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Trial registered on ANZCTR


Registration number
ACTRN12618000306213
Ethics application status
Approved
Date submitted
24/01/2018
Date registered
1/03/2018
Date last updated
16/01/2020
Date data sharing statement initially provided
4/02/2019
Date results information initially provided
16/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of cardio selective beta blockers on rescue beta agonists following controlled bronchoconstriction challenge in Asthmatics
Scientific title
Investigating the impact of regular cardio selective beta blockers on recovery with beta agonists following methacholine bronchoconstriction challenge in Asthmatics
Secondary ID [1] 293838 0
None known
Universal Trial Number (UTN)
U1111-1208-2442
Trial acronym
BBRBA (Beta Blockers effect on Rescue Beta Agonists)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 306282 0
Condition category
Condition code
Respiratory 305371 305371 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cross over study with two blinded arms and a third unblinded arm.
Incrimental once daily oral capsule dose of cardioselective beta blocker (bisoprolol) or placebo going up after at least 48 hours at each step from 1.25mg to 2.5mg (if no symptoms of lightheadedness or fainting on a phone call assessment) then up to 5mg (if heart rate >60 and systolic blood pressure >100 on visit assessment). Minimum time at each step 48 hours, maximum 5 days.
A third open label arm will be run involving any of the participants who tolerated the 5mg bisoprolol. They will be uptitrated after at least 48 hours at each dose from 2.5mg to 5mg to 7.5mg (if no symptoms of lightheadedness or fainting on a phone call assessment to advise on each dose increase) then after a further minimum of 48 hours up to 10mg (if heart rate >60 and systolic blood pressure >100 on visit assessment) which will be continued for a minimum of 48 hours up to and including the date of the final visit with Asthma questionnaire and mannitol challenge.
Strategies used to monitor adherence include drug tablet return.
No wash out period is required as the measure of spirometry will be at the end of each arm and therefore over 7 days since the last dose of the previous study drug was taken. As such there will have been sufficient time for the stabalisation of adrenoreceptors to demonstrate findings sufficiently.
At the end of each of the three arms, on the day of the last study drug administration, controlled bronchoconstriction using mannitol. This follows a strict protocol which administers increasing doses of inhaled dry powder mannitol until a 15% fall in the forced expiratory volume in one second (FEV1) is reached. The response to inhaled salbutamol (100, 100, 200 mg at 5 min intervals) will then be measured. Dose response curves will be compared using an analysis of covariance. Also on this last day a asthma questionnaire will be done. All three of these end of arm measures will be compared to measurements done at baseline on screening visits.
Intervention code [1] 300110 0
Treatment: Drugs
Comparator / control treatment
sugar capsule
Control group
Placebo

Outcomes
Primary outcome [1] 304533 0
Graph drawn of time against FEV1 measured. Points plotted for 0, 5, 10, 15 minutes (each being after 0, 100micrograms, 100micrograms, 200micrograms salbutamol respectively). Area under curve measured to compare recovery with beta agonist following methacholine challenge. FEV1 will be assessed using hand held spirometry.
Timepoint [1] 304533 0
This will be measured immediately after methacholine challenge at 0, 5, 10, 15 minutes (each being after 0, 100micrograms, 100micrograms, 200micrograms salbutamol respectively). This challenge will be undertaken at the end of each study arm.
Secondary outcome [1] 342288 0
PD15 MANNITOL - Concentration of mannitol required to drop the FEV1 15% from baseline as per standardized mannitol challenge protocol . FEV1 will be assessed using hand held spirometry.
Timepoint [1] 342288 0
This will be documented as part of each MANNITOL challenge which is undertaken on the final day of each study arm.
Secondary outcome [2] 342289 0
Time to 80% recovery of FEV1 which will be assessed by plotting the recovery time graph (FEV1 against time) which is required for measuring the primary endpoint of area under the curve. The FEV1 is assessed using hand held spirometry.
Timepoint [2] 342289 0
This will be documented as part of each MANNITOL challenge which is undertaken on the final day of each study arm.
Secondary outcome [3] 342290 0
Dose of salbutamol required to reach 80% recovery of FEV1. This information will be available as part of the primary outcome data using the FEV1 against time recovery graph.
FEV1 will be assessed using hand held spirometry.
Timepoint [3] 342290 0
This will be documented as part of each mannitol challenge which is undertaken on the final day of each study arm.
Secondary outcome [4] 342291 0
Cardiovascular response – blood pressure and pulse measured with sphygmomanometer and pulse oximeter .
Timepoint [4] 342291 0
Measured at minimum of 48 hours after the first dose of 2.5mg bisoprolol oral dose once daily, and if tolerated after 48 hours of 7.5mg bisoprolol oral dose once daily, and also at each mannitol challenge visit on the last day of each study arm.
Secondary outcome [5] 342292 0
Patient reported symptoms: e.g. lightheadedness, shortness of breath, lethargy (patient diary) as a composite outcome
Timepoint [5] 342292 0
At any point up to study end (last Mannitol challenge day)
Secondary outcome [6] 342643 0
Adverse events - such as injury, loss of consciousness (patient diary)
Timepoint [6] 342643 0
At any point until study end (last methacholine challenge day)
Secondary outcome [7] 343576 0
Asthma symptoms questionnaire - using ACQ 5 questionnaire
Timepoint [7] 343576 0
At screening (baseline) and at the end of each study arm.

