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Clinical Trial Results:
201832: A Randomised, Double-Blind, Double-Dummy,Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction.

Summary
EudraCT number	2017-001516-11
Trial protocol	Outside EU/EEA
Global end of trial date	03 Feb 2017

Results information
Results version number	v2(current)
This version publication date	01 Nov 2017
First version publication date	12 Aug 2017
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

201832

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

GlaxoSmithKline

Sponsor organisation address

980 Great West Road, Brentford, Middlesex, United Kingdom,

Public contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Scientific contact

GSK Response Center, GlaxoSmithKline, 1 866-435-7343,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

30 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

03 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with persistent asthma.

Protection of trial subjects

Study specific stopping criteria were included in the protocol including stopping for liver events, QTc changes, severe asthma exacerbation, worsening of asthma requiring additional treatment, and pregnancy. In relation to the exercise challenges, these could be stopped at any time and rescue medication could be given at any time if required. In addition, specific guidelines were given for when rescue medication must be provided i.e. if FEV1 dropped to >=40%. If rescue medication other than salbutamol or ipratropium was required, the patient was to be withdrawn from the study. Exercise challenges were carefully managed with a gradual warm up over 2 minutes and a gradual stop. Handrails were in place on the treadmills to aid the subject should they need them. Subjects not thought able to complete the exercise challenge were not recruited into the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

25 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

United States: 72

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a multicenter, randomized, double-blind, double-dummy, crossover comparison study of fluticasone furoate (FF)/vilanterol (VI) versus fluticasone propionate (FP) in adolescent and adult participants with asthma and exercise-induced bronchoconstriction (EIB). The study was conducted in two countries–United States and Canada.

Screening details

The study consisted of 4-week single-blind run-in, 2-week double-blind treatment period 1, 2-week single-blind wash out, 2-week double-blind treatment period 2 and 1-week Follow-up. A total of 163 participants were screened, 75 were randomized and 74 were included in Intent-To-Treat (ITT) Population who received at least 1 dose of trial medication.

Period 1 title

Treatment period 1 (2 weeks)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

FF/VI 100/25 µg followed by FP 250 µg

Arm description

After screening, the eligible participants entered a 4-week single blind run-in period on FP 250 microgram (µg) twice daily (BID) following which the participants were randomized to receive FF/VI 100/25 µg once daily (QD) via ELLIPTA + Placebo BID via DISKUS in treatment period 1 followed by a 2-week single blind wash-out period on FP 250 µg BID. The participants then received FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA in treatment period 2. The participants were followed up for approximately 7 days after completing Treatment Period 2. Albuterol/salbutamol was issued for rescue use during the run-in, wash-out and treatment periods as needed

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

FP 250 µg followed by FF/VI 100/25 µg

Arm description

After screening, the eligible participants entered a 4-week single blind run-in period on FP 250 µg BID following which the participants were randomized to receive FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA in treatment period 1 followed by a 2-week single blind wash-out period on FP 250 µg BID. The participants then received FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS in treatment period 2. The participants were followed up for approximately 7 days after completing Treatment Period 2. Albuterol/salbutamol was issued for rescue use during the run-in, wash-out and treatment periods as needed.

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

Number of subjects in period 1	FF/VI 100/25 µg followed by FP 250 µg	FP 250 µg followed by FF/VI 100/25 µg
Started	37	37
Completed	36	37
Not completed	1	0
Adverse event, non-fatal	1	-

Period 2 title

Wash-out period (2 weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Are arms mutually exclusive

Yes

FF/VI 100/25 µg followed by FP 250 µg

Arm description

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

FP 250 µg followed by FF/VI 100/25 µg

Arm description

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

Number of subjects in period 2	FF/VI 100/25 µg followed by FP 250 µg	FP 250 µg followed by FF/VI 100/25 µg
Started	36	37
Completed	35	36
Not completed	1	1
Consent withdrawn by subject	1	-
Protocol deviation	-	1

Period 3 title

Treatment Period 2 (2 weeks)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

FF/VI 100/25 µg followed by FP 250 µg

Arm description

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

FP 250 µg followed by FF/VI 100/25 µg

Arm description

Arm type

Experimental

Investigational medicinal product name

FF/VI 100/25 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

100 µg of FF blended with lactose in the first strip and 25 µg of vilanterol blended with lactose and magnesium stearate in the second strip was administered via ELLIPTA inhaler QD in the evening.

Investigational medicinal product name

FP 250 µg

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

250 µg of FP blended with lactose was administered via DISKUS/ACCUHALER inhaler BID, once in the morning and once in the evening.

