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Asthma is a major public health problem in New Zealand. The prevalence rate is among the highest in the world, particularly in adults identifying as Māori, the indigenous people of New Zealand, and Pacific people.1–3 Furthermore, substantial morbidity and mortality persist despite efforts to improve management, with disparities in health outcomes for Māori and Pacific peoples across the severities of asthma.

Systemic issues such as institutional racism and socioeconomic disadvantage are core drivers to these disparities.4 Lower socioeconomic status results in barriers to healthcare access and is associated with worse health literacy and poor adherence to maintenance inhaled corticosteroid (ICS). When healthcare is accessed, despite the burden of asthma being greater among Māori and Pacific people, they are more likely to remain on the lowest steps of asthma treatment.5–7

Over the past decade a number of strategies including community-based education programmes and asthma action plans have contributed to improving outcomes for Māori and Pacific people with asthma, but novel strategies may be required if further progress is to be made.8–10 One strategy has been the combination ICS/fast-onset long acting beta-agonist (LABA) used as both maintenance and reliever therapy, an approach which reduces the risk of severe exacerbations compared with maintenance ICS/LABA and short-acting beta2-agonist (SABA) reliever therapy in children and adults.11 This efficacy benefit has been shown in Māori adults with asthma,12 and has been recommended for use in Māori in local guidelines.13

An extension to this strategy is the use of combination ICS (budesonide)/fast-onset LABA (formoterol) used solely as needed in mild asthma, as an alternative to either SABA as sole reliever therapy or ICS maintenance and SABA reliever therapy. Four clinical trials have demonstrated that as-required budesonide/formoterol is non-inferior14,15 or superior16,17 to regular budesonide plus as needed SABA, and superior to SABA alone,14,16 in reducing severe exacerbation risk. One of these clinical trials, the PRACTICAL study, only recruited patients in New Zealand, which provided the opportunity to investigate whether this novel regimen is effective and safe in Māori and Pacific peoples. In this manuscript, we report a subgroup analyses of the influence of ethnicity on the efficacy of as-needed budesonide-formoterol vs maintenance budesonide and as-needed terbutaline in adults with mild to moderate asthma.

Methods

The PRACTICAL study was a 52-week, open label, parallel group, multicentre, phase III, randomised controlled trial to compare the efficacy and safety of two asthma treatment regimens; budesonide-formoterol Turbuhaler [Symbicort] 200/6mcg, one inhalation for relief of symptoms as required (budesonide-formoterol group), or budesonide Turbuhaler [Pulmicort] 200mcg, one inhalation twice daily and terbutaline Turbuhaler [Bricanyl] 250mcg, two inhalations for relief of symptoms as required (budesonide maintenance group). The PRACTICAL study was funded by the Health Research Council of New Zealand and was undertaken independently of the pharmaceutical industry.

Eight hundred and ninety adult patients, aged 18 to 75, with doctor-diagnosed asthma were recruited from 15 primary care facilities and research centres across New Zealand. Patients taking SABA reliever therapy alone or together with low to moderate doses of inhaled corticosteroid in the 12 weeks prior to randomisation were eligible. This pragmatic study was designed to more closely reflect real-world clinical practice.18 Smokers were only excluded if they had a greater than 20-pack year smoking history or respiratory symptoms that began after the age of 40 in participants with at least a 10-pack year smoking history. Additional key exclusion criteria included self-reported use of LABA or leukotriene receptor antagonist as maintenance therapy in the 12 weeks before potential study entry or the diagnosis of other lung disease.

All participants provided written informed consent and the study was approved by the Northern B ethics committee (15/NTB/178/AM01). Each site sought local Māori research committee approval. Participants and investigators were not masked to group assignment which allowed any real-world advantage of the as-needed ICS/formoterol regimen, that is, the use of a single medication and no requirement for regular inhaler use, to be studied.

Written asthma management plans were provided and inhaler technique was checked at each study visit. Questions on housing conditions and physical residential address, for calculation of deprivation score, were collected at week 0. Validated housing questions were adapted from the New Zealand heating study and Building Research Institute of New Zealand (BRANZ) house condition study.19,20 Detailed trial methodology has been reported elsewhere.21 Patients remained under the care of their primary care physician throughout the trial.

A Kaupapa Māori approach was utilised in some capacity, to increase the number of Māori participants.22 This involved the development of recruitment strategies, including recruiting through Māori providers and clinics, with the support of Kaupapa Māori trained asthma health workers. Participants self-reported their ethnicity at the first study visit. New Zealand national guidelines were used to classify ethnicity for participants reporting more than one ethnicity by a standard system.23

Outcome measures

The primary outcome was the number of severe exacerbations per patient per year. Severe exacerbations were defined as ii) the use of systemic steroids for at least three days because of asthma or ii) hospitalisation or ED visit because of asthma requiring systemic steroids, as recommended by ATS/ERS Task Force.24

Secondary outcomes were rate of asthma exacerbations per patient per year defined as worsening asthma resulting in unplanned medical review or use of systemic glucocorticoids of any duration, asthma control questionnaire 5 (ACQ-5) score, the mean of five questions about asthma symptoms during the previous week, each scored on a 7-point scale between 0 (no impairment) and 6 (maximum impairment),25 on-treatment FEV1 and fractional exhaled nitric oxide (FeNO).

Statistical analysis

The statistical analysis was an intention to treat superiority analysis. The general analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. In the event, none of the interaction terms was statistically significant. For illustration purposes only, the estimates of treatment differences and 95% confidence intervals are shown for each ethnicity from these interaction models and these are not accompanied by P values as there was no evidence that the effects within ethnic groups were different from the Overall rate in models that did not have ethnicity. The Overall rate is accompanied by a confidence interval and associated P value testing the hypotheses that the values of these outcome variables was different depending on treatments. These analyses have not been adjusted for multiple comparisons.

The recognised ethnicities within the PRACTICAL study are Māori, Pacific, Asian, New Zealand European and Other. Given the small number of participants within the Asian and Other ethnicity groups, Asian, New Zealand European and Other ethnicities were analysed together.

Categorical data are presented as the number and proportion expressed as a percentage and continuous data summaries including mean (SD) and median (IQR).

Analysis of the number of severe exacerbations per patient per year and combined rate of exacerbations and severe exacerbation per year was by Poisson regression with an offset for time of observation.

Differences in ACQ-5 and FEV1 were estimated by ANCOVA with the baseline measurement as a continuous co-variate. Spirometry was performed on treatment, ie, without withholding of usual inhaled therapy. Normality assumptions for FeNO were not well met on an untransformed scale but were met on a logarithm transformed scale. ANOVA was used on this scale and the exponent of the difference in logarithm FeNO is interpreted as the ratio of geometric means FeNO. In the models with ethnicity as a potential effect modifier interaction terms were used.

New Zealand deprivation score was calculated by geocoding the address of each participant to a meshblock, merging this geocoded dataset with the NZdep2013 file using meshblock number and linking each geocoded address with its area deprivation score. It is scaled to have mean 1,000 index points and standard deviation 100 index points.26

The Māori subgroup analysis was pre-specified and is exploratory as we did not recruit sufficient Māori participants to detect a difference in the main outcome. We have not adjusted for multiplicity of analysis.

SAS version 9.4 was used for all analyses.

The trial was registered with the Australian and New Zealand Clinical Trials Registry ACTRN12616000377437.

Results

Eight hundred and ninety participants were enrolled between 4 May 2016 and 22 December 2017 of whom 72 (8%) were Māori, 36 (4%) were Pacific and 777 (88%) were New Zealand European/Other (Figure 1).

Figure 1: Consort diagram.

The intention to treat data set included 885 eligible participants and no follow-up data was available in five participants of New Zealand European/Other ethnicity.

At baseline, Māori and Pacific participants had higher (worse) average ACQ-5 scores than New Zealand European/Other participants (mean ACQ-5 1.5, 1.6 and 1.1 respectively) and lower FEV1 values (83% predicted, 84% predicted and 88% predicted respectively). Inhaled corticosteroids were used at baseline by 49 (68%) Māori participants, 21 (58%) Pacific people and 551 (71%) New Zealand European/Other participants. Median (IQR) baseline FeNO was higher in Pacific participants than either Māori or New Zealand European/Other participants; 45.5 ppB, (18–80.5); 26.5 (12.5–50); and 28 (17–56), respectively (Table 1).

