Trial registered on ANZCTR


Trial ID
ACTRN12615000999538
Ethics application status
Approved
Date submitted
14/09/2015
Date registered
24/09/2015
Date last updated
18/09/2017
Type of registration
Prospectively registered

Titles & IDs
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.
Secondary ID [1] 287465 0
EUDRACT Number: 2015-002384-42
Universal Trial Number (UTN)
U1111-1170-2118
Trial acronym
Novel START
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 296193 0
Condition category
Condition code
Respiratory 296468 296468 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 292841 0
Treatment: Drugs
Comparator / control treatment
Comparator 1: Short Acting Beta Agonist (SABA) reliever therapy; salbutamol metered dose inhaler 100 micrograms, 2 inhalations for relief of symptoms as required, for 52 weeks.

Comparator 2: Maintenance Inhaled Corticosteroid (ICS) and Short Acting Beta Agonist (SABA) reliever therapy; budesonide Turbuhaler 200 micrograms, 1 inhalation twice daily and salbutamol metered dose inhaler 100 micrograms 2 inhalations 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.
Control group
Active

Outcomes
Primary outcome [1] 296096 0
Asthma exacerbation rate expressed as number of exacerbations per patient per year.
Timepoint [1] 296096 0
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 use 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 [1] 317479 0
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 use 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
Timepoint [1] 317479 0
Date of first exacerbation
Secondary outcome [2] 317480 0
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
Timepoint [2] 317480 0
Date of withdrawal
Secondary outcome [3] 317482 0
Rate of severe exacerbations defined by the American Thoracic Society/ European Respiratory Society (ATS/ERS) criteria:
The use 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
Timepoint [3] 317482 0
Date of severe exacerbation
Secondary outcome [4] 317484 0
Time to withdrawal due to severe exacerbation, as reported by participant
Timepoint [4] 317484 0
Date of severe exacerbation
Secondary outcome [5] 317488 0
Asthma Control Questionnaire score (ACQ-5 score), as measured by the ACQ-5 validated questionnaire completed by the participant.
Timepoint [5] 317488 0
Weeks 0, 6, 12, 22, 32, 42 and 52
Secondary outcome [6] 317490 0
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.
Timepoint [6] 317490 0
Weeks 0, 6, 12, 22, 32, 42 and 52
Secondary outcome [7] 317491 0
Fractional Exhaled Nitric Oxide, as measured by a NIOX VERO device
Timepoint [7] 317491 0
Weeks 0, 12 and 52
Secondary outcome [8] 317492 0
Mean Inhaled Corticosteroid dose per day (budesonide micrograms/day), as recorded by the electronic monitor devices on each inhaler
Timepoint [8] 317492 0
Duration of study
Secondary outcome [9] 317493 0
Number of days with no inhaled corticosteroid use, as recorded by the electronic monitors on each inhaler
Timepoint [9] 317493 0
Duration of study
Secondary outcome [10] 317494 0
Longest duration of no inhaled corticosteroid use, as recorded by the electronic monitors on each inhaler
Timepoint [10] 317494 0
Duration of study
Secondary outcome [11] 317495 0
Total oral corticosteroid dose, as recorded by the electronic monitors on each inhaler
Timepoint [11] 317495 0
Duration of study
Secondary outcome [12] 317496 0
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.
Timepoint [12] 317496 0
Duration of study
Secondary outcome [13] 317497 0
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
Timepoint [13] 317497 0
Duration of study
Secondary outcome [14] 317498 0
Number of days of high use, as recorded by the electronic monitors on each inhaler
Timepoint [14] 317498 0
Duration of study
Secondary outcome [15] 317503 0
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
Timepoint [15] 317503 0
Duration of study
Secondary outcome [16] 317504 0
Maximum number of beta agonist actuations in a 24 hour period as recorded by the electronic monitors on each inhaler
Timepoint [16] 317504 0
Duration of study
Secondary outcome [17] 317510 0
Adherence Starts with Knowledge-12 Questionnaire score (ASK-12 score), as measured by the ASK-12 questionnaire.
Timepoint [17] 317510 0
Week 0 and Week 52
Secondary outcome [18] 317511 0
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).
Timepoint [18] 317511 0
Duration of study
Secondary outcome [19] 317512 0
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).
Timepoint [19] 317512 0
Duration of study
Secondary outcome [20] 317515 0
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).
Timepoint [20] 317515 0
Duration of study