Eligibility
Key inclusion criteria
• Physician diagnosis of asthma
• Airway hyper responsiveness. Demonstrated with post mannitol ( a 15 percent decrease in FEV1 at a cumulative mannitol dose PD15 <635mg/ml)
• Over 18 years of age
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Pre spirometry FEV1 < 60% predicted or < 1.5L
• Dyspnoea at rest
• Past history of hypotension (baseline BP <100/60)
• ECG abnormalities that could interfere with the interpretation of the study:
• HR<60/min
• Symptomatic hypotension
• ECG findings of severe 1st degree, or 2nd & 3rd degree heart block (defined as PR interval > 0.28s)
• LBBB & RBBB are NOT excluded.
• Known adverse reaction to beta blockers or mannitol
• On other drugs that commonly interact with beta blockers (amiodarone, verapramil, cimetidine, digoxin, phenytoin)
• Already taking beta blockers – including eye-drops.
• Smoking history of >10 pack years
• Recent exacerbation as defined by oral corticosteroid use/hospitalisation within 6 weeks of recruitment
• Pregnant (negative pregnancy test required)
• Under 18 year of age
• Unsuitability as defined by the study doctor

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Participant will be randomised to receive placebo then bisoprolol OR bisoprolol then placebo. Those that tolerate the 5mg bisoprolol then proceed to a third arm following completion of both arms one and two.
Phase
Phase 4
Type of endpoint(s)
Pharmacodynamics
Statistical methods / analysis
To show a standard difference of 30% between placebo and bisoprolol using previous data from our department we would need 18 participants to adequately power the study with 10% extra to account for drop outs we will aim to recruit a minimum of 20 participants, up to 24.

This was calculated using a non inferiority measure with significance level 5%, power 90%, standard deviation 30% and non inferiority limit of 30%.

Calculation based on the formula:

n = f(a, ß) × 2 × s2 / d2
where s is the standard deviation, and
f(a, ß) = [F-1(a) + F-1(ß)]2
F-1 is the cumulative distribution function of a standardised normal deviate.

We will use a paired T test to assess if there is a difference in area under the curve from baseline to the end of each arm (i.e after taking bisoprolol or placebo).
We will use a second paired t test to decide if there is a difference between the area under the curve following placebo and following bisoprolol.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9514 0
New Zealand
State/province [1] 9514 0
Waikato

Funding & Sponsors
Funding source category [1] 298457 0
Other Collaborative groups
Name [1] 298457 0
Waikato District Health Board, Respiratory Research Fund
Address [1] 298457 0
Waikato DHB
Pembroke Street,
Hamilton
3204
Country [1] 298457 0
New Zealand
Primary sponsor type
Other Collaborative groups
Name
Waikato District Health Board, Respiratory Research Fund
Address
Waikato DHB
Pembroke Street,
Hamilton
3204
Country
New Zealand
Secondary sponsor category [1] 297598 0
Hospital
Name [1] 297598 0
Respiratory Research Unit Waikato Hospital
Address [1] 297598 0
Gastro and Respiratory Research Level B1 Menzies Building
Pembroke Street,
Hamilton
3204
Country [1] 297598 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299448 0
Health and Disabilitiy Ethics Comittees
Ethics committee address [1] 299448 0
Health and Disability Ethics Committees
Ministry of Health
133 Molesworth Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 299448 0
New Zealand
Date submitted for ethics approval [1] 299448 0
20/02/2018
Approval date [1] 299448 0
06/07/2018
Ethics approval number [1] 299448 0
18/STH/113

Summary
Brief summary
Double blinded cross over study to investigate the effect of regular cardio selective beta blockers on the ability of beta agonists (salbutamol) to reverse a controlled bronchoconstriction.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80434 0
Dr Miriam Bennett
Address 80434 0
Respiratory Research Department
Level B1 Menzies Building
Waikato DHB
Pembroke Street
Hamilton
3204
Country 80434 0
New Zealand
Phone 80434 0
+64 7839 8899 x 98070
Fax 80434 0
+647858 0984
Email 80434 0
miriam.bennett@waikatodhb.health.nz
Contact person for public queries
Name 80435 0
Dr Miriam Bennett
Address 80435 0
Respiratory Research Department
Level B1 Menzies Building
Waikato DHB
Pembroke Street
Hamilton
3204
Country 80435 0
New Zealand
Phone 80435 0
+64 7839 8899 x 98070
Fax 80435 0
+647858 0984
Email 80435 0
miriam.bennett@waikatodhb.health.nz
Contact person for scientific queries
Name 80436 0
Dr Miriam Bennett
Address 80436 0
Respiratory Research Department
Level B1 Menzies Building
Waikato DHB
Pembroke Street
Hamilton
3204
Country 80436 0
New Zealand
Phone 80436 0
+64 7839 8899 x 98070
Fax 80436 0
+647858 0984
Email 80436 0
miriam.bennett@waikatodhb.health.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not required
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
How or where can supporting documents be obtained?
Type [1] 1275 0
Study protocol
Citation [1] 1275 0
Link [1] 1275 0
Email [1] 1275 0
Other [1] 1275 0
Type [2] 1276 0
Ethical approval
Citation [2] 1276 0
Link [2] 1276 0
Email [2] 1276 0
Other [2] 1276 0
Type [3] 1277 0
Study protocol
Citation [3] 1277 0
Link [3] 1277 0
Email [3] 1277 0
Other [3] 1277 0
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Results – basic reporting
Results – plain English summary