Table 1: Characteristics of participants by ethnicity.

*Values are means, bracketed values are ±SD unless otherwise stated. Patients in the budesonide maintenance group received budesonide (Pulmicort Turbuhaler, AstraZeneca), 200mcg, one inhalation twice daily, plus terbutaline (Bricanyl), 250mcg, two inhalations as needed for symptom relief. Patients in the budesonide–formoterol group received budesonide–formoterol (Symbicort Turbuhaler, AstraZeneca), 200mcg of budesonide and 6mcg of formoterol, one inhalation as needed for symptom relief. FeNO denotes fraction of exhaled nitric oxide, FEV1 forced expiratory volume in one second, IQR interquartile range, ppb parts per billion, and SABA short-acting beta-2-agonist.
†The Asthma Control Questionnaire–5 (ACQ-5) consists of five questions that assess asthma symptoms in the previous week, each of which is scored on a 7-point scale that ranges from 0 (no impairment) to 6 (maximum impairment), in which a 0.5-unit change represents the minimal clinically important difference.
‡Patients received no specific instruction to withhold use of their bronchodilator before measurement of FEV1.
$The NZ deprivation score is a measure of socioeconomic deprivation. It is scaled to have mean 1000 index points and standard deviation 100 index points.

Smoking status was that 19 (26%) Māori participants were current smokers compared to three (8%) Pacific participants and 41 (5%) New Zealand European/Other participants. Māori and Pacific participants lived in more deprived areas than New Zealand European/Other participants as demonstrated by higher mean New Zealand deprivation scores: 1,006.3, 1,021.7 and 961.3 respectively (Table 1).

The proportion of Māori and Pacific participants who reported living in cold, damp and musty smelling housing was higher than that reported by New Zealand European/Other participants. The proportion of participants reporting that their home smelt damp or musty was 38% for Māori participants, 42% for Pacific participants and 25% for New Zealand European/Other participants. The proportion of participants reporting that their house was so cold that they could see their breath in the previous winter was 42% for Māori participants, 44% for Pacific participants and 28% for New Zealand European/Other participants (Table 2).

Table 2: Housing questionnaire.

Budesonide-formoterol as needed versus budesonide maintenance and terbutaline as needed and ethnicity

Table 3 shows the interaction analyses with ethnicity. There was no evidence that ethnicity was an effect modifier for either severe exacerbations or total exacerbations; P=0.70 and 0.43 for the ethnicity-treatment interaction terms respectively. Although the estimates for the difference between treatments within each ethnic group were consistent with Pacific people having more benefit, this lack of a statistically significant interaction term means that the relative rate of severe exacerbations was the same, 0.69 (0.48–1.0), P=0.049, regardless of ethnicity. A similar pattern was seen for any exacerbations, namely that although the point estimates were consistent with more benefit for   Māori and Pacific people the lack of a statistically significant interaction term means there was no evidence that the relative rate of exacerbation, 0.70 (0.51–0.95), P=0.024, was different in relation to ethnicity.

Table 3: Severe asthma exacerbations, asthma control, lung function and FeNO.

*Differences in ACQ-5, FEV1 and FeNO are given for budesonide/formoterol as needed minus budesonide maintenance and terbutaline reliever. The p interaction tests if the difference between budesonide/formoterol and budesonide maintenance and terbutaline reliever differs by ethnicity. For completeness the individual difference within each level of ethnicity is shown, however if the interaction p value is not statistically significant there is no evidence that the treatment differences are different by ethnicity. The P value given for the Overall rate tests if there is a difference between treatments in models that just have the effect of treatment.

There was no evidence that ethnicity was an effect modifier for asthma control as measured by ACQ-5, forced expiratory volume in one second (FEV1) or fractional exhaled nitric oxide (FeNO).

There was no evidence of a treatment effect on ACQ or FEV1, however FeNO was higher in those randomised to as required Budesonide.

Discussion

This randomised controlled trial of as-needed budesonide-formoterol therapy in adults with mild and moderate asthma found no evidence that the regimen was more or less efficacious and safe in Māori and Pacific peoples compared to a New Zealand European/Other population. In other words, the as-needed budesonide-formoterol regimen achieved a clinically important reduction in risk of severe exacerbations compared with maintenance budesonide and terbutaline reliever therapy that did not differ by ethnicity. Similarly, there was no evidence that the the reduction in the risk of moderate and severe exacerbations with the as-needed budesonide-formoterol regimen, and the comparable levels of asthma control and lung function between the regimens, was different across the ethnic groups. This suggests that the pragmatic as-needed budesonide-formoterol regimen may be particularly suitable for Māori and Pacific peoples, who both experience barriers to asthma care, and higher morbidity and mortality from asthma in New Zealand.

At randomisation, Māori and Pacific subgroups had worse asthma control and higher exacerbation rates despite similar rates of prescription of ICS and self-reported adherence to ICS therapy. This suggests that other factors such as environmental and socioeconomic factors related to housing status and deprivation may play a role in the worse asthma outcomes. Many studies have demonstrated that damp and cold homes have a deleterious effect on respiratory health. This study provides evidence of greater disparities in environmental risk factors, as a higher proportion of Māori and Pacific participants reported that they live in cold and damp housing as compared to New Zealand European/Other participants. There is an ongoing need for implementation of effective policies to reduce inequalities in this area.27,28 The higher rates of current smoking in Māori also reinforce the requirement for measures to reduce smoking to be particularly focused on Māori. The study was not designed to specifically explore the effect of deprivation, eg, by stratification by deprivation; however, an analysis (not reported here) found little evidence of an association between exacerbations and New Zealand Deprivation scores.

This analysis has a number of limitations. Assessment of housing conditions was by self-report, which is associated with the risk of responder bias. Analysis of whether treatment group had a differential effect depending on ethnicity was pre-specified, although the trial was not specifically designed to detect differences between Māori, Pacific and New Zealand European/Other ethnicities, and may therefore lack power to detect important differences by ethnicity, particularly with the small number of Pacific participants. Outcomes have not been adjusted for multiplicity of analyses, increasing type-1 error rate. Despite consultation with Māori researchers during the design and implementation of this study and a commitment to recruiting Māori participants, 8% of participants identified as Māori, which is lower than the proportion of adult Māori in the general New Zealand population (9.5%) as identified by census data for 2018. Four percent of participants in the study were of Pacific ethnicity, which mirrors that of the adult general population. In addition, higher smoking rates among Māori people than the general population means they were more likely to have met criteria, which excluded people with a significant smoking history.29

This study builds on a previous randomised controlled trial, which demonstrated that the reduction in the risk of severe exacerbations with budesonide-formoterol compared with salbutamol reliever therapy in adults with high-risk asthma taking maintenance ICS/LABA therapy, was similar in Māori as other ethnicities.12 As a result there is now evidence, across the spectrum of asthma severity, that budesonide-formoterol reliever therapy reduces the risk of severe exacerbations as compared with SABA reliever therapy, both with and without maintenance ICS/LABA therapy, regardless of ethnicity. As Māori and Pacific peoples have higher morbidity from asthma, the absolute benefit from a reduction in exacerbations is likely to be greater, even though the relative reduction in risk with this regimen is similar.

An important consideration is whether the efficacy of the budesonide-formoterol reliever therapy regimen observed in Māori and Pacific adults with asthma in this study may be internationally transferable and apply to other at-risk populations defined by ethnicity, including Aboriginal Australian and African American people with asthma. Many of the barriers to healthcare, inequity in treatment received, and socioeconomic determinants of health outcomes in asthma observed in Māori and Pacific peoples in this study are also present in other indigenous groups. As a result, it is likely that our findings are generalisable, although the demonstration of differences in response to LABA therapy in African Americans emphasises the importance of investigating the impact of ethnicity on outcome in clinical trials.30

In conclusion, this trial has demonstrated that the greater reduction in the risk of severe exacerbations achieved with as-needed budesonide-formoterol compared with maintenance budesonide plus as-needed terbutaline was similar in Māori and Pacific adults as with European/other ethnicities. Implementation of the pragmatic budesonide-formoterol reliever therapy regimen in Māori and Pacific peoples has major potential to improve asthma outcomes and reduce their disproportionate burden from asthma.

