Dose Ranging Study of the Salmeterol Component of Fluticasone /Salmeterol Spiromax Compared to Fluticasone Spiromax and Advair Diskus in Asthma Subjects

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01772368
• Collaborator: (none)
• Enrollment: 72
• Locations: 10
• Arms: 6
• Duration (Months): 5
• Patients Per Site: 7.2
• Patients Per Site Per Month: 1.5

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the dose response, efficacy, and safety of 4 different doses of salmeterol Spiromax (6.25, 12.5, 25, and 50 mcg) each combined with a fixed dose of fluticasone propionate (100 mcg) delivered as Fluticasone/Salmeterol Spiromax® Inhalation Powder (FS Spiromax) when administered as a single dose in subjects 12 years of age and older with persistent asthma.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: Fp MDPI; Drug: FS MDPI; Drug: Advair Diskus; Drug: Albuterol	Phase 2

Detailed Description

This was a multicenter, randomized, double-blind and open-label active-controlled, single-dose, 6 period crossover, dose-ranging study conducted in male and female subjects ages 12 years and older with persistent asthma.

Fluticasone propionate multidose dry powder inhaler (Fp MDPI) 50 mcg was provided (to replace the subject's current inhaled corticosteroid (ICS)) throughout the 14 day run-in period and each of the washout periods between treatments. Subjects were instructed to administer 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily during the run-in and washout periods. All other medications for the treatment of asthma were discontinued at or prior to the screening visit.

A short-acting β2-adrenergic agonist (SABA), salbuterol HFA, MDI, was provided (to replace the subject's current rescue medication) for symptomatic relief of asthma symptoms in each the run-in, treatment, and washout periods.

Treatment period lasted 5 weeks with a 5 to 7 day washout between each of the six single dose treatments:

• fluticasone propionate/salmeterol xinafoate multidose dry powder inhaler (FS MDPI) given in doses of 6.25, 12.5, 25, or 50 mcg of salmeterol xinafoate in blinded fashion.

• fluticasone propionate multidose dry powder inhaler (Fp MDPI) 100 mcg in blinded fashion

• ADVAIR DISKUS, 100/50 mcg in open-label fashion

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Six-Period Crossover, Dose-Ranging Study to Evaluate the Efficacy and Safety of Four Doses of FS Spiromax (Fluticasone Propionate/Salmeterol Xinafoate Inhalation Powder) Administered as Single Doses Compared With Single Doses of Fluticasone Propionate Spiromax and Open Label Advair Diskus in Adult and Adolescent Subjects With Persistent Asthma
• Study Start Date: Jan 1, 2013
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FS MDPI 100/6.25 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.; Other Names: fluticasone propionate inhaled corticosteroid Salmeterol xinafoate β2 adrenoceptor agonist FS Spiromax ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/12.5mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.; Other Names: fluticasone propionate inhaled corticosteroid Salmeterol xinafoate β2 adrenoceptor agonist FS Spiromax ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/25 Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.; Other Names: fluticasone propionate inhaled corticosteroid Salmeterol xinafoate β2 adrenoceptor agonist FS Spiromax ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists
Experimental: FS MDPI 100/50 Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Drug: FS MDPI; FS MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate and salmeterol xinafoate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. The fluticasone propionate component was a fixed dose of 100 mcg. The salmeterol xinofoate dosage varied: 6.25, 12.5, 25 or 50 mcg.; Other Names: fluticasone propionate inhaled corticosteroid Salmeterol xinafoate β2 adrenoceptor agonist FS Spiromax ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists
Active Comparator: Fp MDPI 100 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Drug: Fp MDPI; Fp MDPI is an inhalation-driven multidose dry powder inhaler (MDPI) containing fluticasone propionate dispersed in a lactose monohydrate excipient and contained within a reservoir. A metered dose of drug is delivered to a dose cup via an air pulse activated when the cap is opened. Fp at 100 mcg was an active comparator (single dose). Further, participants were instructed to administer two inhalations of Fp MDPI 50 mcg twice daily (100 mcg total dose) during the Run-in (to replace the participant's current inhaled corticosteroid) and Washout Periods between treatments.; Other Names: fluticasone propionate inhaled corticosteroid Fp Spiromax ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists
Active Comparator: Advair Diskus 100/50 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.	Drug: Advair Diskus; ADVAIR DISKUS (100/50 mcg fluticasone propionate/salmeterol xinafoate) consists of a dry powder formulation of fluticasone propionate and salmeterol xinafoate in a lactose excipient. The dry powder is contained within individual blisters on a double foil strip within the device. Activation of the device opens a single blister of medication which is then dispersed into the air-stream by patient inhalation.; Other Names: fluticasone propionate inhaled corticosteroid salmeterol xinafoate β2 adrenoceptor agonist ; Drug: Albuterol; Albuterol (Pro-Air) hydrofluoroalkane (HFA) metered dose inhaler (MDI), was provided to be used as needed for the relief of asthma symptoms during both the run-in and treatment periods (to replace the subject's current rescue medication).; Other Names: Pro-Air short-acting β2-adrenergic agonists

