0.2927 (0.0162)	0.2720 (0.0161)	0.0575 (0.0353)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MGR001, Placebo
	Comments	MGR001 (Test) vs Placebo
	Type of Statistical Test	Superiority
	Comments	In order for the bioequivalence results to be valid, assay sensitivity had to be established. For assay sensitivity, the following comparisons were performed using the Full Analysis Set for each co-primary endpoint: MGR001 versus placebo, and Advair Diskus versus placebo. Assay sensitivity was demonstrated if the p-values for active treatment versus placebo were less than 0.05
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Advair Diskus, Placebo
	Comments	Advair Diskus (Reference) vs Placebo
	Type of Statistical Test	Superiority
	Comments	In order for the bioequivalence results to be valid, assay sensitivity had to be established. For assay sensitivity, the following comparisons were performed using the Full Analysis Set for each co-primary endpoint: MGR001 versus placebo, and Advair Diskus versus placebo. Assay sensitivity was demonstrated if the p-values for active treatment versus placebo were less than 0.05
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

4. Primary Outcome

Title	FEV1 Trough Value (Bioequivalence)
Description	Change from baseline in trough (pre-dose) FEV1 at Day 29 was based on 2 pre-dose FEV1 assessments performed 30 minutes apart on Day 29. Baseline was calculated by taking the mean of [prebronchodilator FEV1 measured at a run-in visit and the mean of 2 predose FEV1 measures taken at Day 1]
Time Frame	Day 1 and Day 29

Outcome Measure Data

Analysis Population Description

Per Protocol Set

Arm/Group Title	MGR001	Advair Diskus	Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device	Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
Measure Participants	498	497	99
Least Squares Mean (Standard Error) [L]	0.2911 (0.0163)	0.2728 (0.0162)	0.0574 (0.0355)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MGR001, Advair Diskus
	Comments	Equivalence of MGR001 and Advair Diskus is established if the ratio of the LS means and 90% confidence interval are wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).
	Type of Statistical Test	Equivalence
	Comments	A linear analysis of covariance (ANCOVA) model was fitted for the endpoint and least-squares (LS) means were derived for each treatment. To assess equivalence, LS means (one for Test and one for Reference) from the ANCOVA models were used to generate Test/Reference ratios and 90% CIs were calculated by using Fieller's theorem. To demonstrate equivalence, the 90% CIs were each required to be wholly contained within the interval 0.80-1.25 (i.e., 80%-125%).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio (MGR001/Advair Diskus)
	Estimated Value	1.069
	Confidence Interval	(2-Sided) 90%; 0.938 to 1.220
	Parameter Dispersion	Type: Value:
	Estimation Comments	Bioequivalence was established between active treatments (MGR001 and Advair Diskus) for change from baseline in trough FEV1 endpoint on Day 29

Adverse Events

Time Frame	Adverse events (AEs) were collected from the signing of the ICF but are reported from Day 1 to 30 days after the last dose of double-blind study medication.
Adverse Event Reporting Description	Subjects were routinely queried for AEs using open-ended questions. Spontaneously reported AEs were also recorded. The most frequent AEs occurring in at least 3 subjects across the 3 treatment groups are reported, equating to 0.2% of subjects in the Safety Set.
Arm/Group Title	MGR001		Advair Diskus		Placebo
Arm/Group Description	MGR001 administered two times per day by inhalation throughout the study MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device		Advair Diskus administered two times per day by inhalation throughout the study Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate): Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the Diskus inhaler device		Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study Placebo: Placebo administered via the CRC749 and Diskus devices
All Cause Mortality
	MGR001		Advair Diskus		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/512 (0%)		0/512 (0%)		0/103 (0%)
Serious Adverse Events
	MGR001		Advair Diskus		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/512 (0%)		0/512 (0%)		0/103 (0%)
Other (Not Including Serious) Adverse Events
	MGR001		Advair Diskus		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/512 (7.6%)		51/512 (10%)		10/103 (9.7%)
Gastrointestinal disorders
Dyspepsia	1/512 (0.2%)		2/512 (0.4%)		0/103 (0%)
Infections and infestations
Upper respiratory tract infection	7/512 (1.4%)		11/512 (2.1%)		0/103 (0%)
Nasopharyngitis	3/512 (0.6%)		7/512 (1.4%)		2/103 (1.9%)
Sinusitis	3/512 (0.6%)		3/512 (0.6%)		1/103 (1%)
Oral candidiasis	4/512 (0.8%)		2/512 (0.4%)		0/103 (0%)
Urinary tract infection	2/512 (0.4%)		2/512 (0.4%)		0/103 (0%)
Viral upper respiratory tract	1/512 (0.2%)		3/512 (0.6%)		0/103 (0%)
Bronchitis	2/512 (0.4%)		0/512 (0%)		1/103 (1%)
Gastroenteritis	0/512 (0%)		3/512 (0.6%)		0/103 (0%)
Viral infection	1/512 (0.2%)		2/512 (0.4%)		0/103 (0%)
Nervous system disorders
Headache	3/512 (0.6%)		5/512 (1%)		0/103 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	7/512 (1.4%)		10/512 (2%)		5/103 (4.9%)
Oropharyngeal pain	3/512 (0.6%)		5/512 (1%)		1/103 (1%)
Dysphonia	1/512 (0.2%)		3/512 (0.6%)		0/103 (0%)
Cough	1/512 (0.2%)		2/512 (0.4%)		0/103 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.