Summary

Abstract

Aim

In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Māori and Pacific peoples, populations with worse asthma outcomes.

Method

The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable.

Results

Seventy-two participants (8%) identified as Māori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70).

Conclusion

The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Māori and Pacific adults compared with New Zealand European/Other.

Author Information

Jo Hardy, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Jordan Tewhaiti-Smith, Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Christina Baggott, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; James Fingleton, Consultant Physician, Capital and Coast District Health Board, Wellington; Alex Semprini, Deputy Director, Medical Research Institute of New Zealand, Wellington; Mark Holliday, Principal Clinical Operations, Medical Research Institute of New Zealand, Wellington; Robert J Hancox, Associate Professor, University of Otago, Dunedin; Mark Weatherall, Professor of Medicine, University of Otago Wellington, Wellington; Matire Harwood, Associate Professor, University of Auckland, Auckland.

Acknowledgements

The study was funded through a programme grant (15/573) provided by the Health Research Council of New Zealand to the study sponsor, the Medical Research Institute of New Zealand. We thank the study participants for their involvement in the study, the PRACTICAL Data Safety Monitoring Committee, consisting of Prof Rodolfo Morice, Dr Kyle Perrin, Associate Professor Andrew Harrison and Dalice Sim, and the PRACTICAL Study Team: Clinical Horizons (Tauranga, New Zealand): Andrew Corin, Colin Helm, Tracy Paterson; Bhuwan Poudel; Coastal Medical Rooms (Kapiti, New Zealand): Malcolm Dyer, Christine Jasinski; Culloden Research (Papamoa, New Zealand): Davitt Sheahan, Pamela Sheahan; Greenhithe Medical Centre (Auckland, New Zealand): Nick Gailer, Jan Van Zuilen; Henderson Medical Centre (Auckland, New Zealand): Andy Basa, Christine Devereaux, Karin Egan, Sneha Haughey, Rodney Marks, Dirk Venter, Hank Zhang; Lakeland Clinical Trials (Rotorua, New Zealand): Karen Trevithick, Mike Williams; Medical Research Institute of New Zealand and Lower Hutt After Hours Medical Centre (Wellington, New Zealand): Christina Baggott, Richard Beasley, Irene Braithwaite, Alexandra Eathorne, Stefan Ebmeier, James Fingleton, Daniela Hall, Jo Hardy, Matire Harwood, Mark Holliday, Claire Houghton, Saras Mane, John Martindale, Karen Oldfield, Janine Pilcher, Donah Sabbagh, Philippa Shirtcliffe, Suzanne Snively, Jenny Sparks, Alexandra Vohlidkova, Mathew Williams; Optimal Clinical Trials Ltd (Auckland, New Zealand): Patrick Collins, Summer Hassan, Annika Lam, Claudette Lionnet, Barney Montgomery; P3 Clinical Trials (Wellington, New Zealand): Stella Moon, Dean Quinn; RMC Medical Research (Dunedin, New Zealand): Dean Millar-Coote, Jim Reid; South Pacific Clinical Trials (Auckland, New Zealand): Nicola Burton, Tina Mullard, Tyronne Tranquilino, Edward Watson; Southern Clinical Trials (Auckland, New Zealand): Jill Bell, John Richmond; Team Medical (Kapiti, New Zealand): Brent Krivan, Cheryl Robertson; University of Otago, Dunedin: Robert J Hancox; University of Otago, Wellington: Mark Weatherall; Waikanae Medical Centre (Kapiti, New Zealand): Sue Glensor, Anne-Christine Porrachia; Woolcock Institute of Medical Research (Sydney, Australia): Helen K Reddel.

Correspondence

Professor Richard Beasley, Medical Research Institute of New Zealand, Private Bag 7902, Newtown, Wellington 6242.

Correspondence Email

richard.beasley@mrinz.ac.nz

Competing Interests

Dr Baggott reports grants from Health Research Council of New Zealand during the conduct of the study; personal fees from Astra Zeneca, personal fees from Novartis, outside the submitted work. Dr Fingleton reports grants, personal fees and non-financial support from AstraZeneca, grants from Genentech, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Boheringer lngleheim, outside the submitted work. Dr Beasley reports grants from Health Research Council of New Zealand during the conduct of the study; grants and personal fees from Astra Zeneca, personal fees from Avillion, grants from Cephalon, grants from Chiesi, grants and personal fees from Genentech, grants from GlaxoSmithKline, personal fees from Theravance, grants from Novartis, outside the submitted work; Dr Hancox reports grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, other from Menarini, other from Boehringer Ingelheim, outside the submitted work. Dr Hardy reports grants from AstraZeneca, grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, outside the submitted work. Mr Holliday and Dr Harwood report grants from Health Research Council New Zealand during the conduct of the study.

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3. Holt S, Beasley R. The burden of asthma in New Zealand. NZ Med J. 2001; 114:146–7.

4. B Robson, Harris R. Hauora: Māori Standards of Health IV. A Study of the Years 2000-2005. Wellington: Te Rōpū Rangahau Hauora a Eru Pōmare. 2007.

5. Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaled corticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol. 2004; 114:1288–93.

6. Crengle S, Lay-Yee R, Davis P PJ. A Comparison of Māori and Non-Māori Patient Visits to Doctors: The National Primary Medical Care Survey (NatMedCa): 2001/02. 2005.

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8. Garrett JE FJ. Prospective controlled evaluation of the effect of community based asthma education centre in a multiracial working class neighbourhood. Thorax. 1994; 49:976–83.

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Asthma is a major public health problem in New Zealand. The prevalence rate is among the highest in the world, particularly in adults identifying as Māori, the indigenous people of New Zealand, and Pacific people.1–3 Furthermore, substantial morbidity and mortality persist despite efforts to improve management, with disparities in health outcomes for Māori and Pacific peoples across the severities of asthma.

Systemic issues such as institutional racism and socioeconomic disadvantage are core drivers to these disparities.4 Lower socioeconomic status results in barriers to healthcare access and is associated with worse health literacy and poor adherence to maintenance inhaled corticosteroid (ICS). When healthcare is accessed, despite the burden of asthma being greater among Māori and Pacific people, they are more likely to remain on the lowest steps of asthma treatment.5–7

Over the past decade a number of strategies including community-based education programmes and asthma action plans have contributed to improving outcomes for Māori and Pacific people with asthma, but novel strategies may be required if further progress is to be made.8–10 One strategy has been the combination ICS/fast-onset long acting beta-agonist (LABA) used as both maintenance and reliever therapy, an approach which reduces the risk of severe exacerbations compared with maintenance ICS/LABA and short-acting beta2-agonist (SABA) reliever therapy in children and adults.11 This efficacy benefit has been shown in Māori adults with asthma,12 and has been recommended for use in Māori in local guidelines.13

An extension to this strategy is the use of combination ICS (budesonide)/fast-onset LABA (formoterol) used solely as needed in mild asthma, as an alternative to either SABA as sole reliever therapy or ICS maintenance and SABA reliever therapy. Four clinical trials have demonstrated that as-required budesonide/formoterol is non-inferior14,15 or superior16,17 to regular budesonide plus as needed SABA, and superior to SABA alone,14,16 in reducing severe exacerbation risk. One of these clinical trials, the PRACTICAL study, only recruited patients in New Zealand, which provided the opportunity to investigate whether this novel regimen is effective and safe in Māori and Pacific peoples. In this manuscript, we report a subgroup analyses of the influence of ethnicity on the efficacy of as-needed budesonide-formoterol vs maintenance budesonide and as-needed terbutaline in adults with mild to moderate asthma.

Methods

The PRACTICAL study was a 52-week, open label, parallel group, multicentre, phase III, randomised controlled trial to compare the efficacy and safety of two asthma treatment regimens; budesonide-formoterol Turbuhaler [Symbicort] 200/6mcg, one inhalation for relief of symptoms as required (budesonide-formoterol group), or budesonide Turbuhaler [Pulmicort] 200mcg, one inhalation twice daily and terbutaline Turbuhaler [Bricanyl] 250mcg, two inhalations for relief of symptoms as required (budesonide maintenance group). The PRACTICAL study was funded by the Health Research Council of New Zealand and was undertaken independently of the pharmaceutical industry.

