Clinical Trial Results:
Proof of Concept Evaluation of Drug-Device Interaction with aclidinium bromide via Genuair® and tiotropium bromide via HandiHaler® in COPD using Impulse Oscillometry
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Summary
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EudraCT number |
2013-003594-99 |
Trial protocol |
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Global end of trial date |
09 Jul 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Jul 2016
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First version publication date |
21 Jul 2016
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Other versions |
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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 |
2013RC09
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02039050 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Tayside Medical Sciences Centre on behalf of the University of Dundee & NHS Tayside
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Sponsor organisation address |
Residency Block, Level 3, Ninewells Hospital, George Pirie Way, Dundee, United Kingdom, DD1 9SY
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Public contact |
Arvind Manoharan, University of Dundee, 1382383235 +441382383235, a.d.manoharan@dundee.ac.uk
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Scientific contact |
Arvind Manoharan, University of Dundee, 1382383235 +441382383235, a.d.manoharan@dundee.ac.uk
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Aug 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
09 Jul 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jul 2015
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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 compare the chronic dosing impact of drug-device interaction between tiotropium and aclidinium on early morning trough bronchodilator response using impulse oscillometry in patients with COPD taking inhaled corticosteroids/long-acting beta agonists combination therapy.
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Protection of trial subjects |
Subjects were recruited from a database of volunteers who had agreed to be contacted with regard to
participating in departmental research. Subjects received a written information sheet (PIS) with details
of trial requirements, and had this for at least 24 hours before attending for a screening visit. They were
encouraged to discuss the possibility of participation with study staff and others.
Informed consent was obtained before any protocol-specific procedures were carried out. Subjects were
given every opportunity to clarify points they did not understand, and ask for more information. It was
emphasized that the subject could withdraw consent to participate at any time without loss of benefits to
which they otherwise would be entitled. The Chief Investigator could also withdraw a participant at any
point if they felt it would be unsafe or inappropriate for the subject to continue. An informed consent
form was signed and dated by the subject and the person taking consent, and the volunteer received a
copy.
Subjects were only selected if they met the pre-determined inclusion criteria.
Medical history and concomitant medications were reviewed by a medically qualified person to confirm it
was safe for the subject to receive the study drug. A physical examination was conducted before
randomisation.
Participants received an emergency mobile phone number, carried by a study doctor 24 hours a day, to
contact if they experienced any problems.
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Background therapy |
Any participants taking a LAMA at initial screening will have this stopped during the 1 week run-in period. Participants will continue on their ICS/LABA combination inhaler throughout the study but withhold the ICS/LABA for 12 hours prior to the study visits. Participants who are on theophylline can continue with theophylline throughout the study but will need to withhold the medication for 24 hours prior to study visits. | ||
Evidence for comparator |
There are potentially important differences between available LAMA’s for the treatment of COPD which appertain to the unique drug–device interaction when comparing dry powder formulations, namely Spiriva HandiHaler and Eklira Genuair. Firstly there is more homogeneous lung deposition throughout the lung with Eklira Genuair compared to Spiriva HandiHaler(1), which along with better small airways delivery, should translate into an improved bronchodilator response. Furthermore positive feedback from the green light system in terms of peak inspiratory flow with Eklira Genuair(2), is likely to reinforce correct inhaler use and hence more consistent dose delivery. Secondly at trough coinciding with the end of the usual dosing interval – i.e. comparing 12 hours for Eklira Genuair and 24 hours with Spiriva HandiHaler, there is likely to be a superior bronchodilator response.(3) This is likely to assume even greater relevance for patients throughout the night time period, such that patients will perceive improved control on waking, which in turn is likely to result in a better response for the following day time period i.e. better mornings = better days. Taken together this unique device-drug interaction is likely to produce improved long term disease control with Eklira Genuair. One possible way to detect such improvements in bronchodilator response in COPD is to use impulse oscillometry (IOS ), which is an effort independent technique measuring lung resistance and compliance at tidal volume –i.e. this requires minimal patient cooperation.(4) In this regard effort dependent tests such as spirometry accentuate forced expiratory volume and pressure dependent airway closure which occurs in COPD . This in turn results in an attenuated signal for bronchodilator response when comparing spirometry and IOS.(5) Moreover IOS permits the discrimination between central and peripheral airway resistance and reactance. Thus IOS is ideally suited to demonstrate th | ||
Actual start date of recruitment |
08 May 2014
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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 |
United Kingdom: 22
