Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621001503819
Ethics application status
Approved
Date submitted
26/08/2021
Date registered
4/11/2021
Date last updated
4/11/2021
Date data sharing statement initially provided
4/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Inhaled Bronchodilators to support the use of Beta-Blockers in Chronic Obstructive Pulmonary Disease (COPD).
Scientific title
The LABA/LAMA and beta-blocker regimen in COPD: the effect of combination umeclidinium/vilanterol (Anoro®/Ellipta®) therapy on FEV1, exercise tolerance, and broncho-protection in COPD.
Secondary ID [1] 305137 0
None
Universal Trial Number (UTN)
U1111-1216-0362
Trial acronym
LABA/LAMA InhaLErS To prOtect agaiNst adverse airway Effects of beta-blockers in COPD: a novel indication for combination umeclidinium/vilanterol (Anoro®/Ellipta®).
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COPD 323376 0
Cardiac Disease 323377 0
Condition category
Condition code
Respiratory 320949 320949 0 0
Chronic obstructive pulmonary disease
Cardiovascular 320950 320950 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
RESPONSE: Doubling the dose has been explained in following the text from the protocol page 6, Telephone Call:
"One week after starting each treatment, participants will be contacted by telephone to enquire about possible adverse effects to the study medication including dizziness/light-headedness, falls, worsening of respiratory symptoms. If necessary a clinic visit will be arranged to assess these symptoms.
If no symptoms or only minor symptoms have been reported, the participants is willing and it is judged safe to increase the beta-blocker dose, participants will be instructed to double the dose of beta-blocker (taking 2 tablets each morning). If there are concerns about increasing the dose, but the participant is willing to continue in the study, the same dose can be continued (i.e. 2.5mg bisoprolol, 12.5mg carvedilol or matching placebo)."

Eligible participants will undergo baseline measurements before an open-label test dose of ß–blocker (carvedilol 12.5mg).
Participants who tolerate the test dose will be randomised to one of 6 treatment regimens,
a. Placebo inhaler and placebo tablet
b. Placebo inhaler and carvedilol 12.5mg/25mg
c. Placebo inhaler and bisoprolol 2.5mg/5mg
d. Umeclidinium/vilanterol 62.5/25mcg inhaler and placebo tablet
e. Umeclidinium/vilanterol 62.5/25mcg inhaler and carvedilol 12.5mg/25mg
f. Umeclidinium/vilanterol 62.5/25mcg inhaler and bisoprolol 2.5mg/5mg

Treatment (inhaler and tablet) will be administered once per day in the morning. Each treatment arm lasts for 14 days, however 7 days after starting each treatment, participants will be contacted by telephone to enquire about possible adverse effects to the study medication including dizziness/light-headedness, falls, worsening of respiratory symptoms. If necessary a clinic visit will be arranged to assess these symptoms.

If no symptoms or only minor symptoms have been reported, the participant is willing and it is judged safe to increase the beta-blocker dose, participants will be instructed to double the dose of beta-blocker (taking 2 tablets each morning). If there are concerns about increasing the dose, the participant may continue in the study at the same dose (i.e. 2.5mg bisoprolol, 12.5mg carvedilol or matching placebo) at the discretion of the PI and / or the participant is willing to continue.

There will be no washout periods between each arm.

Randomised participants will receive the next treatment pack in a consecutive sequence prepared in accordance with the randomisation schedule. Participants and Investigators will be blinded to the intervention order in the cross-over trial. All investigational drugs will be placebo-matched so the participant and investigators are unaware of the active drugs.

At each treatment arm visit, participants will return ALL their study medication for compliance and reconciliation. Safety procedures will include spirometry testing (1, 2 and 3 hrs post dose), ECG, BP and 6 minute walk test (between 2 and 3 hours post dose). A questionnaire will be completed to reflect the symptoms of the last week.

After completing all 6 treatment arms, the study will be complete.
Intervention code [1] 321546 0
Treatment: Drugs
Comparator / control treatment
The control will be placebo inhaler device containing a lactose only single strip.