Investigational medicinal product name

Placebo ELLIPTA

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Placebo was administered QD in the evening via ELLIPTA inhaler containing lactose in the first strip and a blend of lactose and magnesium stearate in the second strip.

Investigational medicinal product name

Placebo DISKUS/ACCUHALER

Investigational medicinal product code

Other name

Pharmaceutical forms

Inhalation powder, pre-dispensed

Routes of administration

Inhalation use

Dosage and administration details

Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.

Number of subjects in period 3	FF/VI 100/25 µg followed by FP 250 µg	FP 250 µg followed by FF/VI 100/25 µg
Started	35	36
Completed	33	36
Not completed	2	0
Adverse event, non-fatal	1	-
Lack of efficacy	1	-

Baseline characteristics

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Reporting group title

Treatment period 1 (2 weeks)

Reporting group description

After screening, the eligible participants entered a 4-week single blind run-in period on FP 250 µg BID following which the participants were randomized to one of the following two treatment sequences in a ratio of 1:1: FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS in treatment period 1 followed by FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA in treatment period 2 or FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA in treatment period 1 followed by FF/VI 100/25 µg once daily (QD) via ELLIPTA + Placebo BID via DISKUS in treatment period 2. All participants entered a 2-week single blind wash-out period on FP 250 µg BID between the two treatment periods. The participants were followed up for approximately 7 days after completing Treatment Period 2. Albuterol/salbutamol was issued for rescue use during the run-in, wash-out and treatment periods as needed.

Reporting group values	Treatment period 1 (2 weeks)	Total
Number of subjects	74
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	27.8 ( 10.35 )	-
Gender categorical
Units: Subjects
Female	43	43
Male	31	31
Race/Ethnicity, Customized
Units: Subjects
African American/African Heritage	28	28
Asian - South East Asian Heritage	3	3
White - White/Caucasian/European Heritage	42	42
Mixed Race	1	1

End points

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Reporting group title

FF/VI 100/25 µg followed by FP 250 µg

Reporting group description

Reporting group title

FP 250 µg followed by FF/VI 100/25 µg

Reporting group description

Reporting group title

FF/VI 100/25 µg followed by FP 250 µg

Reporting group description

Reporting group title

FP 250 µg followed by FF/VI 100/25 µg

Reporting group description

Reporting group title

FF/VI 100/25 µg followed by FP 250 µg

Reporting group description

Reporting group title

FP 250 µg followed by FF/VI 100/25 µg

Reporting group description

Subject analysis set title

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Subject analysis set type

Sub-group analysis

Subject analysis set description

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Subject analysis set title

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Subject analysis set type

Sub-group analysis

Subject analysis set description

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Primary: Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

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End point title

Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

End point description

The exercise challenge test is a stepped challenge on a treadmill. It was performed at 12 hrs post evening dose at the end of the 2-week treatment period, wherein the participants exercised sufficiently to reach a heart rate between 80 to 95 percent of their predicted maximum within 4 minutes (min) and maintained the heart rate with exercise for an additional 6 min followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Maximal percent decrease was calculated as pre-exercise FEV1 minus minimum post exercise FEV1 (smallest FEV1 value collected within one hr following exercise challenge) divided by pre-exercise FEV1 multiplied by 100. Pre-exercise FEV1 was defined as the FEV1 collected prior to the exercise challenge test at 12 hr post dose. ITT Population comprised of all participants randomized to treatment and who received at least one dose of study medication.

End point type

Primary

End point timeframe

At Week 2 of treatment period 1 and 2

End point values	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Number of subjects analysed	70 ^[1]	69
Units: Percentage of FEV1
least squares mean (standard error)
Percentage of FEV1	15.02 ( 1.058 )	16.71 ( 1.095 )

Notes
[1] - ITT Population. Participants with non-missing covariates and data specific to endpoint were analyzed

Statistical analysis 1

Comparison groups

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS v FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.109 ^[2]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.69

Confidence interval

level

95%

sides

2-sided

lower limit

-3.76

upper limit

0.39

Notes
[2] - Mixed model repeated measures analysis adjusted for fixed effects of treatment, sex, age, treatment period, smoking history, period Baseline FEV1 and the mean of the two period Baseline FEV1 values. Subject is fitted as a random effect.

Secondary: Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

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End point title

Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

End point description

The exercise challenge test is a stepped challenge on a treadmill. It was performed at 23 hrs post evening dose at the end of the 2-week treatment period, wherein the participants exercised sufficiently to reach a heart rate between 80 to 95 percent of their predicted maximum within 4 min and maintained the heart rate with exercise for an additional 6 min followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Maximal percent decrease was calculated as pre-exercise FEV1 minus minimum post exercise FEV1 (smallest FEV1 value collected within one hr following exercise challenge) divided by pre-exercise FEV1 multiplied by 100. Pre-exercise FEV1 was defined as the FEV1 collected prior to the exercise challenge test at 23 hr post dose.

End point type

Secondary

End point timeframe

At Week 2 of treatment period 1 and 2

End point values	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Number of subjects analysed	68 ^[3]	69
Units: Percentage of FEV1
least squares mean (standard error)
Percentage of FEV1	11.90 ( 1.020 )	14.05 ( 1.051 )

Notes
[3] - ITT Population. Participants with non-missing covariates and data specific to endpoint were analyzed

Statistical analysis 1

Comparison groups

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS v FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.051 ^[4]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-2.15

Confidence interval

level

95%

sides

2-sided

lower limit

-4.31

upper limit

0.01

Notes
[4] - Mixed model repeated measures analysis adjusted for fixed effects of treatment, sex, age, treatment period, smoking history, period Baseline FEV1 and the mean of the two period Baseline FEV1 values. Subject is fitted as a random effect.

Secondary: Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

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End point title

Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

End point description

The blinded treatment exercise challenge test was performed at the end of 2-weeks of treatment period 1 and treatment period 2 on a treadmill at 12 hrs and 23 hrs after administration of the evening dose of study treatment. The challenge was followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Pre-exercise FEV1 was defined as the FEV1 value collected prior to the exercise challenge test at 23 hrs post-dose. Number of participants listed is the number in the ITT population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

At Week 2 of treatment period 1 and 2

End point values	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Number of subjects analysed	73 ^[5]	72
Units: Participants
FEV1 >=95% of pre-exercise FEV1, 12 hrs; n=70, 69	34	29
FEV1 < 95% of pre-exercise FEV1, 12 hrs; n=70, 69	36	40
FEV1 >=95% of pre-exercise FEV1, 23 hrs; n=68, 69	42	37
FEV1 < 95% of pre-exercise FEV1, 23 hrs; n=68, 69	26	32

Notes
[5] - ITT Population. Participants with non-missing covariates and data specific to endpoint were analyzed

Statistical analysis 1

Statistical analysis description

12 hrs: modeling the odds of having FEV1 >/=95% of pre exercise FEV1 at each of the two time points.

Comparison groups

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS v FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.266 ^[6]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

2.26

Notes
[6] - Repeated measures logistic regression model with parameters estimated using the Generalized Estimating Equation method. Covariates of treatment, sex, age, treatment period, and period baseline FEV1 were included.

Statistical analysis 2

Statistical analysis description

23 hrs: modeling the odds of having FEV1 >/=95% of pre exercise FEV1 at each of the two time points.

Comparison groups

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS v FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.322 ^[7]

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.37

Confidence interval

level

95%

sides

2-sided

lower limit

0.73

upper limit

2.58

Notes
[7] - Repeated measures logistic regression model with parameters estimated using the Generalized Estimating Equation method

Secondary: Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

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End point title

Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

End point description

The exercise challenge testing at the end of 2 week treatment period was performed on a treadmill at 12 hrs and 23 hrs after administration of the evening dose of double-blind treatment. Following exercise challenge testing, post-exercise FEV1 values were assessed serially at 5, 10, 15, 30, 45 and 60 min. Pre-exercise FEV1 was defined as the FEV1 value collected prior to the exercise challenge test at 23 hrs post-dose. Number of participants listed is the number in the ITT population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles).

End point type

Secondary

End point timeframe

At Week 2 of treatment period 1 and 2

End point values	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Number of subjects analysed	73 ^[8]	72
Units: Percentage of FEV1
least squares mean (standard error)
12 hrs post-dose; n=67, 66	5.87 ( 0.663 )	6.52 ( 0.680 )
23 hrs post-dose; n=68, 67	3.98 ( 0.699 )	5.73 ( 0.747 )

Notes
[8] - ITT Population. Participants with non-missing covariates and data specific to endpoint were analyzed

Statistical analysis 1

Statistical analysis description

12 hrs post-dose

Comparison groups

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA v FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.342 ^[9]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-2.01

upper limit

0.71

Notes
[9] - Mixed model repeated measures analysis adjusted for fixed effects of treatment, sex, age, treatment period, smoking history, period Baseline FEV1 and the mean of the two period Baseline FEV1 values. Subject is fitted as a random effect.