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Worldwide total number of subjects |
22
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EEA total number of subjects |
22
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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) |
0
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Adults (18-64 years) |
6
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From 65 to 84 years |
16
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited from May 2014 until May 2015. A total of 13 subjects completed the study. | |||||||||
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Pre-assignment
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Screening details |
Subjects were assessed at screening against pre-defined inclusion and exclusion criteria. Eligible subjects entered a 1-3 week run-in period. | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
22 | |||||||||
Intermediate milestone: Number of subjects |
Screening visit: 22
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Number of subjects completed |
13 | |||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Unreliable data: 1 | |||||||||
Reason: Number of subjects |
Did not meet inclusion criteria: 7 | |||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 1 | |||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||
Blinding implementation details |
Not applicable
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Arms
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Are arms mutually exclusive |
No
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Arm title
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tiotropium | |||||||||
Arm description |
Patients were randomized to tiotropium (Spiriva HandiHaler, Boehringer, Bracknell, UK) 18 microgram bid | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
tiotropium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder, hard capsule
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Routes of administration |
Inhalation use
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Dosage and administration details |
18 (1 puff) micrograms once daily
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Arm title
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aclidinium | |||||||||
Arm description |
Patients were randomized to either ACL (Eklira Genuair, Astra Zeneca, Luton, UK) 322 microgram bid | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
aclidinium
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Inhalation powder
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Routes of administration |
Inhalation use
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Dosage and administration details |
322 micrograms (2 puff) bid
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Baseline characteristics reporting groups [1]
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Reporting group title |
Overall trial
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: The number of subjects reported in the baseline period refers to the number of participants who completed the study and included in the final analysis. Enrolled participants include screen fails. |
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End points reporting groups
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Reporting group title |
tiotropium
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Reporting group description |
Patients were randomized to tiotropium (Spiriva HandiHaler, Boehringer, Bracknell, UK) 18 microgram bid | ||
Reporting group title |
aclidinium
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Reporting group description |
Patients were randomized to either ACL (Eklira Genuair, Astra Zeneca, Luton, UK) 322 microgram bid | ||
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End point title |
Change in trough R5 | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
1 to 2 weeks
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Statistical analysis title |
Paired Student's t-test | ||||||||||||
Statistical analysis description |
Paired Student's t-test were used to compare between treatment effects after each chronic dosing.
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Comparison groups |
tiotropium v aclidinium
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Number of subjects included in analysis |
26
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
< 0.05 [2] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||
upper limit |
- | ||||||||||||
| Notes [1] - The study was powered at 80% to detect a 0.1 kPa L-1 s difference in the the primary outcome of trough R5 [2] - Alpha error of 0.05 (two-tailed) |
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End point title |
Change in trough R5-R20 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough FEV1 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough FEF25-75 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in 6MWT Distance | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in SGRQ (total score) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough R20 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough X5 | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough RF | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough AX | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough FVC | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change in trough RVC | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
1 to 2 weeks
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All AEs and SAEs were recorded from the time a participant consented to join the study until the last study visit.
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Adverse event reporting additional description |
Subjects were asked about the occurrence of AEs at each study visit and received training on how to
record AEs and concomitant medications. All AEs were recorded on subject-specific logs in the CRFs.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18
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Reporting groups
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Reporting group title |
Completed subjects
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
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 | |||