Outcome Measures

Primary Outcome Measures

1. Standardized Baseline-Adjusted Area Under the Curve For Forced Expiratory Volume In 1 Second Over 12 Hours Post-dose (FEV1 AUC0-12) [Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 0.5, 1, 2, 3, 4, 5, 6, 9, 12 hours]

   Standardized baseline-adjusted FEV1 AUC0-12 was defined as the area under the curve for baseline-adjusted FEV1 measurements from the predose to 12 hours postdose time points using the trapezoidal rule based on actual (not scheduled) time of measurement and was standardized by dividing the actual time of last non-missing FEV1 measurement. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting period-specific baseline FEV1. The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.

Secondary Outcome Measures

1. Change From Baseline at 12 Hours Post-Dose in Forced Expiratory Volume in One Second (FEV1) By Treatment [Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 12 hours]

   The secondary efficacy variable was the change from period-specific baseline in FEV1 at 12 hours, calculated as FEV1 measured at 12 hours postdose after subtracting period-specific baseline FEV1 at each treatment period. The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.

2. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) of Salmeterol [Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose]

   Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.

3. Maximum Observed Plasma Concentration (Cmax) of Salmeterol [Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose]

   Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.

4. Time of Maximum Observed Plasma Concentration (Tmax) of Salmeterol [Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose]

   Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived.

5. Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period [Day 1 up to Day 35]

   TEAEs were recorded during each double-blind treatment. In addition, at the end of each treatment, patients continued to use 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily, so adverse events during this treatment were assigned to Fp MDPI 50 mcg. An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical in

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Written informed consent/assent

• General good health

• Diagnosis of asthma as defined by the National Institutes of Health (NIH)

• A best FEV1 of 40%-85% of the predicted normal value during the screening visit (SV)

• Subjects need to demonstrate a ≥ 15% reversibility of FEV1 within 30 minutes following 4 inhalations of albuterol inhalation aerosol (if required, spacers are permitted for reversibility testing) at the SV.

• Other inclusion criteria apply

Exclusion Criteria:

• History of life-threatening asthma that is defined for this protocol as an asthma episode that required intubation.

• Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that is not resolved within 2 weeks prior to the SV.

• Any asthma exacerbation requiring oral corticosteroids within 3 months of the SV. A subject must not have had any hospitalization for asthma within 6 months prior to the SV.

• Taking long-acting β-agonists within 2 weeks of the SV

• Other exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 10453	Denver	Colorado	United States
2	Teva Investigational Site 10452	North Dartmouth	Massachusetts	United States
3	Teva Investigational Site 10455	Saint Louis	Missouri	United States
4	Teva Investigational Site 10454	Skillman	New Jersey	United States
5	Teva Investigational Site 10448	Raleigh	North Carolina	United States
6	Teva Investigational Site 10451	Medford	Oregon	United States
7	Teva Investigational Site 10449	Portland	Oregon	United States
8	Teva Investigational Site 10457	El Paso	Texas	United States
9	Teva Investigational Site 10450	New Braunfels	Texas	United States
10	Teva Investigational Site 10456	San Antonio	Texas	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01772368
• Other Study ID Numbers: FSS-AS-201
• First Posted: Jan 21, 2013
• Last Update Posted: Jun 12, 2017
• Last Verified: May 1, 2017

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Asthma; dry powder inhaler; long-acting beta2-agonist; bronchodilation; bronchodilator; metered dose inhaler; inhaled corticosteroid
• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Albuterol; Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination; Adrenergic Agonists

Study Results

Participant Flow

Recruitment Details	A total of 105 subjects with asthma were screened for this study. Of the 105 subjects screened, 82 subjects at 10 investigational sites in the US met entry criteria and were considered to be eligible to enter the run-in period.
Pre-assignment Detail	Ten subjects failed randomization.