Eight hundred and ninety adult patients, aged 18 to 75, with doctor-diagnosed asthma were recruited from 15 primary care facilities and research centres across New Zealand. Patients taking SABA reliever therapy alone or together with low to moderate doses of inhaled corticosteroid in the 12 weeks prior to randomisation were eligible. This pragmatic study was designed to more closely reflect real-world clinical practice.18 Smokers were only excluded if they had a greater than 20-pack year smoking history or respiratory symptoms that began after the age of 40 in participants with at least a 10-pack year smoking history. Additional key exclusion criteria included self-reported use of LABA or leukotriene receptor antagonist as maintenance therapy in the 12 weeks before potential study entry or the diagnosis of other lung disease.

All participants provided written informed consent and the study was approved by the Northern B ethics committee (15/NTB/178/AM01). Each site sought local Māori research committee approval. Participants and investigators were not masked to group assignment which allowed any real-world advantage of the as-needed ICS/formoterol regimen, that is, the use of a single medication and no requirement for regular inhaler use, to be studied.

Written asthma management plans were provided and inhaler technique was checked at each study visit. Questions on housing conditions and physical residential address, for calculation of deprivation score, were collected at week 0. Validated housing questions were adapted from the New Zealand heating study and Building Research Institute of New Zealand (BRANZ) house condition study.19,20 Detailed trial methodology has been reported elsewhere.21 Patients remained under the care of their primary care physician throughout the trial.

A Kaupapa Māori approach was utilised in some capacity, to increase the number of Māori participants.22 This involved the development of recruitment strategies, including recruiting through Māori providers and clinics, with the support of Kaupapa Māori trained asthma health workers. Participants self-reported their ethnicity at the first study visit. New Zealand national guidelines were used to classify ethnicity for participants reporting more than one ethnicity by a standard system.23

Outcome measures

The primary outcome was the number of severe exacerbations per patient per year. Severe exacerbations were defined as ii) the use of systemic steroids for at least three days because of asthma or ii) hospitalisation or ED visit because of asthma requiring systemic steroids, as recommended by ATS/ERS Task Force.24

Secondary outcomes were rate of asthma exacerbations per patient per year defined as worsening asthma resulting in unplanned medical review or use of systemic glucocorticoids of any duration, asthma control questionnaire 5 (ACQ-5) score, the mean of five questions about asthma symptoms during the previous week, each scored on a 7-point scale between 0 (no impairment) and 6 (maximum impairment),25 on-treatment FEV1 and fractional exhaled nitric oxide (FeNO).

Statistical analysis

The statistical analysis was an intention to treat superiority analysis. The general analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. In the event, none of the interaction terms was statistically significant. For illustration purposes only, the estimates of treatment differences and 95% confidence intervals are shown for each ethnicity from these interaction models and these are not accompanied by P values as there was no evidence that the effects within ethnic groups were different from the Overall rate in models that did not have ethnicity. The Overall rate is accompanied by a confidence interval and associated P value testing the hypotheses that the values of these outcome variables was different depending on treatments. These analyses have not been adjusted for multiple comparisons.

The recognised ethnicities within the PRACTICAL study are Māori, Pacific, Asian, New Zealand European and Other. Given the small number of participants within the Asian and Other ethnicity groups, Asian, New Zealand European and Other ethnicities were analysed together.

Categorical data are presented as the number and proportion expressed as a percentage and continuous data summaries including mean (SD) and median (IQR).

Analysis of the number of severe exacerbations per patient per year and combined rate of exacerbations and severe exacerbation per year was by Poisson regression with an offset for time of observation.

Differences in ACQ-5 and FEV1 were estimated by ANCOVA with the baseline measurement as a continuous co-variate. Spirometry was performed on treatment, ie, without withholding of usual inhaled therapy. Normality assumptions for FeNO were not well met on an untransformed scale but were met on a logarithm transformed scale. ANOVA was used on this scale and the exponent of the difference in logarithm FeNO is interpreted as the ratio of geometric means FeNO. In the models with ethnicity as a potential effect modifier interaction terms were used.

New Zealand deprivation score was calculated by geocoding the address of each participant to a meshblock, merging this geocoded dataset with the NZdep2013 file using meshblock number and linking each geocoded address with its area deprivation score. It is scaled to have mean 1,000 index points and standard deviation 100 index points.26

The Māori subgroup analysis was pre-specified and is exploratory as we did not recruit sufficient Māori participants to detect a difference in the main outcome. We have not adjusted for multiplicity of analysis.

SAS version 9.4 was used for all analyses.

The trial was registered with the Australian and New Zealand Clinical Trials Registry ACTRN12616000377437.

Results

Eight hundred and ninety participants were enrolled between 4 May 2016 and 22 December 2017 of whom 72 (8%) were Māori, 36 (4%) were Pacific and 777 (88%) were New Zealand European/Other (Figure 1).

Figure 1: Consort diagram.

The intention to treat data set included 885 eligible participants and no follow-up data was available in five participants of New Zealand European/Other ethnicity.

At baseline, Māori and Pacific participants had higher (worse) average ACQ-5 scores than New Zealand European/Other participants (mean ACQ-5 1.5, 1.6 and 1.1 respectively) and lower FEV1 values (83% predicted, 84% predicted and 88% predicted respectively). Inhaled corticosteroids were used at baseline by 49 (68%) Māori participants, 21 (58%) Pacific people and 551 (71%) New Zealand European/Other participants. Median (IQR) baseline FeNO was higher in Pacific participants than either Māori or New Zealand European/Other participants; 45.5 ppB, (18–80.5); 26.5 (12.5–50); and 28 (17–56), respectively (Table 1).

Table 1: Characteristics of participants by ethnicity.

*Values are means, bracketed values are ±SD unless otherwise stated. Patients in the budesonide maintenance group received budesonide (Pulmicort Turbuhaler, AstraZeneca), 200mcg, one inhalation twice daily, plus terbutaline (Bricanyl), 250mcg, two inhalations as needed for symptom relief. Patients in the budesonide–formoterol group received budesonide–formoterol (Symbicort Turbuhaler, AstraZeneca), 200mcg of budesonide and 6mcg of formoterol, one inhalation as needed for symptom relief. FeNO denotes fraction of exhaled nitric oxide, FEV1 forced expiratory volume in one second, IQR interquartile range, ppb parts per billion, and SABA short-acting beta-2-agonist.
†The Asthma Control Questionnaire–5 (ACQ-5) consists of five questions that assess asthma symptoms in the previous week, each of which is scored on a 7-point scale that ranges from 0 (no impairment) to 6 (maximum impairment), in which a 0.5-unit change represents the minimal clinically important difference.
‡Patients received no specific instruction to withhold use of their bronchodilator before measurement of FEV1.
$The NZ deprivation score is a measure of socioeconomic deprivation. It is scaled to have mean 1000 index points and standard deviation 100 index points.

Smoking status was that 19 (26%) Māori participants were current smokers compared to three (8%) Pacific participants and 41 (5%) New Zealand European/Other participants. Māori and Pacific participants lived in more deprived areas than New Zealand European/Other participants as demonstrated by higher mean New Zealand deprivation scores: 1,006.3, 1,021.7 and 961.3 respectively (Table 1).

The proportion of Māori and Pacific participants who reported living in cold, damp and musty smelling housing was higher than that reported by New Zealand European/Other participants. The proportion of participants reporting that their home smelt damp or musty was 38% for Māori participants, 42% for Pacific participants and 25% for New Zealand European/Other participants. The proportion of participants reporting that their house was so cold that they could see their breath in the previous winter was 42% for Māori participants, 44% for Pacific participants and 28% for New Zealand European/Other participants (Table 2).

Table 2: Housing questionnaire.