Eligibility
Key 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.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

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.
Randomisation will be stratified by country.
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

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Current
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 9048 0
Hunter Medical Research Institute - New Lambton Heights
Recruitment postcode(s) [1] 10481 0
2037 - Glebe
Recruitment postcode(s) [2] 17542 0
2305 - New Lambton Heights
Recruitment outside Australia
Country [1] 7165 0
New Zealand
State/province [1] 7165 0
Wellington, Auckland, Tauranga, Waikato, Otago
Country [2] 7166 0
United Kingdom
State/province [2] 7166 0
Nottinghamshire, Oxfordshire
Country [3] 7167 0
Italy
State/province [3] 7167 0
Ferrara, Pavia, Bari, Varese

Funding & Sponsors
Funding source category [1] 292037 0
Commercial sector/Industry
Name [1] 292037 0
AstraZeneca AB
Address [1] 292037 0
SE-43 183 Molndal
Country [1] 292037 0
Sweden
Primary sponsor type
Charities/Societies/Foundations
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] 290707 0
Charities/Societies/Foundations
Name [1] 290707 0
The Woolcock Institute of Medical Research
Address [1] 290707 0
Level 2, 431 Glebe Point Road
Glebe
New South Wales 2037
Country [1] 290707 0
Australia
Secondary sponsor category [2] 290708 0
University
Name [2] 290708 0
University of Oxford
Address [2] 290708 0
Joint Research Office
Block 60
Churchill Hospital
Oxford OX3 7LE
Country [2] 290708 0
United Kingdom
Secondary sponsor category [3] 290709 0
Hospital
Name [3] 290709 0
Azienda Ospedaliero Universitaria di Ferrara
Address [3] 290709 0
Via Aldo Moro,
8 – 44124 Cona
Ferrara
Country [3] 290709 0
Italy

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293523 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 293523 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 293523 0
New Zealand
Date submitted for ethics approval [1] 293523 0
Approval date [1] 293523 0
09/06/2015
Ethics approval number [1] 293523 0
15/NTB/96

Summary
Brief summary
Asthma is a major health problem globally. Clinical research and management mainly focus on moderate to severe asthma, however most adults with asthma have mild disease. Short Acting Beta Agonist (SABA) reliever therapy alone is currently the internationally recommended treatment in mild asthma. However, there is substantial morbidity in this population and previous studies have shown that those with intermittent or mild persistent asthma who were Inhaled Corticosteroid (ICS) free experienced severe exacerbations. Evidence suggests that a combination Inhaled Corticosteroid/ Long Acting Beta Agonist (ICS/LABA) inhaler used as reliever therapy may be preferable to SABA only reliever therapy and represent an alternative to maintenance ICS and SABA reliever therapy. The major advantage of the combination ICS/LABA as needed over SABA monotherapy is the ICS therapy is being self-titrated according to symptoms in a group of patients that would not otherwise receive ICS. It may improve adherence to ICS use and enable high dose ICS therapy to be promptly delivered by patients with worsening asthma.
We are therefore investigating the safety and efficacy of 3 treatment regimens in mild asthma:
1. A combination inhaled corticosteroid (ICS) and Long Acting Beta Agonist (LABA) as required
2. SABA only as required
3. Regular ICS maintenance, and SABA as required.
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 562 562 0 0
http://www.anzctr.org.au/AnzctrAttachments/369311-HDEC Letter 15NTB96 Approved FULL Application with Non Standard Conditions.pdf

Contacts
Principal investigator
Name 60302 0
Prof Richard Beasley
Address 60302 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 60302 0
New Zealand
Phone 60302 0
+64 4 805 0147
Fax 60302 0
Email 60302 0
richard.beasley@mrinz.ac.nz
Contact person for public queries
Name 60303 0
Mr Mark Holliday
Address 60303 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 60303 0
New Zealand
Phone 60303 0
+64 4 805 0147
Fax 60303 0
Email 60303 0
mark.holliday@mrinz.ac.nz
Contact person for scientific queries
Name 60304 0
Dr Janine Pilcher
Address 60304 0
Medical Research Institute of New Zealand
Level 7 CSB Building
Wellington Hospital
Riddiford Street
Newtown
Wellington 6021
Country 60304 0
New Zealand
Phone 60304 0
+64 4 805 0147
Fax 60304 0
Email 60304 0
janine.pilcher@mrinz.ac.nz