This document summarizes the proceedings of the Small Airways Working Group Meeting held on September 9th, 2017 in Milan. It includes the agenda, list of attendees, and progress updates on several studies. Multiple studies comparing the effectiveness of extra-fine particle inhaled corticosteroids to fine particle ICS have been published or are underway. Preliminary results suggest extra-fine ICS may achieve better asthma control at lower doses and with fewer side effects like pneumonia. The group discussed potential future studies on flexible dosing strategies, metabolic effects of high dose ICS, and the impact of particle size in patients with obesity or GERD. Priority research areas and ongoing protocols were reviewed for continued relevance and feasibility.

1. ERS 2017
Milan, 9th September 2017
Small Airways Working Group Meeting

2. Agenda
• Working group progress update
• Priorities for future research
o Review potential studies
– Are they still relevant, feasible, valid and a priority
o Other research ideas
o Setting priorities
• Additional items

3. Attendees
• O Usmani (chair)
• A Azuma
• S Turner
• A Niimi
• R Dandurand
• A Papi
• J Grigg
• H Hoch

4. Progress update
• Published studies
– R04612b: Cost-effectiveness of asthma step-up therapy as an increased dose
of small-particle inhaled corticosteroid or add-on long-acting beta2-agonist
– R02511/02611: Comparative effectiveness of extra-fine particle inhaled
corticosteroid (ICS) and alternative guideline-recommended step-up options in
pre-school children
– R02911: Effectiveness of initiating extrafine versus fine particle inhaled
cortiscosteroids as asthma therapy in the Netherlands
– R05513: Effectiveness of spacers for the delivery of Qvar® and Fluticasone
Propionate ICS in patients with asthma
– R05612: Dose response study: small particle (Qvar + Ciclesonide) vs. large
particle (FP + Clenil)
– R00114: Ciclesonide Study: Comparison of propensity score matching
approaches

5. Published study
• R05312: Implications of ICS particle size on potential long-term asthma treatment-
related side effects (e.g. metabolic and musculoskeletal comorbidities, pneumonia)
o Pneumonia results published in PloS one in June 2017
o Retrospective cohort study using OPCRD
o Conclusions:
– Patients stepping up their ICS therapy as small particle ICS were significantly less likely to be
coded for pneumonia or to experience adverse respiratory outcomes compared with patients
stepping up their ICS therapy as large particle ICS.
– An analysis by average daily consumed dose suggests that the higher ICS doses consumed
by patients prescribed large particle ICS may be driving the higher incidence rates of
pneumonia
– Results from the initiation cohort and analyses of diabetes-related endpoints in the ICS step-
up cohort were unconvincing (likely due to low patient numbers and low event rates) but
unmatched results did indicate a quicker progression to insulin treatment amongst diabetic
patients prescribed large particle versus small particle ICS.

6. Complete studies: REG-RES1318
• Implications of ICS prescription duration on asthma outcomes
o Final report complete
o Conclusion:
– Results from the current study indicate that increasing the duration or
strength of ICS therapy is associated with a reduction in the number of
exacerbations experienced.
– Patients are also more likely to achieve better asthma control than
patients that are kept on the same script duration.
– Finally, patients that are switched to either an increased script duration
or strength are more likely to be adherent, as was determined by
medication possession ratio.

7. Complete studies: REG-RES1318
• Decision to end study at final report, as multivariable matched
analysis would be required to validate findings.

8. Active study update (1)
• REG-RES1509: Comparative effectiveness of guideline recommended
treatment options for patients with pre-school asthma / wheeze
o Historical matched cohort analysis:
– Index date: Time of first prescription for asthma controller therapy or repeat
prescription for SABA.
– Study period: One baseline year for clinical characterisation and one outcome year
were considered for each child.
– Inclusion criteria: 1-5 years of age at index date, with ≥2 wheezing episodes or ≥2
prescriptions for OCS with accompanying lower respiratory complaint, and an index
date from January 1988 to May 2015.
– Exclusion criteria: Children <1 year, those with other chronic respiratory diseases or
ICS/LTRA prescription during baseline, combination LABA-ICS prescription during the
baseline year or on the index date, or multiple step-up therapies on the index date.