Arm/Group Title	All Participants
Arm/Group Description	All subjects, regardless of the order of treatments to which they were randomized in this cross-over study.
Period Title: Overall Study
STARTED	72
Received Fp MDPI 100 mcg	67
Received FS MDPI 100/6.25 mcg	68
Received FS MDPI 100/12.5mcg	69
Received FS MDPI 100/25 mcg	67
Received FS MDPI 100/50 mcg	68
Received Advair Diskus 100/50 mcg	66
COMPLETED	65
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All subjects, regardless of the order of treatments to which they were randomized in this cross-over study.
Overall Participants	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.5 (13.87)
Sex: Female, Male (Count of Participants)
Female	37 51.4%
Male	35 48.6%
Race/Ethnicity, Customized (Count of Participants)
White	64 88.9%
Black	7 9.7%
Other	1 1.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	79.2 (14.17)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	170.0 (9.76)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.3 (3.35)

Outcome Measures

1. Primary Outcome

Title	Standardized Baseline-Adjusted Area Under the Curve For Forced Expiratory Volume In 1 Second Over 12 Hours Post-dose (FEV1 AUC0-12)
Description	Standardized baseline-adjusted FEV1 AUC0-12 was defined as the area under the curve for baseline-adjusted FEV1 measurements from the predose to 12 hours postdose time points using the trapezoidal rule based on actual (not scheduled) time of measurement and was standardized by dividing the actual time of last non-missing FEV1 measurement. Baseline-adjusted FEV1 was calculated as postdose FEV1 after subtracting period-specific baseline FEV1. The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.
Time Frame	Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 0.5, 1, 2, 3, 4, 5, 6, 9, 12 hours

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all subjects in the ITT population who received at least 1 dose of study drug and had at least 1 evaluable standardized baseline-adjusted FEV1 AUC0-12.

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Measure Participants	67	68	69	67	68	66
Least Squares Mean (Standard Error) [mL]	52.13 (38.071)	203.84 (38.072)	248.98 (38.025)	279.69 (38.121)	303.43 (38.062)	245.56 (38.148)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/6.25 mcg, FS MDPI 100/12.5mcg, FS MDPI 100/25 mcg, FS MDPI 100/50 mcg
	Comments	A linear in log-dose-trend contrast was constructed to evaluate the dose-response trend, where the logarithm of dose was defined precisely as log (dose+1) to accommodate the case of Fp MDPI 100 mcg, since the dose used in this trend analysis was the salmeterol dose. The study was considered positive if the trend test was positive and the test involving the highest FS MDPI dose (100/50 mcg) compared with Fp MDPI 100 mcg was positive, regardless of the results of the tests for the other doses.
	Type of Statistical Test	Other
	Comments	linearity statistical test
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/50 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	251.30
	Confidence Interval	(2-Sided) 95%; 215.6 to 287.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/50 mcg - Fp MDPI 100 mcg

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/25 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/25 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	227.56
	Confidence Interval	(2-Sided) 95%; 191.6 to 263.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/25 mcg - Fp MDPI 100 mcg

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/12.5mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/512.5 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	196.85
	Confidence Interval	(2-Sided) 95%; 161.2 to 232.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/12.5 mcg - Fp MDPI 100 mcg

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/6.25 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/6.25 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	151.71
	Confidence Interval	(2-Sided) 95%; 115.9 to 187.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/6.25 mcg - Fp MDPI 100 mcg

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between Advair Diskus 100/50 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	193.42
	Confidence Interval	(2-Sided) 95%; 157.4 to 229.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Advair Diskus 100/50 mcg - Fp MDPI 100

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/50 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/50 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0017
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	57.88
	Confidence Interval	(2-Sided) 95%; 22.0 to 93.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/50 - Advair Diskus 100/50 mcg

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/25 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/25 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0624
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	34.14
	Confidence Interval	(2-Sided) 95%; -1.8 to 70.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/25 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/12.5mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/12.5 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8503
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	3.42
	Confidence Interval	(2-Sided) 95%; -32.3 to 39.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/12.5mcg - Advair Diskus 100/50 mcg

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/6.25 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between FS MDPI 100/6.25 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0229
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-41.72
	Confidence Interval	(2-Sided) 95%; -77.6 to -5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/6.25 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between Fp MDPI 100 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A fixed-sequence testing procedure was employed to control the overall Type I error rate at the 2 sided 0.05 level.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-193.42
	Confidence Interval	(2-Sided) 95%; -229.5 to -157.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fp MDPI 100 mcg - Advair Diskus 100/50 mcg

2. Secondary Outcome

Title	Change From Baseline at 12 Hours Post-Dose in Forced Expiratory Volume in One Second (FEV1) By Treatment
Description	The secondary efficacy variable was the change from period-specific baseline in FEV1 at 12 hours, calculated as FEV1 measured at 12 hours postdose after subtracting period-specific baseline FEV1 at each treatment period. The period-specific baseline FEV1 was measured at predose within 5 minutes of AM dose administration at each treatment visit. If that value was missing, then FEV1 measured at 30 minutes predose was used as the period-specific baseline.
Time Frame	Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 12 hours

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) included all subjects in the ITT population who received at least 1 dose of study drug and had at least 1 evaluable standardized baseline-adjusted FEV1 AUC0-12.