Budesonide-formoterol as needed versus budesonide maintenance and terbutaline as needed and ethnicity

Table 3 shows the interaction analyses with ethnicity. There was no evidence that ethnicity was an effect modifier for either severe exacerbations or total exacerbations; P=0.70 and 0.43 for the ethnicity-treatment interaction terms respectively. Although the estimates for the difference between treatments within each ethnic group were consistent with Pacific people having more benefit, this lack of a statistically significant interaction term means that the relative rate of severe exacerbations was the same, 0.69 (0.48–1.0), P=0.049, regardless of ethnicity. A similar pattern was seen for any exacerbations, namely that although the point estimates were consistent with more benefit for   Māori and Pacific people the lack of a statistically significant interaction term means there was no evidence that the relative rate of exacerbation, 0.70 (0.51–0.95), P=0.024, was different in relation to ethnicity.

Table 3: Severe asthma exacerbations, asthma control, lung function and FeNO.

*Differences in ACQ-5, FEV1 and FeNO are given for budesonide/formoterol as needed minus budesonide maintenance and terbutaline reliever. The p interaction tests if the difference between budesonide/formoterol and budesonide maintenance and terbutaline reliever differs by ethnicity. For completeness the individual difference within each level of ethnicity is shown, however if the interaction p value is not statistically significant there is no evidence that the treatment differences are different by ethnicity. The P value given for the Overall rate tests if there is a difference between treatments in models that just have the effect of treatment.

There was no evidence that ethnicity was an effect modifier for asthma control as measured by ACQ-5, forced expiratory volume in one second (FEV1) or fractional exhaled nitric oxide (FeNO).

There was no evidence of a treatment effect on ACQ or FEV1, however FeNO was higher in those randomised to as required Budesonide.

Discussion

This randomised controlled trial of as-needed budesonide-formoterol therapy in adults with mild and moderate asthma found no evidence that the regimen was more or less efficacious and safe in Māori and Pacific peoples compared to a New Zealand European/Other population. In other words, the as-needed budesonide-formoterol regimen achieved a clinically important reduction in risk of severe exacerbations compared with maintenance budesonide and terbutaline reliever therapy that did not differ by ethnicity. Similarly, there was no evidence that the the reduction in the risk of moderate and severe exacerbations with the as-needed budesonide-formoterol regimen, and the comparable levels of asthma control and lung function between the regimens, was different across the ethnic groups. This suggests that the pragmatic as-needed budesonide-formoterol regimen may be particularly suitable for Māori and Pacific peoples, who both experience barriers to asthma care, and higher morbidity and mortality from asthma in New Zealand.

At randomisation, Māori and Pacific subgroups had worse asthma control and higher exacerbation rates despite similar rates of prescription of ICS and self-reported adherence to ICS therapy. This suggests that other factors such as environmental and socioeconomic factors related to housing status and deprivation may play a role in the worse asthma outcomes. Many studies have demonstrated that damp and cold homes have a deleterious effect on respiratory health. This study provides evidence of greater disparities in environmental risk factors, as a higher proportion of Māori and Pacific participants reported that they live in cold and damp housing as compared to New Zealand European/Other participants. There is an ongoing need for implementation of effective policies to reduce inequalities in this area.27,28 The higher rates of current smoking in Māori also reinforce the requirement for measures to reduce smoking to be particularly focused on Māori. The study was not designed to specifically explore the effect of deprivation, eg, by stratification by deprivation; however, an analysis (not reported here) found little evidence of an association between exacerbations and New Zealand Deprivation scores.

This analysis has a number of limitations. Assessment of housing conditions was by self-report, which is associated with the risk of responder bias. Analysis of whether treatment group had a differential effect depending on ethnicity was pre-specified, although the trial was not specifically designed to detect differences between Māori, Pacific and New Zealand European/Other ethnicities, and may therefore lack power to detect important differences by ethnicity, particularly with the small number of Pacific participants. Outcomes have not been adjusted for multiplicity of analyses, increasing type-1 error rate. Despite consultation with Māori researchers during the design and implementation of this study and a commitment to recruiting Māori participants, 8% of participants identified as Māori, which is lower than the proportion of adult Māori in the general New Zealand population (9.5%) as identified by census data for 2018. Four percent of participants in the study were of Pacific ethnicity, which mirrors that of the adult general population. In addition, higher smoking rates among Māori people than the general population means they were more likely to have met criteria, which excluded people with a significant smoking history.29

This study builds on a previous randomised controlled trial, which demonstrated that the reduction in the risk of severe exacerbations with budesonide-formoterol compared with salbutamol reliever therapy in adults with high-risk asthma taking maintenance ICS/LABA therapy, was similar in Māori as other ethnicities.12 As a result there is now evidence, across the spectrum of asthma severity, that budesonide-formoterol reliever therapy reduces the risk of severe exacerbations as compared with SABA reliever therapy, both with and without maintenance ICS/LABA therapy, regardless of ethnicity. As Māori and Pacific peoples have higher morbidity from asthma, the absolute benefit from a reduction in exacerbations is likely to be greater, even though the relative reduction in risk with this regimen is similar.

An important consideration is whether the efficacy of the budesonide-formoterol reliever therapy regimen observed in Māori and Pacific adults with asthma in this study may be internationally transferable and apply to other at-risk populations defined by ethnicity, including Aboriginal Australian and African American people with asthma. Many of the barriers to healthcare, inequity in treatment received, and socioeconomic determinants of health outcomes in asthma observed in Māori and Pacific peoples in this study are also present in other indigenous groups. As a result, it is likely that our findings are generalisable, although the demonstration of differences in response to LABA therapy in African Americans emphasises the importance of investigating the impact of ethnicity on outcome in clinical trials.30

In conclusion, this trial has demonstrated that the greater reduction in the risk of severe exacerbations achieved with as-needed budesonide-formoterol compared with maintenance budesonide plus as-needed terbutaline was similar in Māori and Pacific adults as with European/other ethnicities. Implementation of the pragmatic budesonide-formoterol reliever therapy regimen in Māori and Pacific peoples has major potential to improve asthma outcomes and reduce their disproportionate burden from asthma.

Summary

Abstract

Aim

In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Māori and Pacific peoples, populations with worse asthma outcomes.

Method

The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable.

Results

Seventy-two participants (8%) identified as Māori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70).

Conclusion

The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Māori and Pacific adults compared with New Zealand European/Other.

Author Information

Jo Hardy, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Jordan Tewhaiti-Smith, Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Christina Baggott, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; James Fingleton, Consultant Physician, Capital and Coast District Health Board, Wellington; Alex Semprini, Deputy Director, Medical Research Institute of New Zealand, Wellington; Mark Holliday, Principal Clinical Operations, Medical Research Institute of New Zealand, Wellington; Robert J Hancox, Associate Professor, University of Otago, Dunedin; Mark Weatherall, Professor of Medicine, University of Otago Wellington, Wellington; Matire Harwood, Associate Professor, University of Auckland, Auckland.

Acknowledgements

The study was funded through a programme grant (15/573) provided by the Health Research Council of New Zealand to the study sponsor, the Medical Research Institute of New Zealand. We thank the study participants for their involvement in the study, the PRACTICAL Data Safety Monitoring Committee, consisting of Prof Rodolfo Morice, Dr Kyle Perrin, Associate Professor Andrew Harrison and Dalice Sim, and the PRACTICAL Study Team: Clinical Horizons (Tauranga, New Zealand): Andrew Corin, Colin Helm, Tracy Paterson; Bhuwan Poudel; Coastal Medical Rooms (Kapiti, New Zealand): Malcolm Dyer, Christine Jasinski; Culloden Research (Papamoa, New Zealand): Davitt Sheahan, Pamela Sheahan; Greenhithe Medical Centre (Auckland, New Zealand): Nick Gailer, Jan Van Zuilen; Henderson Medical Centre (Auckland, New Zealand): Andy Basa, Christine Devereaux, Karin Egan, Sneha Haughey, Rodney Marks, Dirk Venter, Hank Zhang; Lakeland Clinical Trials (Rotorua, New Zealand): Karen Trevithick, Mike Williams; Medical Research Institute of New Zealand and Lower Hutt After Hours Medical Centre (Wellington, New Zealand): Christina Baggott, Richard Beasley, Irene Braithwaite, Alexandra Eathorne, Stefan Ebmeier, James Fingleton, Daniela Hall, Jo Hardy, Matire Harwood, Mark Holliday, Claire Houghton, Saras Mane, John Martindale, Karen Oldfield, Janine Pilcher, Donah Sabbagh, Philippa Shirtcliffe, Suzanne Snively, Jenny Sparks, Alexandra Vohlidkova, Mathew Williams; Optimal Clinical Trials Ltd (Auckland, New Zealand): Patrick Collins, Summer Hassan, Annika Lam, Claudette Lionnet, Barney Montgomery; P3 Clinical Trials (Wellington, New Zealand): Stella Moon, Dean Quinn; RMC Medical Research (Dunedin, New Zealand): Dean Millar-Coote, Jim Reid; South Pacific Clinical Trials (Auckland, New Zealand): Nicola Burton, Tina Mullard, Tyronne Tranquilino, Edward Watson; Southern Clinical Trials (Auckland, New Zealand): Jill Bell, John Richmond; Team Medical (Kapiti, New Zealand): Brent Krivan, Cheryl Robertson; University of Otago, Dunedin: Robert J Hancox; University of Otago, Wellington: Mark Weatherall; Waikanae Medical Centre (Kapiti, New Zealand): Sue Glensor, Anne-Christine Porrachia; Woolcock Institute of Medical Research (Sydney, Australia): Helen K Reddel.

