ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616000377437

Ethics application status

Approved

Date submitted

18/03/2016

Date registered

23/03/2016

Date last updated

30/01/2020

Date data sharing statement initially provided

3/05/2019

Date results provided

3/05/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

Randomised Controlled Trial of the efficacy and safety of an Inhaled Corticosteroid and Long Acting Beta Agonist reliever therapy regimen in asthma

Scientific title

A 52-week, open label, parallel group, multicentre, phase III, randomised controlled trial to compare the efficacy and safety of Budesonide/formoterol turbuhaler taken as required for relief of symptoms and Budesonide turbuhaler as maintenance and terbutaline turbuhaler as required for relief of symptoms of asthma in adults.

Secondary ID [1]

None known

Universal Trial Number (UTN)

U1111-1174-2273

Trial acronym

PRACTICAL: PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long-acting beta agonist

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Asthma

Condition category

Condition code

Respiratory

Asthma

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Inhaled corticosteroid/Long acting beta Agonist (ICS/LABA) reliever therapy; budesonide/formoterol turbuhaler 200micrograms/6micrograms taken one inhalation for relief of symptoms as required for 52 weeks. These participants will receive no maintenance therapy.

In the electronic monitor sub-study, 110 patients will have an electronic monitor incorporated into each turbuhaler device to record the date and time of actuations to allow a detailed assessment of patterns of use of randomised treatments. 55 participants will be recruited from the ICS/LABA reliever group and 55 participants from the maintenance ICS and SABA reliever therapy group. This substudy will run for 52 weeks.

Inhaler use will be monitored electronically. An electronic monitor device will be attached to each inhaler, which is able to measure the date and time of each actuation performed.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Maintenance Inhaled Corticosteroid (ICS) and Short Acting Beta Agonist (SABA) reliever therapy; budesonide Turbuhaler 200 micrograms, 1 inhalation twice daily and terbutaline metered dose inhaler 250 micrograms 2 inhalations for relief of symptoms as required, for 52 weeks.

In the electronic monitoring sub-study, inhaler use will be monitored electronically. An electronic monitor device will be attached to each inhaler, which is able to measure the date and time of each actuation performed. The electronic monitoring sub-study will run for 52 weeks.

Control group

Active

Outcomes

Primary outcome [1]

The primary outcome variable is severe asthma exacerbation rate expressed as number of exacerbations per patient per year.

Timepoint [1]

Timepoint is determined by occurrence of either the use of systemic corticosteroids for at least 3 days because of asthma, or Hospitalisation or emergency department (ED) visit because of asthma, requiring systemic corticosteroids

These criteria will be determined from participant self report.
Asthma exacerbations will be assessed throughout the 52 week intervention period

Secondary outcome [1]

Time to first severe exacerbation of asthma, which is defined as either the use of systemic corticosteroids for at least 3 days because of asthma, or Hospitalisation or emergency department (ED) visit because of asthma, requiring systemic corticosteroids. This outcome will be assessed by participant self report at interview.

Timepoint [1]

This outcome measure is measured from date intervention commenced, to the date first severe exacerbation begins.

Secondary outcome [2]

Asthma Control Questionnaire score (ACQ-5 score), as measured by the ACQ-5 validated questionnaire completed by the participant

Timepoint [2]

Weeks 0, 4, 16, 28, 40 and 52

Secondary outcome [3]

On-treatment Forced Expiratory Volume in 1 second (FEV1) (litres), as measured by spirometry assessment.

Timepoint [3]

Weeks 0, 4, 16, 28, 40 and 52

Secondary outcome [4]

Fractional Exhaled Nitric Oxide, as measured by a NIOX VERO device

Timepoint [4]

Weeks 0, 16 and 52

Secondary outcome [5]

Mean Inhaled Corticosteroid dose per day (budesonide micrograms/day), as recorded by the electronic monitor devices on nested substudy inhalers

Timepoint [5]

Data collected over duration of study using electronic monitors, and will be assessed week 0 to 52.

Secondary outcome [6]

Proportion of patients with at least one day of no inhaled corticosteroid use, as recorded by the electronic monitors on inhalers in nested sub study

Timepoint [6]

Duration of study; week 0 to 52.

Secondary outcome [7]

Longest duration of no inhaled corticosteroid use, as recorded by the electronic monitors on inhalers in nested substudy

Timepoint [7]

Duration of study; week 0 to 52.

Secondary outcome [8]

Total systemic corticosteroid exposure.
In the nested sub-study, systemic corticosteroid exposure/year in which the total inhaled Corticosteroid dose/year (as recorded by the electronic monitors on each inhaler)is converted to oral prednisone-equivalent dose and added to the participant self-reported oral corticosteroid use.

Timepoint [8]

Duration of study; week 0 to 52

Secondary outcome [9]

To examine patient attitudes to the treatment regimens through the validated belief about medicines questionnaire.

Timepoint [9]

Week 0 and 52

Secondary outcome [10]

To determine whether baseline socioeconomic characteristics such as housing status predict preferential response to randomised treatment through completion of Housing status questionnaire.

Timepoint [10]

Week 0

Secondary outcome [11]

Proportion of participants with at least one episode of high use, defined as greater than 16 actuations of Terbutaline in a 24 hour period, or greater than 8 actuations of budesonide/formoterol in a 24 hour period, as recorded by the electronic monitors on inhalers in the nested sub-study.

Timepoint [11]

Duration of study; week 0 to 52.

Secondary outcome [12]

Number of days of high beta agonist use, defined as greater than 16 actuations of Terbutaline in a 24 hour period, or greater than 8 actuations of budesonide/formoterol in a 24 hour period, as recorded by the electronic monitors on inhalers in the nested sub-study

Timepoint [12]

Duration of stud; week 0 to 52.

Secondary outcome [13]

Number of days of high use without medical review within 48 hours, in participants with at least one high use episode, as recorded by the electronic monitors on inhalers in the nested substudy. Medical review will be assessed by participant self-report.

Timepoint [13]

Duration of study; week 0 to 52.

Secondary outcome [14]

Maximum number of beta agonist actuations in a 24 hour period as recorded by the electronic monitors on inhaler in the nested substudy.

Timepoint [14]

Duration of study; week 0 to 52.

Secondary outcome [15]

For the rate of exacerbations (measured by self report) a differential effect of treatment will be explored with each of the following baseline moderating variables: Short Acting Beta Agonist (SABA) use (measured as the average number of occasions per week of self-reported SABA use in the four weeks before enrolment), ICS stratum at baseline (measured as the self-reported use of ICS within the 3 months before enrolment), ICS adherence at baseline, in those using ICS at baseline, measured as the average self-reported adherence per day, within the four weeks before enrolment with self-reported adherence measured as a proportion of the prescribed dose, smoking status at baseline, whether there has been a severe exacerbation in the year prior to enrolment (measured by participant self-report), age (measured by self-report), sex (measured by self-report), smoking status (measured by self report), baseline Asthma Control Questionnaire-5 (ACQ-5) score (measured by ACQ-5 score), Fractional Exhaled Volume in 1 second (FEV1) percent predicted (measured by predicted values based on self reported height, age and ethnicity), Fractional Exhaled Nitric Oxide (FeNO, measured by NIOX VERO device), blood eosinophil count (measured by laboratory test),

Timepoint [15]

Duration of study; week 0 to 52.

Secondary outcome [16]

The proportion of exacerbations defined by the use of systemic corticosteroids for at least 3 days because of asthma, and the proportion defined by the requirement for Hospitalisation or emergency department (ED) visit because of asthma, requiring systemic corticosteroids.

Timepoint [16]

Weeks 0, 4, 16, 28, 40 and 52

Secondary outcome [17]

The proportion of patients with at least one severe exacerbation.
This outcome will be assessed by participant self report at interview. Participant NHI number will be used to centrally validate exacerbation outcome data relating to hospital attendance and/or admission.

Timepoint [17]

Weeks 0, 4, 16, 28, 40 and 52

Secondary outcome [18]

Proportion of participants withdrawn and reason. The Proportion of participants withdrawn due to “treatment failure” will also be presented. Treatment failure is defined as withdrawal due to uncontrolled asthma under the randomised regimen resulting in safety concerns, as judged by the investigator or if randomised treatment is modified by the participant’s GP or other healthcare provider

Data is measured from self-report by participant

Timepoint [18]

Date of withdrawal

Secondary outcome [19]

Cost effectiveness will be calculated for each treatment regimen (medications, emergency medical attention, ED visits, hospital admissions and non medical costs including days off work). The following represent current indicative figures, which will be updated to current actual figures at the time of analysis; medications (terbutaline $22/turbuhaler, budesonide $19/turbuhaler, budesonide/formoterol $60/turbuhaler), emergency medical ($86/visit) and ED visits ($339/visit), and hospital admissions (medical ward $1,194/day, high dependency unit $2,763/day, ICU $5,570/day)] and non-medical costs (days off work $167/day). The cost-effectiveness data collected will allow extrapolation to future pricing models with lower cost generic medications. This outcome data will be assessed by participant self report at interview.

Timepoint [19]

Duration of study; week 0 to 52.

Secondary outcome [20]

Proportion of participants with at least one episode of marked beta agonist overuse, defined as greater than 24 actuations of Terbutaline in a 24 hour period, or greater than 12 actuations of budesonide/formoterol in a 24 hour period, as recorded by the electronic monitors on inhalers in the nested sub-study.

Timepoint [20]

Duration of study; week 0 to 52.

Secondary outcome [21]

Timepoint [21]

Duration of study; week 0 to 52.

Secondary outcome [22]

Number of marked beta agonist use episodes without medical review in the following 48 hour period, 7 day period and 14 day period in participants who had a least one marked beta agonist use episode. Where marked beta agonist use is defined as greater than 24 actuations of Terbutaline in a 24 hour period, or greater than 12 actuations of budesonide/formoterol in a 24 hour period, as recorded by the electronic monitors on inhalers in the nested sub-study.

Timepoint [22]

Duration of study; week 0 to 52.

Secondary outcome [23]

Mean beta agonist dose per day as recorded by the electronic monitors on inhalers in the nested sub-study.

Timepoint [23]

Duration of study; week 0 to 52.

Secondary outcome [24]

Total oral corticosteroid dose recorded using patient self report.

Timepoint [24]

Duration of study: week 0 to week 52

Secondary outcome [25]

Number of courses of oral corticosteroid per year recorded through patient self-report.

Timepoint [25]

Duration of Study: week 0 to week 52

Eligibility

Key inclusion criteria

Adults aged 18 to 75 years.

Self-report of a doctor’s diagnosis of asthma.

Not used Inhaled corticosteroids in the 12 weeks prior to entry into the study and suffering from asthma symptoms or
Need for SABA on two or more occasions in the last 4 weeks, or
Waking due to asthma once or more in the last 4 weeks, or
Exacerbation requiring oral corticosteroids in the last 52 weeks

Or has used inhaled corticosteroids in the 12 weeks prior to entry in the study, and is prescribed ICS at low or moderate doses (<500micrograms/day fluticasone propionate or small particle formulation beclomethasone diproprionate (QVAR); 800 micrograms/day budesonide; 1,000 micrograms/day beclomethasone diproprionate (Beclazone)), and:
i. has partly or well controlled asthma as defined by GINA guidelines
OR
ii. has uncontrolled asthma as defined by GINA guidelines and either poor adherence to ICS and/ or unsatisfactory inhaler technique.

Willing and able to give informed consent for participation in the trial.

In the investigator's opinion, able and willing to comply with all trial requirements.

Willing to allow their GP (and specialist if appropriate) to be notified of participation in the trial.

Minimum age

18 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

Self-reported use of LABA, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone as maintenance therapy in the 12 weeks before potential study entry.
Nasal corticosteroid therapy is permitted.

Self-reported past admission to the Intensive Care Unit (ICU) with life-threatening asthma (representing patients at highest risk of adverse asthma outcomes).

Self-reported treatment with oral prednisone or other systemic corticosteroids in the six weeks before potential study entry (representing recent unstable asthma).

A home supply of prednisone for use in worsening asthma, as part of a current asthma plan.

Self-reported diagnosis of COPD, bronchiectasis or interstitial lung disease.

Self-reported greater than 20 pack year smoking history, or onset of respiratory symptoms after the age of 40 years in current or ex-smokers with more than or equal to a 10 pack year history.

Self-reported current pregnancy or breast feeding at the time of enrolment or planned pregnancy within the study period.

Unwilling or unable to switch from current asthma treatment regimen.

Other illness(es) likely to compromise participant safety or impact on the feasibility of results, at the discretion of the investigator (examples include unstable coronary disease and malignancy).

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)

The central electronic Case Report Form (eCRF) system will perform randomisation. It will conceal the allocations and will release a participant’s randomisation outcome only at the time of randomisation. The randomisation schedule will not be accessed by study staff.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

A computer-generated randomisation number sequence will be created by the study statistician, independent of the investigators undertaking recruitment and subsequent visits.
Participants will be block randomised.
Randomisation will be stratified according to whether participants used ICS therapy prior to enrolment or not.
A computer-generated randomisation number sequence will be created by the study statistician, independent of the investigators undertaking recruitment and subsequent visits.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Primary outcome variable analysis
This will be an ‘intention to treat’ superiority analysis. The primary analysis of the primary outcome variable is comparison of the rate of severe exacerbations per patient per year until completion of the study or withdrawal from the study. This will be by Poisson regression with an offset for the time of observation. Over-dispersion will be evaluated prior to analysis and a corrected analysis applied if necessary.

Secondary outcome variable analyses
The following methods will be used:
Survival analysis illustrated by Kaplan-Meier plots and use of Cox proportional hazards regression to estimate the hazard ratio in relation to the randomised treatment:
Time to first severe exacerbation
Simple t-tests by time of measurement and mixed linear models for repeated measures by time for ACQ-5 score, FEV1 , FEV1 percentage predicted, FeNO, likely on the logarithm transformed scale based on our previous experience with the skewed distribution of this variable and that normality assumptions were better met on the logarithm transformed scale.

The Work Productivity Activity impairment Asthma questionnaire consists of four sub-scores and t-tests will be used to compare each sub-score by randomised treatment if normality assumptions are met and the Mann-Whitney test if they are not.
Beliefs about Medicines Questionnaire consists of five sub-scores and we plan to use t-tests comparing each sub-score by randomised treatment if normality assumptions are met and the Mann-Whitney test if they are not. Estimation of costs will be analysed by simple t-test.

The primary outcome variable is the rate of severe asthma exacerbations per patient per year. Assuming a drop-out rate of 10%, 890 patients will be recruited to enable a sample size of 400 completed patients in each treatment arm, resulting in 90% power, alpha 5%, to detect a 38% reduction in the rate of severe exacerbations from 0.30 to 0.185.

The conservative baseline rate of severe exacerbations per patient per year of 0.30 is derived from previous randomised controlled trials which have reported a rate of 0.21 in steroid-naïve subjects treated with budesonide 200micrograms/day, (using the same criteria for severe exacerbations, peak flow criteria excluded) and rates in subjects previously treated with ICS at baseline of 0.92 and 0.96 (budesonide 200 and 400micrograms/day), 0.35 (budesonide 800micrograms/day), and 0.35 (budesonide 400micrograms/day). Past research shows a relative risk (RR) of severe exacerbations of budesonide/ formoterol reliever therapy compared with SABA reliever therapy of between 0.52 and 0.55, and a non-significant 38% reduction in severe exacerbations with ICS and SABA reliever therapy (separate inhalers) vs physician-adjusted maintenance ICS. This 38% reduction in severe exacerbations would be expected to be less than that observed in the proposed study, due to their study of highly compliant patients, the use of separate inhalers rather than a combination inhaler, and ICS/SABA rather than ICS/LABA reliever therapy. These estimates are directly relevant to this proposed study, and for the purpose of this power calculation, we plan to detect a conservative relative rate of severe exacerbations per patient per year of 0.62 with the ICS/LABA reliever regimen.

The primary outcome variable for the sub-study is the mean ICS dose per day. Assuming a drop-out rate of 10%, 110 patients will be recruited into the substudy to ensure a sample size of 50 completed patients in each treatment arm, resulting in 90% power, alpha 5% to detect a 18% decrease in ICS use (µg/day) with ICS/LABA reliever therapy, compared with 264 µg/day in the standard ICS and SABA regimen. This calculation is based on data from our previous study of ICS compliance in stable asthma in which participants took a mean (SD) 66% of their prescribed ICS dose.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

5/04/2016

Actual

4/05/2016

Date of last participant enrolment

Anticipated

1/11/2017

Actual

22/12/2017

Date of last data collection

Anticipated

22/12/2018

Actual

21/12/2018

Sample size

Target

890

Accrual to date

Final

890

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington

Country [2]

New Zealand

State/province [2]

Auckland

Country [3]

New Zealand

State/province [3]

Tauranga

Country [4]

New Zealand

State/province [4]

Rotorua

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Health Research Council of New Zealand

Address [1]

Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street, Auckland 1010

Country [1]

New Zealand

Primary sponsor type

Other

Name

Medical Research Institute of New Zealand

Address

Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Northern B Health and Disability Ethics Committee

Ethics committee address [1]

Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

Approval date [1]

18/11/2015

Ethics approval number [1]

15/NTB/178

Summary

Brief summary

The Global Initiative for Asthma (GINA) has established internationally accepted diagnostic and management strategies which aim to achieve optimum asthma control for individual patients however, numerous surveys in NZ and internationally show low adherence to guidelines, suboptimal management, and preventable morbidity.
A number of factors contribute to this largely preventable morbidity in intermittent and mild persistent asthma. The most important are failure to prescribe inhaled corticosteroids (ICS) and poor adherence with them.. Since 2014, the GINA guidelines have recommended that most patients with asthma should be prescribed ICS as first line regular maintenance therapy.This recommendation is based on the evidence that the regular use of ICS reduces symptoms, improves lung function, reduces severe exacerbations, prevents hospital admissions, and reduces the risk of mortality.
The benefits of ICS in clinical practice are limited by poor adherence which is not surprising as patients are required to take twice daily treatment regardless of whether they have symptoms. This is an important issue as poor ICS adherence contributes to asthma treatment failure, resulting in increased morbidity, risk of mortality, and consumption of healthcare resources. A symptom-based ICS/LABA combination inhaler regimen is appealing because it couples ICS and LABA use to automatically ensure adherence to ICS. This has the potential to improve the frequency of daily ICS use in patients with symptomatic asthma, and to lead to a rapid increase in use during worsening asthma. 
We are therefore investigating the safety and efficacy of 2 treatment regimens in mild asthma:
1. A combination inhaled corticosteroid (ICS) and Long Acting Beta Agonist (LABA) as required
2. Regular ICS maintenance, and SABA as required

Trial website

Trial related presentations / publications

Public notes

Attachments [1]

/AnzctrAttachments/370122-HDEC Letter 15NTB178 Approved FULL Application.pdf

Attachments [2]

/AnzctrAttachments/370122-Protocol PRACTICAL V4.0 CLEAN 21 FEB 2018.pdf (Protocol)

Contacts

Principal investigator

Name

Prof Richard Beasley

Address

Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 805 0147

Fax

[email protected]

Contact person for public queries

Name

Mark Holliday

Address

Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 805 0147

Fax

[email protected]

Contact person for scientific queries

Name

James Fingleton

Address

Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021

Country

New Zealand

Phone

+64 4 805 0147

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).

When will data be available (start and end dates)?

One year after publication until a minimum of 5 years after publication.

Available to whom?

Researchers who provide a methodologically sound proposal that has been approved by the PRACTICAL steering committee.

Available for what types of analyses?

To achieve the aims outlined in the approved proposal.

How or where can data be obtained?

Through a signed data access agreement.

What supporting documents are/will be available?

Doc. No.	Type	Email
6660	Study protocol	[email protected]
6661	Statistical analysis plan	[email protected]
6662	Informed consent form	[email protected]
6663	Ethical approval	[email protected]
6664	Analytic code	[email protected]

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Dimensions AI	As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma	2018	https://doi.org/10.1056/nejmoa1715275
Dimensions AI	Inhaled Combined Budesonide–Formoterol as Needed in Mild Asthma	2018	https://doi.org/10.1056/nejmoa1715274
Embase	Patient preferences for symptom-driven or regular preventer treatment in mild to moderate asthma - findings from the PRACTICAL study, a randomised clinical trial.	2020	https://dx.doi.org/10.1183/13993003.02073-2019
Embase	What matters most to patients when choosing treatment for mild-moderate asthma? Results from a discrete choice experiment.	2020	https://dx.doi.org/10.1136/thoraxjnl-2019-214343

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

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Documents added automatically