ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12615000999538

Ethics application status

Approved

Date submitted

14/09/2015

Date registered

24/09/2015

Date last updated

13/04/2021

Date data sharing statement initially provided

3/07/2019

Date results provided

3/07/2019

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]

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

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 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]

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]

Asthma exacerbation rate expressed as number of exacerbations per patient per year.

Timepoint [1]

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 [1]

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

Timepoint [1]

Date of first exacerbation

Secondary outcome [2]

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]

Date of withdrawal

Secondary outcome [3]

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

Timepoint [3]

Date of severe exacerbation

Secondary outcome [4]

Time to withdrawal due to severe exacerbation, as reported by participant

Timepoint [4]

Date of severe exacerbation

Secondary outcome [5]

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

Timepoint [5]

Weeks 0, 6, 12, 22, 32, 42 and 52

Secondary outcome [6]

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]

Weeks 0, 6, 12, 22, 32, 42 and 52

Secondary outcome [7]

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

Timepoint [7]

Weeks 0, 12 and 52

Secondary outcome [8]

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

Timepoint [8]

Duration of study

Secondary outcome [9]

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

Timepoint [9]

Duration of study

Secondary outcome [10]

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

Timepoint [10]

Duration of study

Secondary outcome [11]

Total oral corticosteroid dose, as recorded by the electronic monitors on each inhaler

Timepoint [11]

Duration of study

Secondary outcome [12]

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]

Duration of study

Secondary outcome [13]

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]

Duration of study

Secondary outcome [14]

Number of days of high use, as recorded by the electronic monitors on each inhaler

Timepoint [14]

Duration of study

Secondary outcome [15]

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]

Duration of study

Secondary outcome [16]

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

Timepoint [16]

Duration of study

Secondary outcome [17]

Adherence Starts with Knowledge-12 Questionnaire score (ASK-12 score), as measured by the ASK-12 questionnaire.

Timepoint [17]

Week 0 and Week 52

Secondary outcome [18]

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]

Duration of study

Secondary outcome [19]

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]

Duration of study

Secondary outcome [20]

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]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Completed

Date of first participant enrolment

Anticipated

29/02/2016

Actual

17/03/2016

Date of last participant enrolment

Anticipated

30/09/2017

Actual

29/08/2017

Date of last data collection

Anticipated

29/08/2018

Actual

30/08/2018

Sample size

Target

675

Accrual to date

Final

675

Recruitment in Australia

Recruitment state(s)

NSW

Recruitment hospital [1]

Hunter Medical Research Institute - New Lambton Heights

Recruitment postcode(s) [1]

2037 - Glebe

Recruitment postcode(s) [2]

2305 - New Lambton Heights

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Wellington, Auckland, Tauranga, Waikato, Otago

Country [2]

United Kingdom

State/province [2]

Nottinghamshire, Oxfordshire

Country [3]

Italy

State/province [3]

Ferrara, Pavia, Bari, Varese

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

AstraZeneca AB

Country [1]

Sweden

Primary sponsor type

Charities/Societies/Foundations

Name

Medical Research Institute of New Zealand

Country

New Zealand

Secondary sponsor category [1]

Charities/Societies/Foundations

Name [1]

The Woolcock Institute of Medical Research

Country [1]

Australia

Secondary sponsor category [2]

University

Name [2]

University of Oxford

Country [2]

United Kingdom

Secondary sponsor category [3]

Hospital

Name [3]

Azienda Ospedaliero Universitaria di Ferrara

Country [3]

Italy

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]

09/06/2015

Ethics approval number [1]

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

Public notes

Attachments [1]

/AnzctrAttachments/369311-HDEC Letter 15NTB96 Approved FULL Application with Non Standard Conditions.pdf

Attachments [2]

/AnzctrAttachments/369311-Protocol MRINZ-15-A1 Version 2.3 (9 DEC 2015).pdf

Attachments [3]

/AnzctrAttachments/369311-Protocol MRINZ-15-A1 Version 3.0 (15 JUL 2016).pdf (Protocol)

Attachments [4]

/AnzctrAttachments/369311-Protocol MRINZ-15-A1 Version 4.0 (22 SEP 2016).pdf (Protocol)

Attachments [5]

/AnzctrAttachments/369311-Protocol MRINZ-15-A1 Version 5.0 (06 Apr 2018) Clean.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

richard.beasley@mrinz.ac.nz

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

mark.holliday@mrinz.ac.nz

Contact person for scientific queries

Name

Janine Pilcher

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

janine.pilcher@mrinz.ac.nz

Data sharing statement

Will the study consider sharing individual participant data?

Yes

Will there be any conditions when requesting access to individual participant data?

Persons/groups eligible to request access:
• Researchers who provide a methodologically sound proposal that has been approved by the study steering committee.

Conditions for requesting access:
• -

What individual participant data might be shared?

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

What types of analyses could be done with individual participant data?

• To achieve the aims outlined in the approved proposal.

When can requests for individual participant data be made (start and end dates)?

From:
One year after publication until 5 years after publication.

To:
-

Where can requests to access individual participant data be made, or data be obtained directly?

• Through a signed data access agreement.

Are there extra considerations when requesting access to individual participant data?

What supporting documents are/will be available?

Doc. No.	Type	Email	Attachment
2707	Analytic code	richard.beasley@mrinz.ac.nz
2708	Study protocol		Study-related document.pdf
2709	Statistical analysis plan		Study-related document.pdf
2710	Informed consent form	richard.beasley@mrinz.ac.nz
2711	Ethical approval	richard.beasley@mrinz.ac.nz

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	Description of a randomised controlled trial of inhaled corticosteroid/fast-onset LABA reliever therapy in mild asthma	2016	https://doi.org/10.1183/13993003.01692-2015
Embase	Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma.	2018	https://dx.doi.org/10.1056/NEJMoa1715274
Dimensions AI	As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma	2018	https://doi.org/10.1056/nejmoa1715275
Embase	Patient experiences of as-needed budesonide-formoterol by Turbuhaler for treatment of mild asthma; a qualitative study.	2020	https://dx.doi.org/10.1016/j.rmed.2020.106154
Embase	Predictive value of blood eosinophils and exhaled nitric oxide in adults with mild asthma: a prespecified subgroup analysis of an open-label, parallel-group, randomised controlled trial.	2020	https://dx.doi.org/10.1016/S2213-2600%2820%2930053-9
Embase	SMART and as-needed therapies in mild to severe asthma: A network meta-analysis.	2020	https://dx.doi.org/10.1183/13993003.00625-2020
Dimensions AI	Budesonide–formoterol reliever therapy in intermittent versus mild persistent asthma	2020	https://doi.org/10.1183/13993003.03064-2020
Embase	Perspectives of mild asthma patients on maintenance versus as-needed preventer treatment regimens: A qualitative study.	2022	https://dx.doi.org/10.1136/bmjopen-2020-048537

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

Trial Review

Documents added manually

Documents added automatically