Correspondence

Professor Richard Beasley, Medical Research Institute of New Zealand, Private Bag 7902, Newtown, Wellington 6242.

Correspondence Email

richard.beasley@mrinz.ac.nz

Competing Interests

Dr Baggott reports grants from Health Research Council of New Zealand during the conduct of the study; personal fees from Astra Zeneca, personal fees from Novartis, outside the submitted work. Dr Fingleton reports grants, personal fees and non-financial support from AstraZeneca, grants from Genentech, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Boheringer lngleheim, outside the submitted work. Dr Beasley reports grants from Health Research Council of New Zealand during the conduct of the study; grants and personal fees from Astra Zeneca, personal fees from Avillion, grants from Cephalon, grants from Chiesi, grants and personal fees from Genentech, grants from GlaxoSmithKline, personal fees from Theravance, grants from Novartis, outside the submitted work; Dr Hancox reports grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, other from Menarini, other from Boehringer Ingelheim, outside the submitted work. Dr Hardy reports grants from AstraZeneca, grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, outside the submitted work. Mr Holliday and Dr Harwood report grants from Health Research Council New Zealand during the conduct of the study.

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Asthma is a major public health problem in New Zealand. The prevalence rate is among the highest in the world, particularly in adults identifying as Māori, the indigenous people of New Zealand, and Pacific people.1–3 Furthermore, substantial morbidity and mortality persist despite efforts to improve management, with disparities in health outcomes for Māori and Pacific peoples across the severities of asthma.

Systemic issues such as institutional racism and socioeconomic disadvantage are core drivers to these disparities.4 Lower socioeconomic status results in barriers to healthcare access and is associated with worse health literacy and poor adherence to maintenance inhaled corticosteroid (ICS). When healthcare is accessed, despite the burden of asthma being greater among Māori and Pacific people, they are more likely to remain on the lowest steps of asthma treatment.5–7

Over the past decade a number of strategies including community-based education programmes and asthma action plans have contributed to improving outcomes for Māori and Pacific people with asthma, but novel strategies may be required if further progress is to be made.8–10 One strategy has been the combination ICS/fast-onset long acting beta-agonist (LABA) used as both maintenance and reliever therapy, an approach which reduces the risk of severe exacerbations compared with maintenance ICS/LABA and short-acting beta2-agonist (SABA) reliever therapy in children and adults.11 This efficacy benefit has been shown in Māori adults with asthma,12 and has been recommended for use in Māori in local guidelines.13

An extension to this strategy is the use of combination ICS (budesonide)/fast-onset LABA (formoterol) used solely as needed in mild asthma, as an alternative to either SABA as sole reliever therapy or ICS maintenance and SABA reliever therapy. Four clinical trials have demonstrated that as-required budesonide/formoterol is non-inferior14,15 or superior16,17 to regular budesonide plus as needed SABA, and superior to SABA alone,14,16 in reducing severe exacerbation risk. One of these clinical trials, the PRACTICAL study, only recruited patients in New Zealand, which provided the opportunity to investigate whether this novel regimen is effective and safe in Māori and Pacific peoples. In this manuscript, we report a subgroup analyses of the influence of ethnicity on the efficacy of as-needed budesonide-formoterol vs maintenance budesonide and as-needed terbutaline in adults with mild to moderate asthma.

Methods

The PRACTICAL study was a 52-week, open label, parallel group, multicentre, phase III, randomised controlled trial to compare the efficacy and safety of two asthma treatment regimens; budesonide-formoterol Turbuhaler [Symbicort] 200/6mcg, one inhalation for relief of symptoms as required (budesonide-formoterol group), or budesonide Turbuhaler [Pulmicort] 200mcg, one inhalation twice daily and terbutaline Turbuhaler [Bricanyl] 250mcg, two inhalations for relief of symptoms as required (budesonide maintenance group). The PRACTICAL study was funded by the Health Research Council of New Zealand and was undertaken independently of the pharmaceutical industry.

Eight hundred and ninety adult patients, aged 18 to 75, with doctor-diagnosed asthma were recruited from 15 primary care facilities and research centres across New Zealand. Patients taking SABA reliever therapy alone or together with low to moderate doses of inhaled corticosteroid in the 12 weeks prior to randomisation were eligible. This pragmatic study was designed to more closely reflect real-world clinical practice.18 Smokers were only excluded if they had a greater than 20-pack year smoking history or respiratory symptoms that began after the age of 40 in participants with at least a 10-pack year smoking history. Additional key exclusion criteria included self-reported use of LABA or leukotriene receptor antagonist as maintenance therapy in the 12 weeks before potential study entry or the diagnosis of other lung disease.

All participants provided written informed consent and the study was approved by the Northern B ethics committee (15/NTB/178/AM01). Each site sought local Māori research committee approval. Participants and investigators were not masked to group assignment which allowed any real-world advantage of the as-needed ICS/formoterol regimen, that is, the use of a single medication and no requirement for regular inhaler use, to be studied.

Written asthma management plans were provided and inhaler technique was checked at each study visit. Questions on housing conditions and physical residential address, for calculation of deprivation score, were collected at week 0. Validated housing questions were adapted from the New Zealand heating study and Building Research Institute of New Zealand (BRANZ) house condition study.19,20 Detailed trial methodology has been reported elsewhere.21 Patients remained under the care of their primary care physician throughout the trial.

A Kaupapa Māori approach was utilised in some capacity, to increase the number of Māori participants.22 This involved the development of recruitment strategies, including recruiting through Māori providers and clinics, with the support of Kaupapa Māori trained asthma health workers. Participants self-reported their ethnicity at the first study visit. New Zealand national guidelines were used to classify ethnicity for participants reporting more than one ethnicity by a standard system.23

Outcome measures

The primary outcome was the number of severe exacerbations per patient per year. Severe exacerbations were defined as ii) the use of systemic steroids for at least three days because of asthma or ii) hospitalisation or ED visit because of asthma requiring systemic steroids, as recommended by ATS/ERS Task Force.24

Secondary outcomes were rate of asthma exacerbations per patient per year defined as worsening asthma resulting in unplanned medical review or use of systemic glucocorticoids of any duration, asthma control questionnaire 5 (ACQ-5) score, the mean of five questions about asthma symptoms during the previous week, each scored on a 7-point scale between 0 (no impairment) and 6 (maximum impairment),25 on-treatment FEV1 and fractional exhaled nitric oxide (FeNO).

Statistical analysis

The statistical analysis was an intention to treat superiority analysis. The general analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable. In the event, none of the interaction terms was statistically significant. For illustration purposes only, the estimates of treatment differences and 95% confidence intervals are shown for each ethnicity from these interaction models and these are not accompanied by P values as there was no evidence that the effects within ethnic groups were different from the Overall rate in models that did not have ethnicity. The Overall rate is accompanied by a confidence interval and associated P value testing the hypotheses that the values of these outcome variables was different depending on treatments. These analyses have not been adjusted for multiple comparisons.

The recognised ethnicities within the PRACTICAL study are Māori, Pacific, Asian, New Zealand European and Other. Given the small number of participants within the Asian and Other ethnicity groups, Asian, New Zealand European and Other ethnicities were analysed together.