The placebo tablet composition will be calcium lactate.
Control group
Placebo

Outcomes
Primary outcome [1] 328730 0
Difference in FEV1 between patients taking carvedilol and placebo with and without inhaled umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arms A minus B vs. D minus E
Timepoint [1] 328730 0
Difference in FEV1 defined as 2 hours post participants taking carvedilol or placebo with and without inhaled umeclidinium / vilanterol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [1] 400173 0
Difference in FEV1 between patients taking bisoprolol and placebo with and without inhaled umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arms A minus C vs. D minus F
Timepoint [1] 400173 0
Difference in FEV1 defined as 2 hours post participants taking bisoprolol or placebo with and without inhaled umeclidinium/vilanterol. at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [2] 400174 0
Difference in FEV1 between patients taking umeclidinium/vilanterol on placebo beta-blocker and umeclidinium/vilanterol on carvedilol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arms D vs. E
Timepoint [2] 400174 0
Difference in FEV1 defined as 2 hours post participants taking umeclidinium/vilanterol on placebo beta-blocker and umeclidinium/vilanterol on carvedilol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [3] 400175 0
Difference in FEV1 between patients taking umeclidinium/vilanterol on placebo beta-blocker and umeclidinium/vilanterol on bisoprolol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arms D vs. F
Timepoint [3] 400175 0
Difference in FEV1 defined as 2 hours post participants taking umeclidinium/vilanterol on placebo beta-blocker and umeclidinium/vilanterol on bisoprolol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [4] 400176 0
Difference in FEV1 between patients taking bisoprolol vs carvedilol while treated with placebo inhalers. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arms B vs. C
Timepoint [4] 400176 0
Difference in FEV1 defined as 2 hours post participants taking bisoprolol vs carvedilol while treated with placebo inhalers at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [5] 400177 0
Difference in FEV1 between patients taking bisoprolol vs carvedilol while treated with umeclidinium/vilanterol. FEV1 will be measured using spirometry according to American Thoracic Society / European Respiratory Society (ATS / ERS) guidelines.

i.e. FEV1 of arm E vs. F
Timepoint [5] 400177 0
Difference in FEV1 defined as 2 hours post participants taking bisoprolol vs carvedilol while treated with umeclidinium/vilanterol at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).
Secondary outcome [6] 402128 0
Difference in 6MWT distance between patients taking carvedilol and placebo with and without umeclidinium/vilanterol.

i.e. 6MWT distance of arms A-B vs. D-E
Timepoint [6] 402128 0
Difference in 6MWT distance between patients taking carvedilol and placebo with and without umeclidinium/vilanterol. at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [7] 402129 0
Difference in 6MWT distance between patients taking bisoprolol and placebo with and without umeclidinium/vilanterol.

i.e. 6MWT distance of arms A-C vs. D-F
Timepoint [7] 402129 0
Difference in 6MWT distance between patients taking bisoprolol and placebo with and without umeclidinium/vilanterol. at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [8] 402130 0
Difference in 6MWT distance between patients taking carvedilol vs. placebo while treated with umeclidinium/vilanterol

i.e. 6MWT distance of arms D vs. E
Timepoint [8] 402130 0
Difference in 6MWT distance between patients taking carvedilol vs. placebo while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [9] 402131 0
Difference in 6MWT distance between patients taking bisoprolol vs. placebo while treated with umeclidinium/vilanterol.

i.e. 6MWT distance of arms D vs. F
Timepoint [9] 402131 0
Difference in 6MWT distance between patients taking bisoprolol vs. placebo while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [10] 402132 0
Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with placebo inhaler.

i.e. 6MWT distance of arms B vs. C
Timepoint [10] 402132 0
Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with placebo inhaler.at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [11] 402133 0
Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with umeclidinium/vilanterol.

i.e. 6MWT distance of arm E vs. F
Timepoint [11] 402133 0
Difference in 6MWT distance between patients taking bisoprolol vs. carvedilol while treated with umeclidinium/vilanterol at visits 1B, 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment) between the 2nd and 3rd hour after taking the medication.
Secondary outcome [12] 402134 0
Difference in Area Under Curve FEV1 before taking the study medication and at 1, 2, and 3 hours after administration of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.
Timepoint [12] 402134 0
Difference in Area Under Curve FEV1 before taking the study medication and at 1, 2, and 3 hours after administration at visits 3, 4, 5, 6, 7 & 8 (ie. day 14 of each study treatment).

The medication/placebo combinations of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol are as described in Primary outcome 1 and Secondary outcomes 1-5.
Secondary outcome [13] 402136 0
Difference in change in heart rate and blood pressure following carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.
Timepoint [13] 402136 0
Heart rate and blood pressure will be measured between the 2nd and 3rd hour after taking the medication.

The medication/placebo combinations of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol are as described in Primary outcome 1 and Secondary outcomes 1-5.
Secondary outcome [14] 402137 0
Differences in COPD Assessment Test (CAT) score (for respiratory symptoms in the last week) while on a combination of carvedilol and bisoprolol vs placebo with and without inhaled umeclidinium/vilanterol.
Timepoint [14] 402137 0
Differences in COPD Assessment Test (CAT) score (for respiratory symptoms in the last week) as assessed by the CAT questionnaire which will be completed at visits 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment), to reflect the symptoms of last 1 week. Any adverse effects will be recorded.
Secondary outcome [15] 402138 0
Differences in any serious adverse events (SAEs) and Adverse Events (AEs) that occurred during each intervention including:
a. Withdrawals
b. AEs & SAEs with each intervention
Timepoint [15] 402138 0
Differences in any SAEs and AEs as assessed at telephone calls One week after starting each treatment and at visits 3, 4, 5, 6, 7, & 8 (ie. day 14 of each study treatment).

