MGR001 / Advair Diskus Local Equivalence Study in Asthma | NCT02245672

Status Module

Oversight Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
MGR001	Experimental	MGR001 administered two times per day by inhalation throughout the study	Drug: MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate)
Advair Diskus	Active Comparator	Advair Diskus administered two times per day by inhalation throughout the study	Drug: Advair (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate)
Placebo	Placebo Comparator	Placebo for Advair Diskus and MGR001 administered two times per day by inhalation throughout the study	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
MGR001 (Fixed dose combination of Fluticasone propionate and salmeterol xinafoate)	Drug	Fluticasone propionate (100 mcg) and salmeterol xinafoate (50 mcg) administered via the CRC749 inhaler device

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity)	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	0-12 hours after dosing on Day 1
Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence)	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	0-12 hours after dosing on Day 1
FEV1 Trough Value (Assay Sensitivity)	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.	Day 1 and Day 29
FEV1 Trough Value (Bioequivalence)	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]	Day 1 and Day 29

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Dik WH Ng, PhD	Mylan Pharma UK Ltd.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Mylan Investigative Site #1		Birmingham	Alabama	35209	United States
Mylan Investigative Site #2

PubMed Identifier	Type	Citation	Retractions
31634023	Result	Ng D, Kerwin EM, White MV, Miller SD, Haughie S, Ward JK, Allan R. Clinical Bioequivalence of Wixela Inhub and Advair Diskus in Adults With Asthma. J Aerosol Med Pulm Drug Deliv. 2020 Apr;33(2):99-107. doi: 10.1089/jamp.2019.1547. Epub 2019 Oct 31.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	MGR001	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
FG001	Advair Diskus

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	MGR001	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
BG001	Advair Diskus	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
BG002	Placebo	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
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00042.6± 14.08 BG00142.5± 14.21 BG00243.5± 13.85 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000306 BG001309 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG000102 BG00192 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0010 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG000512 BG001512 BG002

Body Mass Index (BMI)

Mean

Standard Deviation

kg/m^2

Title

Denominators

Categories

Title	Measurements
	BG00029.38± 6.026 BG00129.12± 5.886 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Assay Sensitivity)

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

Full Analysis Set

Posted

Least Squares Mean

Standard Error

L*hr

0-12 hours after dosing on Day 1

ID	Title	Description
OG000	MGR001	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
OG001	Advair Diskus	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
OG002	Placebo	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

Units	Counts
Participants	OG000508 OG001510 OG002102

Title

Denominators

Categories

Title	Measurements
	OG0003.9534± 0.1609 OG0013.4964± 0.1595 OG0020.8191± 0.3477

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002	MGR001 (Test) vs Placebo	ANCOVA		<0.0001														Superiority	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

Primary

Forced Exhaled Volume in 1 Sec (FEV1) Area Under the Effect Curve on Day 1 (Bioequivalence)

Per Protocol Set

Posted

Least Squares Mean

Standard Error

L*hr

0-12 hours after dosing on Day 1

ID	Title	Description
OG000	MGR001	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
OG001	Advair Diskus	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
OG002	Placebo	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

Primary

FEV1 Trough Value (Assay Sensitivity)

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.

Full Analysis Set

Posted

Least Squares Mean

Standard Error

Day 1 and Day 29

ID	Title	Description
OG000	MGR001	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
OG001	Advair Diskus	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
OG002	Placebo	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

Primary

FEV1 Trough Value (Bioequivalence)

Per Protocol Set

Posted

Least Squares Mean

Standard Error

Day 1 and Day 29

ID	Title	Description
OG000	MGR001	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
OG001	Advair Diskus	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
OG002	Placebo	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

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	MGR001	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	512	512	39	512
EG001	Advair Diskus	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	512	512	51	512
EG002	Placebo	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	103	103	10	103

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0007 affected512 at risk EG00111 affected512 at risk EG0020 affected103 at risk
Nasopharyngitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0003 affected512 at risk EG0017 affected512 at risk EG0022 affected103 at risk
Sinusitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0003 affected512 at risk EG0013 affected512 at risk EG0021 affected103 at risk
Oral candidiasis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0004 affected512 at risk EG0012 affected512 at risk EG0020 affected103 at risk
Urinary tract infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0002 affected512 at risk EG0012 affected512 at risk EG0020 affected103 at risk
Viral upper respiratory tract	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected512 at risk EG0013 affected512 at risk EG0020 affected103 at risk
Bronchitis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0002 affected512 at risk EG0010 affected512 at risk EG0021 affected103 at risk
Gastroenteritis	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0000 affected512 at risk EG0013 affected512 at risk EG0020 affected103 at risk
Viral infection	Infections and infestations	MedDRA 18.0	Systematic Assessment	EG0001 affected512 at risk EG0012 affected512 at risk EG0020 affected103 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0007 affected512 at risk EG00110 affected512 at risk EG0025 affected103 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0003 affected512 at risk EG0015 affected512 at risk EG0021 affected103 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected512 at risk EG0013 affected512 at risk EG0020 affected103 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected512 at risk EG0012 affected512 at risk EG0020 affected103 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA 18.0	Systematic Assessment	EG0001 affected512 at risk EG0012 affected512 at risk EG0020 affected103 at risk
Headache	Nervous system disorders	MedDRA 18.0	Systematic Assessment	EG0003 affected512 at risk EG0015 affected512 at risk EG0020 affected103 at risk

ID	Term
D001982	Bronchial Diseases
D012140	Respiratory Tract Diseases
D008173	Lung Diseases, Obstructive
D008171	Lung Diseases
D012130	Respiratory Hypersensitivity
D006969	Hypersensitivity, Immediate
D006967	Hypersensitivity
D007154	Immune System Diseases

ID	Term
D000068299	Salmeterol Xinafoate
D000068297	Fluticasone-Salmeterol Drug Combination

ID	Term
D000420	Albuterol
D004983	Ethanolamines
D000605	Amino Alcohols
D000438	Alcohols
D009930	Organic Chemicals
D000588	Amines
D010627	Phenethylamines
D005021	Ethylamines
D000068298	Fluticasone
D000730	Androstadienes
D000736	Androstenes
D000731	Androstanes
D013256	Steroids
D000072473	Fused-Ring Compounds
D011083	Polycyclic Compounds
D004338	Drug Combinations
D004364	Pharmaceutical Preparations