Categorical data are presented as the number and proportion expressed as a percentage and continuous data summaries including mean (SD) and median (IQR).

Analysis of the number of severe exacerbations per patient per year and combined rate of exacerbations and severe exacerbation per year was by Poisson regression with an offset for time of observation.

Differences in ACQ-5 and FEV1 were estimated by ANCOVA with the baseline measurement as a continuous co-variate. Spirometry was performed on treatment, ie, without withholding of usual inhaled therapy. Normality assumptions for FeNO were not well met on an untransformed scale but were met on a logarithm transformed scale. ANOVA was used on this scale and the exponent of the difference in logarithm FeNO is interpreted as the ratio of geometric means FeNO. In the models with ethnicity as a potential effect modifier interaction terms were used.

New Zealand deprivation score was calculated by geocoding the address of each participant to a meshblock, merging this geocoded dataset with the NZdep2013 file using meshblock number and linking each geocoded address with its area deprivation score. It is scaled to have mean 1,000 index points and standard deviation 100 index points.26

The Māori subgroup analysis was pre-specified and is exploratory as we did not recruit sufficient Māori participants to detect a difference in the main outcome. We have not adjusted for multiplicity of analysis.

SAS version 9.4 was used for all analyses.

The trial was registered with the Australian and New Zealand Clinical Trials Registry ACTRN12616000377437.

Results

Eight hundred and ninety participants were enrolled between 4 May 2016 and 22 December 2017 of whom 72 (8%) were Māori, 36 (4%) were Pacific and 777 (88%) were New Zealand European/Other (Figure 1).

Figure 1: Consort diagram.

The intention to treat data set included 885 eligible participants and no follow-up data was available in five participants of New Zealand European/Other ethnicity.

At baseline, Māori and Pacific participants had higher (worse) average ACQ-5 scores than New Zealand European/Other participants (mean ACQ-5 1.5, 1.6 and 1.1 respectively) and lower FEV1 values (83% predicted, 84% predicted and 88% predicted respectively). Inhaled corticosteroids were used at baseline by 49 (68%) Māori participants, 21 (58%) Pacific people and 551 (71%) New Zealand European/Other participants. Median (IQR) baseline FeNO was higher in Pacific participants than either Māori or New Zealand European/Other participants; 45.5 ppB, (18–80.5); 26.5 (12.5–50); and 28 (17–56), respectively (Table 1).

Table 1: Characteristics of participants by ethnicity.

*Values are means, bracketed values are ±SD unless otherwise stated. Patients in the budesonide maintenance group received budesonide (Pulmicort Turbuhaler, AstraZeneca), 200mcg, one inhalation twice daily, plus terbutaline (Bricanyl), 250mcg, two inhalations as needed for symptom relief. Patients in the budesonide–formoterol group received budesonide–formoterol (Symbicort Turbuhaler, AstraZeneca), 200mcg of budesonide and 6mcg of formoterol, one inhalation as needed for symptom relief. FeNO denotes fraction of exhaled nitric oxide, FEV1 forced expiratory volume in one second, IQR interquartile range, ppb parts per billion, and SABA short-acting beta-2-agonist.
†The Asthma Control Questionnaire–5 (ACQ-5) consists of five questions that assess asthma symptoms in the previous week, each of which is scored on a 7-point scale that ranges from 0 (no impairment) to 6 (maximum impairment), in which a 0.5-unit change represents the minimal clinically important difference.
‡Patients received no specific instruction to withhold use of their bronchodilator before measurement of FEV1.
$The NZ deprivation score is a measure of socioeconomic deprivation. It is scaled to have mean 1000 index points and standard deviation 100 index points.

Smoking status was that 19 (26%) Māori participants were current smokers compared to three (8%) Pacific participants and 41 (5%) New Zealand European/Other participants. Māori and Pacific participants lived in more deprived areas than New Zealand European/Other participants as demonstrated by higher mean New Zealand deprivation scores: 1,006.3, 1,021.7 and 961.3 respectively (Table 1).

The proportion of Māori and Pacific participants who reported living in cold, damp and musty smelling housing was higher than that reported by New Zealand European/Other participants. The proportion of participants reporting that their home smelt damp or musty was 38% for Māori participants, 42% for Pacific participants and 25% for New Zealand European/Other participants. The proportion of participants reporting that their house was so cold that they could see their breath in the previous winter was 42% for Māori participants, 44% for Pacific participants and 28% for New Zealand European/Other participants (Table 2).

Table 2: Housing questionnaire.

Budesonide-formoterol as needed versus budesonide maintenance and terbutaline as needed and ethnicity

Table 3 shows the interaction analyses with ethnicity. There was no evidence that ethnicity was an effect modifier for either severe exacerbations or total exacerbations; P=0.70 and 0.43 for the ethnicity-treatment interaction terms respectively. Although the estimates for the difference between treatments within each ethnic group were consistent with Pacific people having more benefit, this lack of a statistically significant interaction term means that the relative rate of severe exacerbations was the same, 0.69 (0.48–1.0), P=0.049, regardless of ethnicity. A similar pattern was seen for any exacerbations, namely that although the point estimates were consistent with more benefit for   Māori and Pacific people the lack of a statistically significant interaction term means there was no evidence that the relative rate of exacerbation, 0.70 (0.51–0.95), P=0.024, was different in relation to ethnicity.

Table 3: Severe asthma exacerbations, asthma control, lung function and FeNO.

*Differences in ACQ-5, FEV1 and FeNO are given for budesonide/formoterol as needed minus budesonide maintenance and terbutaline reliever. The p interaction tests if the difference between budesonide/formoterol and budesonide maintenance and terbutaline reliever differs by ethnicity. For completeness the individual difference within each level of ethnicity is shown, however if the interaction p value is not statistically significant there is no evidence that the treatment differences are different by ethnicity. The P value given for the Overall rate tests if there is a difference between treatments in models that just have the effect of treatment.

There was no evidence that ethnicity was an effect modifier for asthma control as measured by ACQ-5, forced expiratory volume in one second (FEV1) or fractional exhaled nitric oxide (FeNO).

There was no evidence of a treatment effect on ACQ or FEV1, however FeNO was higher in those randomised to as required Budesonide.

Discussion

This randomised controlled trial of as-needed budesonide-formoterol therapy in adults with mild and moderate asthma found no evidence that the regimen was more or less efficacious and safe in Māori and Pacific peoples compared to a New Zealand European/Other population. In other words, the as-needed budesonide-formoterol regimen achieved a clinically important reduction in risk of severe exacerbations compared with maintenance budesonide and terbutaline reliever therapy that did not differ by ethnicity. Similarly, there was no evidence that the the reduction in the risk of moderate and severe exacerbations with the as-needed budesonide-formoterol regimen, and the comparable levels of asthma control and lung function between the regimens, was different across the ethnic groups. This suggests that the pragmatic as-needed budesonide-formoterol regimen may be particularly suitable for Māori and Pacific peoples, who both experience barriers to asthma care, and higher morbidity and mortality from asthma in New Zealand.

At randomisation, Māori and Pacific subgroups had worse asthma control and higher exacerbation rates despite similar rates of prescription of ICS and self-reported adherence to ICS therapy. This suggests that other factors such as environmental and socioeconomic factors related to housing status and deprivation may play a role in the worse asthma outcomes. Many studies have demonstrated that damp and cold homes have a deleterious effect on respiratory health. This study provides evidence of greater disparities in environmental risk factors, as a higher proportion of Māori and Pacific participants reported that they live in cold and damp housing as compared to New Zealand European/Other participants. There is an ongoing need for implementation of effective policies to reduce inequalities in this area.27,28 The higher rates of current smoking in Māori also reinforce the requirement for measures to reduce smoking to be particularly focused on Māori. The study was not designed to specifically explore the effect of deprivation, eg, by stratification by deprivation; however, an analysis (not reported here) found little evidence of an association between exacerbations and New Zealand Deprivation scores.

