Trial Outcomes & Findings for Dose Ranging Study of the Salmeterol Component of Fluticasone /Salmeterol Spiromax Compared to Fluticasone Spiromax and Advair Diskus in Asthma Subjects (NCT NCT01772368)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

72 participants

Primary outcome timeframe

Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 0.5, 1, 2, 3, 4, 5, 6, 9, 12 hours

Results posted on

2017-06-12

Participant Flow

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.

Ten subjects failed randomization.

Participant milestones

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

Reasons for withdrawal

Reasons for withdrawal
Measure	All Participants All subjects, regardless of the order of treatments to which they were randomized in this cross-over study.
Overall Study Adverse Event	1
Overall Study Withdrawal by Subject	3
Overall Study Protocol Violation	2
Overall Study Other	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Participants n=72 Participants All subjects, regardless of the order of treatments to which they were randomized in this cross-over study.
Age, Continuous	42.5 years STANDARD_DEVIATION 13.87 • n=5 Participants
Sex: Female, Male Female	37 Participants n=5 Participants
Sex: Female, Male Male	35 Participants n=5 Participants
Race/Ethnicity, Customized White	64 Participants n=5 Participants
Race/Ethnicity, Customized Black	7 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants
Weight	79.2 kg STANDARD_DEVIATION 14.17 • n=5 Participants
Height	170.0 cm STANDARD_DEVIATION 9.76 • n=5 Participants
Body Mass Index	27.3 kg/m^2 STANDARD_DEVIATION 3.35 • n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 0.5, 1, 2, 3, 4, 5, 6, 9, 12 hours

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=69 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=66 Participants 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.	Fp MDPI 50 mcg X 2 BID 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.
Standardized Baseline-Adjusted Area Under the Curve For Forced Expiratory Volume In 1 Second Over 12 Hours Post-dose (FEV1 AUC0-12)	52.13 mL Standard Error 38.071	203.84 mL Standard Error 38.072	248.98 mL Standard Error 38.025	279.69 mL Standard Error 38.121	303.43 mL Standard Error 38.062	245.56 mL Standard Error 38.148	—

SECONDARY outcome

Timeframe: Pre-dose: 30 minutes prior, within 5 minutes of dose. Post-dose: 12 hours

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=66 Participants 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.	Fp MDPI 50 mcg X 2 BID 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.
Change From Baseline at 12 Hours Post-Dose in Forced Expiratory Volume in One Second (FEV1) By Treatment	11.53 mL Standard Error 29.058	128.49 mL Standard Error 29.109	170.51 mL Standard Error 28.990	209.85 mL Standard Error 29.127	238.30 mL Standard Error 28.988	170.54 mL Standard Error 29.230	—

SECONDARY outcome

Timeframe: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

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

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.

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=62 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=65 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=62 Participants 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.	Fp MDPI 50 mcg X 2 BID 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.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Measurable Concentration (AUC0-t) of Salmeterol	—	32.8 pg*hr/mL Standard Deviation 20.98	69.9 pg*hr/mL Standard Deviation 35.36	133.5 pg*hr/mL Standard Deviation 63.13	309.3 pg*hr/mL Standard Deviation 143.43	173.5 pg*hr/mL Standard Deviation 106.59	—

SECONDARY outcome

Timeframe: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

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

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.

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=62 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=65 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=62 Participants 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.	Fp MDPI 50 mcg X 2 BID 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.
Maximum Observed Plasma Concentration (Cmax) of Salmeterol	—	16.0 pg/mL Standard Deviation 8.86	35.8 pg/mL Standard Deviation 20.25	67.5 pg/mL Standard Deviation 34.71	154.5 pg/mL Standard Deviation 80.28	42.3 pg/mL Standard Deviation 19.28	—

SECONDARY outcome

Timeframe: Predose (0), and at 5, 10, 15 and 30 minutes, 1, 1.5, 2, 3, 4, 8, and 12 hours postdose

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

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.

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=62 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=65 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=61 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=62 Participants 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.	Fp MDPI 50 mcg X 2 BID 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.
Time of Maximum Observed Plasma Concentration (Tmax) of Salmeterol	—	0.1 hours Interval 0.1 to 12.1	0.1 hours Interval 0.1 to 2.0	0.1 hours Interval 0.1 to 2.0	0.1 hours Interval 0.1 to 1.5	0.5 hours Interval 0.1 to 2.0	—

SECONDARY outcome

Timeframe: Day 1 up to Day 35

Population: Safety population

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

Outcome measures

Outcome measures
Measure	Fp MDPI 100 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=69 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=67 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=68 Participants Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=66 Participants 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.	Fp MDPI 50 mcg X 2 BID n=72 Participants 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.
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Any adverse event	2 Participants	2 Participants	3 Participants	1 Participants	1 Participants	3 Participants	17 Participants
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Severe adverse event	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Treatment-related adverse event	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Deaths	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Other serious adverse events	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Patients With Treatment-Emergent Adverse Experiences (TEAE) During the Treatment Period Withdrawn from treatment due to AE	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Fp MDPI 100 mcg n=67 participants at risk Subjects inhaled a single dose of 100 mcg fluticasone propionate.	FS MDPI 100/6.25 mcg n=68 participants at risk Subjects inhaled a single dose of 100 mcg fluticasone propionate and 6.25 mcg salmeterol xinafoate.	FS MDPI 100/12.5mcg n=69 participants at risk Subjects inhaled a single dose of 100 mcg fluticasone propionate and 12.5 mcg salmeterol xinafoate.	FS MDPI 100/25 mcg n=67 participants at risk Subjects inhaled a single dose of 100 mcg fluticasone propionate and 25 mcg salmeterol xinafoate.	FS MDPI 100/50 mcg n=68 participants at risk Subjects inhaled a single dose of 100 mcg fluticasone propionate and 50 mcg salmeterol xinafoate.	Advair Diskus 100/50 mcg n=66 participants at risk 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.	Fp MDPI 50 mcg X 2 BID n=72 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	0.00% 0/67 • Day 1 to Day 35	0.00% 0/68 • Day 1 to Day 35	0.00% 0/69 • Day 1 to Day 35	0.00% 0/67 • Day 1 to Day 35	0.00% 0/68 • Day 1 to Day 35	0.00% 0/66 • Day 1 to Day 35	5.6% 4/72 • Day 1 to Day 35

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc.

Phone: 1-215-591-3000

Results disclosure agreements

Principal investigator is a sponsor employee 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.
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