Statistical analysis 2

Statistical analysis description

23 hrs post-dose

Comparison groups

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA v FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Number of subjects included in analysis

145

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.041 ^[10]

Method

Mixed models analysis

Parameter type

Mean difference (final values)

Point estimate

-1.75

Confidence interval

level

95%

sides

2-sided

lower limit

-3.42

upper limit

-0.07

Notes
[10] - Mixed model repeated measures analysis adjusted for fixed effects of treatment, sex, age, treatment period, smoking history, period Baseline FEV1 and the mean of the two period Baseline FEV1 values.

Adverse events

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Timeframe for reporting adverse events

The on-treatment adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment until the follow-up contact (approximately up to 51 days).

Adverse event reporting additional description

ITT Population

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Reporting group description

FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS

Reporting group title

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Reporting group description

FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA

Serious adverse events	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 73 (1.37%)	0 / 72 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 73 (1.37%)	0 / 72 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 3%

Non-serious adverse events	FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS	FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 73 (6.85%)	4 / 72 (5.56%)
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	5 / 73 (6.85%)	4 / 72 (5.56%)
occurrences all number	5	4

More information

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Were there any global substantial amendments to the protocol? Yes

25 Aug 2015

- To include an additional exercise challenge procedure at 23 hrs after the first dose of double-blinded study medication in each Treatment Period. The purpose is to demonstrate that inhaled FF/VI 100/25 µg provides improved bronchoprotection against EIB compared with FP 250 µg after 23 hrs of treatment with blinded medication. In addition, it will allow for an evaluation of the presence and extent of tachyphylaxis. - The study title was revised to indicate the study is a ‘randomized’ study with a ‘crossover’ design.

16 Dec 2015

- To increase the screen failure rate to 20 percent (from 10 percent) and the run-in failure rate to 70 percent (from 55 percent). This takes into consideration the challenge of enrolling EIB participants with Symptomatic Allergic Rhinitis (SAR) at screening and also the challenge for participants to demonstrate a decrease in FEV1 of >=20 percent at one time point within 30 min of the end of the exercise challenge at Visit 2 after taking FP for approximately four weeks during the run-in period. - The amendment also allows participants with SAR at screening to be treated with intranasal corticosteroids for up to four weeks, followed by a repeat screening visit to determine eligibility prior to entry into the study. Participants with SAR during the study may be treated with intranasal corticosteroids at a constant dose for the duration of the study. - The time window for the repeat exercise challenge has been extended from 24-48 hrs to up to one week; taking into consideration the challenge for participants to return within 48 hrs for a repeat procedure. - The Asthma Control Test (ACT) questionnaire has been replaced by the Asthma Control Questionnaire-5 (ACQ-5) questionnaire given the mismatch between treatment periods of two weeks and the recall period of 4 weeks for the ACT. - Tobacco/marijuana use and pregnancy have been added as exclusion criteria. - The secondary endpoint for time to recovery has been changed to a binary endpoint defining recovery as those participants who have a 30 min post-exercise FEV1 measurement that is no more than 5 percent lower than their pre-exercise FEV1. In addition, the statistical testing hierarchy has been changed to prioritize the maximal percentage FEV1 reduction (primary endpoint) and binary recovery endpoints following the 12 hr post-dose exercise challenge.

25 May 2016

- To adjust text to better reflect the intention of the protocol with regard to visit timing: Visit 2 (currently Day 1) redefined as Day 0 and Visit 3 (currently Day 2) redefined as Day 1. Visit window around Day 29 removed and footnote added. Text regarding timing of visits clarified to ensure that the intention of the protocol is clearly reflected. - Participant number will be assigned at Pre-Screening following informed consent rather than at Visit 1. - Nucala added as an example prohibited medication. - Rescue medication supply strategy has been removed. - Confirmation that post exercise vital signs will be immediately post exercise, not after 5 min of rest.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
201832: A Randomised, Double-Blind, Double-Dummy,Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

Primary: Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

Secondary: Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

Secondary: Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

Secondary: Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: 201832: A Randomised, Double-Blind, Double-Dummy,Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

Primary: Maximal percent decrease in forced expiratory volume in one second (FEV1) following exercise challenge at 12 hours (hrs) post evening dose from pre-exercise FEV1.

Secondary: Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

Secondary: Maximal percent decrease in FEV1 following exercise challenge at 23 hrs post evening dose from pre-exercise FEV1.

Secondary: Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Proportion of participants with a 30 min post-challenge FEV1 no more than 5 percent lower than pre-exercise FEV1 following the exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

Secondary: Weighted mean 0-60 min for percentage decrease from pre-exercise FEV1 following exercise challenge at 12 hrs and 23 hrs post evening dose.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
201832: A Randomised, Double-Blind, Double-Dummy,Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects with Asthma and Exercise-Induced Bronchoconstriction.