This analysis has a number of limitations. Assessment of housing conditions was by self-report, which is associated with the risk of responder bias. Analysis of whether treatment group had a differential effect depending on ethnicity was pre-specified, although the trial was not specifically designed to detect differences between Māori, Pacific and New Zealand European/Other ethnicities, and may therefore lack power to detect important differences by ethnicity, particularly with the small number of Pacific participants. Outcomes have not been adjusted for multiplicity of analyses, increasing type-1 error rate. Despite consultation with Māori researchers during the design and implementation of this study and a commitment to recruiting Māori participants, 8% of participants identified as Māori, which is lower than the proportion of adult Māori in the general New Zealand population (9.5%) as identified by census data for 2018. Four percent of participants in the study were of Pacific ethnicity, which mirrors that of the adult general population. In addition, higher smoking rates among Māori people than the general population means they were more likely to have met criteria, which excluded people with a significant smoking history.29

This study builds on a previous randomised controlled trial, which demonstrated that the reduction in the risk of severe exacerbations with budesonide-formoterol compared with salbutamol reliever therapy in adults with high-risk asthma taking maintenance ICS/LABA therapy, was similar in Māori as other ethnicities.12 As a result there is now evidence, across the spectrum of asthma severity, that budesonide-formoterol reliever therapy reduces the risk of severe exacerbations as compared with SABA reliever therapy, both with and without maintenance ICS/LABA therapy, regardless of ethnicity. As Māori and Pacific peoples have higher morbidity from asthma, the absolute benefit from a reduction in exacerbations is likely to be greater, even though the relative reduction in risk with this regimen is similar.

An important consideration is whether the efficacy of the budesonide-formoterol reliever therapy regimen observed in Māori and Pacific adults with asthma in this study may be internationally transferable and apply to other at-risk populations defined by ethnicity, including Aboriginal Australian and African American people with asthma. Many of the barriers to healthcare, inequity in treatment received, and socioeconomic determinants of health outcomes in asthma observed in Māori and Pacific peoples in this study are also present in other indigenous groups. As a result, it is likely that our findings are generalisable, although the demonstration of differences in response to LABA therapy in African Americans emphasises the importance of investigating the impact of ethnicity on outcome in clinical trials.30

In conclusion, this trial has demonstrated that the greater reduction in the risk of severe exacerbations achieved with as-needed budesonide-formoterol compared with maintenance budesonide plus as-needed terbutaline was similar in Māori and Pacific adults as with European/other ethnicities. Implementation of the pragmatic budesonide-formoterol reliever therapy regimen in Māori and Pacific peoples has major potential to improve asthma outcomes and reduce their disproportionate burden from asthma.

Summary

Abstract

Aim

In the PRACTICAL study, as-needed budesonide/formoterol reduced the rate of severe exacerbations compared with maintenance budesonide plus as-needed terbutaline. In a pre-specified analysis we analysed the efficacy in Māori and Pacific peoples, populations with worse asthma outcomes.

Method

The PRACTICAL study was a 52-week, open-label, parallel group, randomised controlled trial of 890 adults with mild to moderate asthma, who were randomised to budesonide/formoterol Turbuhaler 200/6mcg one actuation as required or budesonide Turbuhaler 200mcg one actuation twice daily and terbutaline Turbuhaler 250mcg two actuations as required. The primary outcome was rate of severe exacerbations. The analysis strategy was to test an ethnicity-treatment interaction term for each outcome variable.

Results

Seventy-two participants (8%) identified as Māori, 36 participants (4%) as Pacific ethnicity. There was no evidence that ethnicity was an effect modifier for severe exacerbations (P interaction 0.70).

Conclusion

The reduction in severe exacerbation risk with budesonide-formoterol reliever compared with maintenance budesonide was similar in Māori and Pacific adults compared with New Zealand European/Other.

Author Information

Jo Hardy, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Jordan Tewhaiti-Smith, Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; Christina Baggott, Senior Clinical Research Fellow, Medical Research Institute of New Zealand, Wellington; James Fingleton, Consultant Physician, Capital and Coast District Health Board, Wellington; Alex Semprini, Deputy Director, Medical Research Institute of New Zealand, Wellington; Mark Holliday, Principal Clinical Operations, Medical Research Institute of New Zealand, Wellington; Robert J Hancox, Associate Professor, University of Otago, Dunedin; Mark Weatherall, Professor of Medicine, University of Otago Wellington, Wellington; Matire Harwood, Associate Professor, University of Auckland, Auckland.

Acknowledgements

The study was funded through a programme grant (15/573) provided by the Health Research Council of New Zealand to the study sponsor, the Medical Research Institute of New Zealand. We thank the study participants for their involvement in the study, the PRACTICAL Data Safety Monitoring Committee, consisting of Prof Rodolfo Morice, Dr Kyle Perrin, Associate Professor Andrew Harrison and Dalice Sim, and the PRACTICAL Study Team: Clinical Horizons (Tauranga, New Zealand): Andrew Corin, Colin Helm, Tracy Paterson; Bhuwan Poudel; Coastal Medical Rooms (Kapiti, New Zealand): Malcolm Dyer, Christine Jasinski; Culloden Research (Papamoa, New Zealand): Davitt Sheahan, Pamela Sheahan; Greenhithe Medical Centre (Auckland, New Zealand): Nick Gailer, Jan Van Zuilen; Henderson Medical Centre (Auckland, New Zealand): Andy Basa, Christine Devereaux, Karin Egan, Sneha Haughey, Rodney Marks, Dirk Venter, Hank Zhang; Lakeland Clinical Trials (Rotorua, New Zealand): Karen Trevithick, Mike Williams; Medical Research Institute of New Zealand and Lower Hutt After Hours Medical Centre (Wellington, New Zealand): Christina Baggott, Richard Beasley, Irene Braithwaite, Alexandra Eathorne, Stefan Ebmeier, James Fingleton, Daniela Hall, Jo Hardy, Matire Harwood, Mark Holliday, Claire Houghton, Saras Mane, John Martindale, Karen Oldfield, Janine Pilcher, Donah Sabbagh, Philippa Shirtcliffe, Suzanne Snively, Jenny Sparks, Alexandra Vohlidkova, Mathew Williams; Optimal Clinical Trials Ltd (Auckland, New Zealand): Patrick Collins, Summer Hassan, Annika Lam, Claudette Lionnet, Barney Montgomery; P3 Clinical Trials (Wellington, New Zealand): Stella Moon, Dean Quinn; RMC Medical Research (Dunedin, New Zealand): Dean Millar-Coote, Jim Reid; South Pacific Clinical Trials (Auckland, New Zealand): Nicola Burton, Tina Mullard, Tyronne Tranquilino, Edward Watson; Southern Clinical Trials (Auckland, New Zealand): Jill Bell, John Richmond; Team Medical (Kapiti, New Zealand): Brent Krivan, Cheryl Robertson; University of Otago, Dunedin: Robert J Hancox; University of Otago, Wellington: Mark Weatherall; Waikanae Medical Centre (Kapiti, New Zealand): Sue Glensor, Anne-Christine Porrachia; Woolcock Institute of Medical Research (Sydney, Australia): Helen K Reddel.

Correspondence

Professor Richard Beasley, Medical Research Institute of New Zealand, Private Bag 7902, Newtown, Wellington 6242.

Correspondence Email

richard.beasley@mrinz.ac.nz

Competing Interests

Dr Baggott reports grants from Health Research Council of New Zealand during the conduct of the study; personal fees from Astra Zeneca, personal fees from Novartis, outside the submitted work. Dr Fingleton reports grants, personal fees and non-financial support from AstraZeneca, grants from Genentech, grants, personal fees and non-financial support from GlaxoSmithKline, personal fees and non-financial support from Boheringer lngleheim, outside the submitted work. Dr Beasley reports grants from Health Research Council of New Zealand during the conduct of the study; grants and personal fees from Astra Zeneca, personal fees from Avillion, grants from Cephalon, grants from Chiesi, grants and personal fees from Genentech, grants from GlaxoSmithKline, personal fees from Theravance, grants from Novartis, outside the submitted work; Dr Hancox reports grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, other from Menarini, other from Boehringer Ingelheim, outside the submitted work. Dr Hardy reports grants from AstraZeneca, grants from Health Research Council of New Zealand, during the conduct of the study; other from Astra Zeneca, outside the submitted work. Mr Holliday and Dr Harwood report grants from Health Research Council New Zealand during the conduct of the study.

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