Eligibility
Key inclusion criteria
• Physician diagnosis of COPD
• Post-bronchodilator FEV1/FVC <0.70
• Post-bronchodilator FEV1 between 30% and 80% of predicted
• Minimum 10 pack-year smoking history
• Age 40 years and over
• BP and spirometry criteria must be met after test dose of carvedilol
• Written informed consent
Minimum age
40 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Self-reported diagnosis of asthma
• Post-bronchodilator improvement in FEV1 >400ml
• Lower respiratory tract infection within the previous 8 weeks
• COPD not clinically stable/COPD exacerbation within previous 8 weeks
• Requiring home oxygen/resting O2 saturations <90% on air when stable
• Currently in the acute phase of a pulmonary rehabilitation program
• Previously recorded allergy or intolerance of beta-blockers or any anticholinergic/muscarinic receptor antagonist, symp, lactose/milk protein or magnesium stearate
• Frequent episodes of hypoglycaemia (in patients with Diabetes Mellitus)
• Pregnancy & breastfeeding
• Concurrent use of other rate-limiting medication (e.g. rate-limiting calcium channel blockers)
• Already taking beta-blocker treatment
• Uncontrolled Heart Failure
• Systolic Blood Pressure less or equal to 110mmHg or >180mmHg at time of screening
• Diastolic blood pressure >100mmHg
• Bradycardia defined as <60bpm at time of screening
• Persistent tachyarrhythmia, including atrial fibrillation rate >120bpm
• Pre-existing 2nd/3rd degree AV-block
• Clinical instability or major cardiac event in the previous 12 weeks
• Severe Peripheral Vascular Disease
• Severe or unstable liver disease
• Acute angle closure glaucoma
• Any other condition, at the discretion of the investigator, which may impact on the safety of participants or feasibility of study results

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)
Randomisation will be via a computer-generated sequence in a balanced Latin-square design provided by the study research pharmacist
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
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
In our previous study of formoterol in COPD patients the paired standard deviation for FEV1 was 180mL. The minimally clinically important difference in FEV1 in patients with COPD is 100mL. To achieve 80% power, with alpha 0.05 (two-sided), we need 28 participants in a paired design. We aim to recruit 36 participants to allow for up to a 20% withdrawal rate

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/12/2021
Actual
Date of last participant enrolment
Anticipated
29/04/2022
Actual
Date of last data collection
Anticipated
13/01/2023
Actual
Sample size
Target
36
Accrual to date
Final
Recruitment outside Australia
Country [1] 24063 0
New Zealand
State/province [1] 24063 0
Waikato

Funding & Sponsors
Funding source category [1] 309530 0
Commercial sector/Industry
Name [1] 309530 0
Glaxo Smith Kline (GSK)
Country [1] 309530 0
New Zealand
Primary sponsor type
Hospital
Name
Waikato District Health Board
Address
Waikato Hospital,
Pembroke St,
Hamilton 3240
New Zealand
Country
New Zealand
Secondary sponsor category [1] 310518 0
None
Name [1] 310518 0
Address [1] 310518 0
Country [1] 310518 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309312 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 309312 0
Health and Disability Ethics Committee
133 Molesworth St
PO Box 5013
Wellington 6011
New Zealand
Ethics committee country [1] 309312 0
New Zealand
Date submitted for ethics approval [1] 309312 0
18/08/2020
Approval date [1] 309312 0
05/11/2020
Ethics approval number [1] 309312 0
20/NTB/197

Summary
Brief summary
Beta-blocker therapy has been shown to markedly reduce the risk of mortality in patients with cardiovascular disease but are withheld to patients with COPD because of concerns that they may worsen airways disease.
We want to study whether giving a combination of Long-Acting Muscarinic Antagonist (LAMA used to treat the symptoms of COPD such wheezing, coughing and shortness of breath ) and Long-acting bronchodilator inhalers (LABAs relax the muscles around your airways to help keep your airways open) can prevent any potential negative effects of beta-blockers on the lungs of people with COPD.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113718 0
Dr Catherina Chang
Address 113718 0
Waikato Hospital,
Pembroke St,
Hamilton 3204
New Zealand
Country 113718 0
New Zealand
Phone 113718 0
+64 21 744228
Fax 113718 0
Email 113718 0
[email protected]
Contact person for public queries
Name 113719 0
Mrs Christine Tuffery
Address 113719 0
Waikato Hospital,
Pembroke St,
Hamilton 3204
New Zealand
Country 113719 0
New Zealand
Phone 113719 0
+64 21 759531
Fax 113719 0
Email 113719 0
[email protected]
Contact person for scientific queries
Name 113720 0
Dr Catherina Chang
Address 113720 0
Waikato Hospital,
Pembroke St,
Hamilton 3204
New Zealand
Country 113720 0
New Zealand
Phone 113720 0
+64 7 8398899
Fax 113720 0
Email 113720 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.