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Measure Participants	67	67	68	67	68	66
Least Squares Mean (Standard Error) [mL]	11.53 (29.058)	128.49 (29.109)	170.51 (28.990)	209.85 (29.127)	238.30 (28.988)	170.54 (29.230)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/50 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	226.77
	Confidence Interval	(2-Sided) 95%; 172.4 to 281.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/50 mcg - Fp MDPI 100 mcg

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/25 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/25 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	198.32
	Confidence Interval	(2-Sided) 95%; 143.7 to 252.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/25 mcg - Fp MDPI 100 mcg

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/12.5mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/12.5 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	158.99
	Confidence Interval	(2-Sided) 95%; 104.7 to 213.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/12.5 mcg - Fp MDPI 100 mcg

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, FS MDPI 100/6.25 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/6.25 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	116.96
	Confidence Interval	(2-Sided) 95%; 62.4 to 171.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/6.25 mcg - Fp MDPI 100 mcg

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each Advair Diskus 100/50 mcg dose group and Fp MDPI 100 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	159.01
	Confidence Interval	(2-Sided) 95%; 104.3 to 213.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Advair Diskus 100/50 mcg - Fp MDPI 100 mcg

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/50 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/50 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0150
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	67.76
	Confidence Interval	(2-Sided) 95%; 13.3 to 122.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/50 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/25 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/25 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1578
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	39.31
	Confidence Interval	(2-Sided) 95%; -15.3 to 94.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/25 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/12.5mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/12.5 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9993
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -54.4 to 54.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/12.5 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/6.25 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each FS MDPI 100/6.25 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1311
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-42.05
	Confidence Interval	(2-Sided) 95%; -96.7 to 12.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	FS MDPI 100/6.25 mcg - Advair Diskus 100/50 mcg

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Fp MDPI 100 mcg, Advair Diskus 100/50 mcg
	Comments	The estimated treatment difference from the ANCOVA model between each Fp MDPI 100 mcg dose group and Advair Diskus 100/50 mcg group is presented together with the two-sided 95% CI for the difference and the p-value.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance of 0.05 or alpha of 0.05.
	Method	ANCOVA
	Comments	Fixed effects of sequence, period and treatment; a random effect of subject within sequence; and a covariate of period-specific baseline FEV1.
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	-159.01
	Confidence Interval	(2-Sided) 95%; -213.7 to -104.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Fp MDPI 100 mcg - Advair Diskus 100/50 mcg

3. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) of Salmeterol
Description	Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.
Time Frame	Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis set. PK parameters for Salmeterol were not run for Fp MDPI experience.

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Measure Participants	0	62	65	61	61	62
Mean (Standard Deviation) [pg*hr/mL]	32.8 (20.98)	69.9 (35.36)	133.5 (63.13)	309.3 (143.43)	173.5 (106.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/50 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=58
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	1.929
	Confidence Interval	(2-Sided) 90%; 1.690 to 2.202
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/25 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=59
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	0.800
	Confidence Interval	(2-Sided) 90%; 0.702 to 0.911
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/12.5mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=61
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	0.427
	Confidence Interval	(2-Sided) 90%; 0.376 to 0.485
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/6.25 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=59
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LSM difference
	Estimated Value	0.172
	Confidence Interval	(2-Sided) 90%; 0.151 to 0.196
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) of Salmeterol
Description	Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived. The primary pharmacokinetic parameters were AUC0-t and Cmax for Salmeterol.
Time Frame	Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis set. PK parameters for Salmeterol were not run for Fp MDPI experience.