9. REG-RES1509: Treatment of pre-school asthma/wheeze
Conclusions
• No significant differences in wheezing/asthma
attack rates during the outcome year in any of
the four treatment comparisons.
• The only statistically significant difference
observed during the outcome year (2% ED
visits in ICS vs. 1% SABA cohorts) is perhaps not
clinically significant.
• Our findings suggest that watchful waiting, in
conjunction with as-needed symptom
management, may be the best approach for
many children with preschool wheeze.
Manuscript submitted to Thorax and poster at ERS

10. Active study update (2)
• REG-RES1513: A systematic review of the comparative effectiveness
literature considering extra-fine particle ICS with licensed alternatives
o Provisionally accepted by JACI
o Conclusion:
– Extra-fine ICS have significantly higher odds of achieving asthma control with
lower exacerbation rates at significantly lower doses than fine-particle ICS
– Whether this is the result of the broader distribution of the extra-fine
formulation through the airways or whether it is due to increased deposition in
the small airways is still largely unknown
– Physicians must consider the potential benefits of prescribing extra-fine
formulations of ICS to asthmatics.

11. Active study update (3)
• RP00113: Characterisation of current asthma management practice
and asthma-related morbidity (State of the Union)
o Conclusions:
– A high proportion patients suffer from uncontrolled asthma and experience
frequent exacerbations
– The proportion of patients with uncontrolled asthma and severe exacerbations
is greater at the higher GINA steps despite being prescribed combination
therapy from step 3 onwards
– This lack of control is seen despite the fact that patients with higher
exacerbation levels are more adherent to medication
– Current and former smokers were significantly more likely to have had
uncontrolled asthma and to have experienced ≥1 severe exacerbation
o Manuscript under development
o Final analysis being reworked – note, numbers may therefore change

12. Active study update (4)
• REG_P006: Harmonizing the nomenclature for therapeutic
aerosol particle size: A proposal
o Proposal:
– To harmonize particle size nomenclature using the terms “extrafine”
and “fine” to denote aerosols with MMAD of 5 µm.
– To use of the terms extrafine-particle dose and coarse-particle dose to
denote the mass of particles 5 µm, respectively.
o Under submission with J Aerosol Med Pulm Drug Del

13. Future interests
• Four studies with protocols/concept sheets
o Are they still relevant, feasible, valid and a priority?

14. Working title
CURRENT BURDEN OF UNCONTROLLED ASTHMA IN THE GENERAL
POPULATION: THE OPCRD ASTHMA STATE OF THE UNION STUDY
Objective
• Characterise the state of asthma treatment and associated patterns of
control in a UK primary care population across guideline recommended
(GINA) treatment steps by:
• Describing asthma control of patients on different treatment options at each GINA
management step
• Quantifying “excessive” use of SABA and associated control at each GINA step
• Evaluating the prevalence of poor adherence to ICS therapy and it’s impact on
asthma control
• Evaluate whether entirely flexible dosing of FDC low dose ICS + LABA
provides better asthma control than an increase of the dose of ICS alone as
maintenance therapy
• Evaluate whether FDC low dose ICS + LABA as MART provides better
asthma control than FDC low dose ICS + LABA as maintenance treatment
plus as-needed SABA
• Explore the association between sustained high dose ICS and metabolic
consequences in UK asthma patients treated in routine primary care
Rationale
• Only 15% of inhaled corticosteroid (ICS) users and
45% of non-ICS users achieve fully-controlled asthma
• More up-to-date understanding of the current state of
asthma management is required
• There is a need to quantify the potential value of
alternative management approaches for improving
outcomes
Proposed methodology
Design: Historical observational cohort study using
OPCRD
Outcomes: Asthma control at each GINA step,
effectiveness of completely flexible dosing, effectiveness
of MART, metabolic consequences of high dose ICS
Asthma state of treatment: asthma control and metabolic
consequences (REG_RES1506)

15. Working title
• HEALTH CONSEQUENCES ASSOCIATED WITH
CHOICE OF INHALED CORTICOSTEROID PARTICLE
SIZE IN THE LONG-TERM MANAGEMENT OF
OBSTRUCTIVE LUNG DISEASE
Objective
• To compare whether patients prescribed EF ICS are
associated with a slower diabetic progression than F
ICS in asthma.
• To compare the:
• Annual incidence of ICS risks and benefits in patients
with OLD managed on EF vs F ICS and on EF vs F
ICS/LABA
• Time to first event or rate of ICS risks and benefits as
appropriate in patients with OLD managed on EF vs F
ICS and on EF vs F ICS/LABA
• The relationship between ICS exposure (average daily
dose or change in average daily dose) and ICS risks
and benefits.
Rationale
• Lower doses of ICS have been shown to have fewer risks
when compared to higher doses
• Pharmacokinetic studies have demonstrated that ICS with
higher fine particle fractions are associated with greater
levels of lung deposition
• An exploratory study conducted by Research in Real Life
UK suggested that patients with OLD stepping up their dose
of ICS as EF, compared to fine particle ICS, had lower
exacerbation rates and a lower incidence of pneumonia
Proposed methodology
Design: Matched historical observational cohort study using
OPCRD
Exposures: EF ICS treatment, F ICS treatment
Outcomes: Diabetic risks, respiratory-related risks,
respiratory-related benefits, osteoporosis related risks,
cardiovascular risks, BMI risks
Metabolic implications of particle size (REG_RES1512)

16. Working title
• Implications of inhaled corticosteroid particle size in the
management of asthma in patients excess weight/obesity
and/or GERD
Objective
1. Evaluate the comparative effectiveness of extra-fine and non extra-
fine inhaled corticosteroid (ICS) treatment in patients with asthma
and comorbid GERD ± obesity
2. Determine the relationship between overweight/obesity and GERD
as determinants of poor asthma control
Rationale
• Positive correlation BMI and development of asthma.
• GERD is a risk factor for asthma
• High BMI and GERD may impair asthma control through:
– Obesity: systemic inflammation, modified lung mechanics
– GERD: increased airways inflammation
which could be associated with more distal inflammation
Outputs from the research
• Hypothesis testing: contribute to the evidence for the presence
and potential management implications of distal airway
inflammation in patients with asthma ± excess weight ± GERD
• Informing targeted management options: inform management
decisions in patients with comorbid asthma, GERD and obesity
• Research dissemination: Respiratory conference abstract &
open access peer review journal publication
Proposed methodology
Design: 2-year observational matched cohort study study: 1
baseline year; an index date at which patients initiate or step-up ICS
therapy; 1 outcome year
Population: adult asthma patients (i) Population A: initiating and (ii)
Population B: stepping up asthma maintenance therapy as extra-
fine vs non extra-fine ICS will be matched on key baseline
characteristics (age, sex, exacerbations, BMI, comorbid GERD)
A priori subgroups: (i) asthma only; (ii) asthma+GERD; (iii)
asthma+obesity; (iv) asthma+obesity+ GERD
Outcomes: database measures of asthma control, acute
respiratory events and asthma exacerbation rates.
Asthma & GERD ± Obesity Research Concept (REG_PO23)
Proposed by Nicolas Roche; May 2015

17. Working title
• Implications of inhaled corticosteroid particle size in the
management of patients with a mixed asthma-COPD
phenotype
Objective
1. Evaluate the comparative effectiveness of
extra-fine and non extra-fine inhaled
corticosteroid treatment in patients with ACO
(vs asthma vs COPD)
2. Evaluate the consistency of outcomes across
different research definitions of ACO
Rationale
• Patients with an apparently mixed asthma–COPD
phenotype (ACO) have distinct characteristics of each
condition and characteristics common to both.
• Some of the differences in the pathophysiological
mechanisms present in asthma and COPD, may be
attributed to the differential involvement of the distal
airways.
• The distal airways may present a marker of likely ICS
therapy response clinical target to optimise outcomes
in patients with ACO
Outputs from the research
• Improve understanding: of the respective involvement of
distal airways across OLD conditions: asthma, COPD,
ACOS (and sub-categories of ACOS)
• Informing targeted management options: inform ICS
management decisions in patients with a mixed asthma-
COPD phenotype
• Research dissemination: Respiratory conference abstract
& open access peer review journal publication
Proposed methodology
Design: 2-year observational matched cohort study study: 1 baseline
year; an index date at which patients initiate or step-up ICS therapy; 1
outcome year
Population: ACO patients (i) Population A: initiating and (ii) Population
B: stepping up asthma maintenance therapy as extra-fine vs non extra-
fine ICS will be matched on key baseline characteristics (age, sex,
acute respiratory event rate, ICS dose and OLD diagnosis)
A priori subgroups: (i) asthma only; (ii) COPD; (iii) asthma+COPD;
repeat in different operationalisable definitions of ACO (defined by the
REG ACO Working Group)
Outcomes: database measures of OLD control, acute respiratory
events and OLD exacerbation rates.
ACO Research Concept (REG_P035)
Proposed by Nicolas Roche; May 2015

18. Other research ideas?

19. Setting priorities
• Are these projects still:
o Relevant?
o Feasible?
o Valid?
o A priority?
• How do we set priorities in small airways research?
• How to we ensure these priorities are pursued?
• What are the two most important projects to push forwards?

20. Child health
• A teleconference will be organised after ERS to discuss the work
of the child health working group

21. Any other business?