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
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EudraCT number |
2017-001516-11 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
03 Feb 2017
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Results information
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Results version number |
v1 |
This version publication date |
12 Aug 2017
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First version publication date |
12 Aug 2017
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
201832
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
GlaxoSmithKline
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Sponsor organisation address |
980 Great West Road, Brentford, Middlesex, United Kingdom,
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Public contact |
GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
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Scientific contact |
GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 May 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Feb 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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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.
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 May 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 2
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Country: Number of subjects enrolled |
United States: 72
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Worldwide total number of subjects |
74
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
17
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Adults (18-64 years) |
57
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | ||||||||||||||||
Pre-assignment
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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
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||
Arms
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Arm title
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All treatment combined | ||||||||||||||||
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 one of the following two treatment sequences in a ratio of 1:1: FF/VI 100/25 µg once daily (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. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
FF/VI 100/25 µg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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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.
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Investigational medicinal product name |
FP 250 µg
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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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.
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Investigational medicinal product name |
Placebo ELLIPTA
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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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.
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Investigational medicinal product name |
Placebo DISKUS/ACCUHALER
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, pre-dispensed
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Routes of administration |
Inhalation use
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Dosage and administration details |
Lactose was administered BID, once in the morning and once in the evening via DISKUS/ACCUHALER.
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Baseline characteristics reporting groups
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Reporting group title |
All treatment combined
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Reporting group 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 one of the following two treatment sequences in a ratio of 1:1: FF/VI 100/25 µg once daily (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. | |||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
All treatment combined
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Reporting group 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 one of the following two treatment sequences in a ratio of 1:1: FF/VI 100/25 µg once daily (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. | ||
Subject analysis set title |
FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS
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Subject analysis set title |
FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
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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 hour post dose. ITT Population comprised of all participants randomized to treatment and who received at least one dose of study medication.
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End point type |
Primary
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End point timeframe |
At Week 2 of treatment period 1 and 2
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Notes [1] - ITT Population |
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Statistical analysis title |
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
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Number of subjects included in analysis |
139
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.109 [2] | |||||||||||||||
Method |
Mixed models analysis | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
-1.69
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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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. |
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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.
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End point type |
Secondary
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End point timeframe |
At Week 2 of treatment period 1 and 2
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Notes [3] - ITT Population |
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Statistical analysis title |
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
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Number of subjects included in analysis |
137
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.051 [4] | |||||||||||||||
Method |
Mixed models analysis | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
-2.15
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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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. |
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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 if 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).
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End point type |
Secondary
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End point timeframe |
At Week 2 of treatment period 1 and 2
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Notes [5] - ITT Population |
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Statistical analysis title |
Statistical analysis 1 | |||||||||||||||||||||
Statistical analysis description |
12 hrs
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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
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Number of subjects included in analysis |
145
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.266 [6] | |||||||||||||||||||||
Method |
Regression, Logistic | |||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||
Point estimate |
1.34
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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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. |
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Statistical analysis title |
Statistical analysis 2 | |||||||||||||||||||||
Statistical analysis description |
23 hrs
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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
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Number of subjects included in analysis |
145
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.322 [7] | |||||||||||||||||||||
Method |
Regression, Logistic | |||||||||||||||||||||
Parameter type |
Odds ratio (OR) | |||||||||||||||||||||
Point estimate |
1.37
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
0.73 | |||||||||||||||||||||
upper limit |
2.58 | |||||||||||||||||||||
Notes [7] - Repeated measures logistic regression model with parameters estimated using the Generalized Estimating Equation method |
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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 if 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).
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End point type |
Secondary
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End point timeframe |
At Week 2 of treatment period 1 and 2
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Notes [8] - ITT Population |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||||||||
Statistical analysis description |
12 hrs post-dose
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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
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Number of subjects included in analysis |
145
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.342 [9] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||
Point estimate |
-0.65
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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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. |
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Statistical analysis title |
Statistical analysis 2 | ||||||||||||||||||
Statistical analysis description |
23 hrs post-dose
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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
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Number of subjects included in analysis |
145
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
= 0.041 [10] | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||||||||
Point estimate |
-1.75
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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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. |
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Adverse events information
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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).
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Adverse event reporting additional description |
ITT Population
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||
Dictionary version |
19.1
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Reporting groups
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Reporting group title |
FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA
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Reporting group description |
FP 250 µg BID via DISKUS + Placebo QD via ELLIPTA | ||||||||||||||||||||||||||||||
Reporting group title |
FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS
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Reporting group description |
FF/VI 100/25 µg QD via ELLIPTA + Placebo BID via DISKUS | ||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | |||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |