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

• Register: ANZCTR
• Last refreshed on: 19 April 2021
• Main ID: ACTRN12615000999538
• Date of registration: 24/09/2015
• Prospective Registration: Yes
• Primary sponsor: Medical Research Institute of New Zealand
• Public title: Randomised Controlled Trial of the efficacy and safety of an Inhaled Corticosteroid / 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 salbutamol metered dose inhaler taken as required for relief of symptoms, and budesonide/formoterol Turbuhaler taken as required for relief of symptoms, and regular budesonide Turbuhaler plus salbutamol metered dose inhaler taken as required for relief of symptoms, in adult patients with asthma.
• Date of first enrolment: 17/03/2016
• Target sample size: 675
• Recruitment status: Completed
• URL: https://anzctr.org.au/ACTRN12615000999538.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Open (masking not used);Assignment: Parallel;Type of endpoint: Safety/efficacy;
• Phase: Phase 3

Countries of recruitment

Australia, Italy, New Zealand, United Kingdom

Contacts

• Name: Dr Janine Pilcher

• Name: Mr Mark Holliday

Key inclusion & exclusion criteria

Inclusion criteria: Adults aged 18 to 75 years.

Self-report of a doctor’s diagnosis of asthma with:

a. Self-reported use of a SABA on greater than or equal to 2 occasions in the previous 4 weeks but on average equal to or less than 2 occasions per day in the previous 4 weeks, if there have been no severe exacerbations in the last 12 months, or

b. Self-reported use of a SABA on average equal to or less than 2 occasions per day in the previous 4 weeks, if there has been a history of a severe exacerbation in the last 12 months.

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 General Practitioner and/ or consultant, if appropriate, to be notified of participation in the trial.

Exclusion criteria: Self-reported use of Inhaled Corticosteroid, Long Acting Beta Agonist, leukotriene receptor antagonist, theophylline, anticholinergic agent or cromone as regular maintenance therapy in the 3 months before potential study entry. Note nasal corticosteroid therapy is permitted.

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

Self-reported hospital admission for asthma in the 12 months before potential study entry (patients at highest risk of adverse asthma outcomes).

Self-reported treatment with oral prednisone in the six weeks before potential study entry, representing recent unstable asthma.

A home supply of prednisone for use in worsening asthma.

Self-reported diagnosis of Chronic Obstructive Pulmonary Disease (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 greater than or equal to 10 pack year history.

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

Self-reported congestive heart failure, unstable coronary artery disease, atrial fibrillation or other clinically significant cardiac disease.

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.

Self-report of participation in another research trial involving an investigational product, in the past 12 weeks.

An on treatment FEV1 less than or equal to 50% of predicted at Visit 1 (predicted values must be calculated using the Global Lung Function Initiative equations).

Any known or suspected contraindications to the Investigational Medicinal Products or excipients.

Age minimum: 18 Years
Age maximum: 75 Years
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Asthma;
Asthma

Respiratory - Asthma

Intervention(s)

Inhaled Corticosteroid/Long Acting Beta Agonist (ICS/LABA) reliever therapy; budesonide/formoterol Turbuhaler 200/6 micrograms, one inhalation for relief of symptoms as required, 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.

Primary Outcome(s)

Asthma exacerbation rate expressed as number of exacerbations per patient per year. [Timepoint is determined by occurrence of any of the following events: Worsening asthma resulting in urgent medical review (primary care visit, Emergency Department visit or hospital admission) and/or, Worsening asthma resulting in prescription of systemic corticosteroids, such as a course of prednisone for any duration and/or, Worsening asthma resulting in a high beta agonist use episode, defined as greater than 16 actuations of salbutamol or greater than 8 actuations of budesonide/formoterol per 24 hour period. Criteria 1 and 2 will be determined from participant self report. Criteria 3 will be determined from electronic inhaler monitor data. Asthma exacerbations will be assessed throughout the 52 week intervention period.]

Secondary Outcome(s)

Asthma Control Questionnaire score (ACQ-5 score), as measured by the ACQ-5 validated questionnaire completed by the participant.[Weeks 0, 6, 12, 22, 32, 42 and 52]

Maximum number of beta agonist actuations in a 24 hour period as recorded by the electronic monitors on each inhaler[Duration of study]

Rate of severe exacerbations defined by the American Thoracic Society/ European Respiratory Society (ATS/ERS) criteria: The prescription of systemic corticosteroids for at least 3 days, or Hospitalisation or Emergency Department visit because of asthma, requiring systemic corticosteroids, as reported by the participant[Date of severe exacerbation]

Total systemic corticosteroid exposure.
Systemic corticosteroid exposure/year in which the total Inhaled Coritcosteroid dose/year (as recorded by the electronic monitors on each inhaler), converted to oral prednisone-equivalent dose is added to the participant self-reported oral corticosteroid use.[Duration of study]

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 each inhaler. Medical review will be assessed by participant self-report[Duration of study]

Number of days with no inhaled corticosteroid use, as recorded by the electronic monitors on each inhaler[Duration of study]

Fractional Exhaled Nitric Oxide, as measured by a NIOX VERO device[Weeks 0, 12 and 52]

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), 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), serum periostin level (measured by laboratory test) and T helper cell 2 (Th2) status (a Th2 score based on tertiles for each baseline measure of blood eosinophil count, FeNO, serum periostin).[Duration of study]

Adherence Starts with Knowledge-12 Questionnaire score (ASK-12 score), as measured by the ASK-12 questionnaire.[Week 0 and Week 52]

Proportion of participants with at least one episode of high use, defined as greater than 16 actuations of salbutamol 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 each inhaler [Duration of study]

Time to first exacerbation of asthma, which is defined as: Worsening asthma resulting in urgent medical review (primary care visit, Emergency Department visit or hospital admission), as self-reported by participant, and/or Worsening asthma resulting in prescription of systemic corticosteroids, such as a course of prednisone for any duration, as self-reported by participant and/or Worsening asthma resulting in a high beta agonist use episode, defined as greater than 16 actuations of salbutamol or greater than 8 actuations of budesonide/formoterol per 24 hour period, as recorded by electronic monitors on each inhaler[Date of first exacerbation
]

For the Asthma Control Questionnaire (measured by the ACQ-5 questionnaire completed by the participant) 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), 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), serum periostin level (measured by laboratory test) and T helper cell 2 (Th2) status (a Th2 score based on tertiles for each baseline measure of blood eosinophil count, FeNO, serum periostin).[Duration of study]

For the rate of severe 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), 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), serum periostin level (measured by laboratory test) and T helper cell 2 (Th2) status (a Th2 score based on tertiles for each baseline measure of blood eosinophil count, FeNO, serum periostin).[Duration of study]

Longest duration of no inhaled corticosteroid use, as recorded by the electronic monitors on each inhaler[Duration of study]

Mean Inhaled Corticosteroid dose per day (budesonide micrograms/day), as recorded by the electronic monitor devices on each inhaler[Duration of study]

Number of days of high use, as recorded by the electronic monitors on each inhaler [Duration of study]

Proportion of participants withdrawn due to treatment failure. Treatment failure is defined as:
One severe exacerbation, or
Three exacerbations, or
If randomised treatment is modified by the participant’s GP or other healthcare provider

Data is measured from self-report by participant
[Date of withdrawal]

On-treatment Forced Expiratory Volume in 1 second (FEV1) percentage predicted, as measrued by spiromtetry assessment. Percentage predicted values will be obtained for each participant from height, age and ethnicity recorded as part of demographics and processed according to Quanjer et al 2012. [Weeks 0, 6, 12, 22, 32, 42 and 52]

Time to withdrawal due to severe exacerbation, as reported by participant[Date of severe exacerbation]

Total oral corticosteroid dose, as recorded by the electronic monitors on each inhaler[Duration of study]

Secondary ID(s)

EUDRACT Number: 2015-002384-42

Source(s) of Monetary Support

AstraZeneca AB

Secondary Sponsor(s)

Azienda Ospedaliero Universitaria di Ferrara

The Woolcock Institute of Medical Research

University of Oxford

Ethics review

Status: Approved
Approval date: 09/06/2015
Contact:

Results

• Results available: Yes
• Date Posted: 03/07/2019
• Date Completed: 30/08/2018