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Measure Participants	0	62	65	61	61	62
Mean (Standard Deviation) [pg/mL]	16.0 (8.86)	35.8 (20.25)	67.5 (34.71)	154.5 (80.28)	42.3 (19.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/50 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=58
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	3.622
	Confidence Interval	(2-Sided) 90%; 3.149 to 4.168
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/25 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=59
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	1.534
	Confidence Interval	(2-Sided) 90%; 1.335 to 1.763
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/12.5mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=61
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	0.795
	Confidence Interval	(2-Sided) 90%; 0.694 to 0.911
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FS MDPI 100/6.25 mcg, Advair Diskus 100/50 mcg
	Comments	The analysis is based on ANOVA model of the log transformed data, with fixed effects of sequence, period and treatment, and a random effect for subject within sequence. n=59
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	geometric mean ratio
	Estimated Value	0.339
	Confidence Interval	(2-Sided) 90%; 0.295 to 0.390
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Time of Maximum Observed Plasma Concentration (Tmax) of Salmeterol
Description	Blood samples for measurement of plasma SAL concentrations were obtained during each treatment visit (subjects 18 years of age and older only) and pharmacokinetic parameters were derived.
Time Frame	Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis set. PK parameters for Salmeterol were not run for Fp MDPI experience.

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.
Measure Participants	0	62	65	61	61	62
Median (Full Range) [hours]	0.1	0.1	0.1	0.1	0.5

6. Secondary Outcome

Title	Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period
Description	TEAEs were recorded during each double-blind treatment. In addition, at the end of each treatment, patients continued to use 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily, so adverse events during this treatment were assigned to Fp MDPI 50 mcg. An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents normal daily activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical in
Time Frame	Day 1 up to Day 35

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Fp MDPI 100 mcg	FS MDPI 100/6.25 mcg	FS MDPI 100/12.5mcg	FS MDPI 100/25 mcg	FS MDPI 100/50 mcg	Advair Diskus 100/50 mcg	Fp MDPI 50 mcg X 2 BID
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.	Patients used 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily during the 'washout' between treatment periods, so adverse events during this treatment were assigned to Fp MDPI 50 mcg.
Measure Participants	67	68	69	67	68	66	72
Any adverse event	2 2.8%	2 NaN	3 NaN	1 NaN	1 NaN	3 NaN	17 NaN
Severe adverse event	0 0%	0 NaN	0 NaN	0 NaN	1 NaN	0 NaN	1 NaN
Treatment-related adverse event	0 0%	0 NaN	1 NaN	0 NaN	0 NaN	1 NaN	1 NaN
Deaths	0 0%	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN
Other serious adverse events	0 0%	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN
Withdrawn from treatment due to AE	0 0%	0 NaN	0 NaN	0 NaN	0 NaN	0 NaN	1 NaN

Adverse Events

Time Frame	Day 1 to Day 35
Arm/Group Title	Fp MDPI 100 mcg		FS MDPI 100/6.25 mcg		FS MDPI 100/12.5mcg		FS MDPI 100/25 mcg		FS MDPI 100/50 mcg		Advair Diskus 100/50 mcg		Fp MDPI 50 mcg X 2 BID
Arm/Group Description	Subjects inhaled a single dose of 100 mcg fluticasone propionate.		Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.		Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.		Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.		Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.		Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate. This arm is the only arm which is open-label because the inhaler device was different than the MDPI used in the other treatment arms.		Patients used 2 inhalations of Fp MDPI 50 mcg (100 mcg total dose) twice daily during the 'washout' between treatment periods, so adverse events during this treatment were assigned to Fp MDPI 50 mcg.
All Cause Mortality
	Fp MDPI 100 mcg		FS MDPI 100/6.25 mcg		FS MDPI 100/12.5mcg		FS MDPI 100/25 mcg		FS MDPI 100/50 mcg		Advair Diskus 100/50 mcg		Fp MDPI 50 mcg X 2 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		0/68 (0%)		0/69 (0%)		0/67 (0%)		0/68 (0%)		0/66 (0%)		0/72 (0%)
Serious Adverse Events
	Fp MDPI 100 mcg		FS MDPI 100/6.25 mcg		FS MDPI 100/12.5mcg		FS MDPI 100/25 mcg		FS MDPI 100/50 mcg		Advair Diskus 100/50 mcg		Fp MDPI 50 mcg X 2 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		0/68 (0%)		0/69 (0%)		0/67 (0%)		0/68 (0%)		0/66 (0%)		0/72 (0%)
Other (Not Including Serious) Adverse Events
	Fp MDPI 100 mcg		FS MDPI 100/6.25 mcg		FS MDPI 100/12.5mcg		FS MDPI 100/25 mcg		FS MDPI 100/50 mcg		Advair Diskus 100/50 mcg		Fp MDPI 50 mcg X 2 BID
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0%)		0/68 (0%)		0/69 (0%)		0/67 (0%)		0/68 (0%)		0/66 (0%)		4/72 (5.6%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	0/67 (0%)		0/68 (0%)		0/69 (0%)		0/67 (0%)		0/68 (0%)		0/66 (0%)		4/72 (5.6%)

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.