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

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

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

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

Published study R05312: Implications of ICS particle size on potential long-term asthma treatment-related side effects (e.g. metabolic and musculoskeletal comorbidities, pneumonia) Pneumonia results published in PloS one in June 2017 Retrospective cohort study using OPCRD 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.

Complete studies: REG-RES1318 Implications of ICS prescription duration on asthma outcomes Final report complete 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.

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

Active study update (1) REG-RES1509: Comparative effectiveness of guideline recommended treatment options for patients with pre-school asthma / wheeze 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.

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

Active study update (2) REG-RES1513: A systematic review of the comparative effectiveness literature considering extra-fine particle ICS with licensed alternatives Provisionally accepted by JACI 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.

Active study update (3) RP00113: Characterisation of current asthma management practice and asthma-related morbidity (State of the Union) 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 Manuscript under development Final analysis being reworked – note, numbers may therefore change

Active study update (4) REG_P006: Harmonizing the nomenclature for therapeutic aerosol particle size: A proposal 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. Under submission with J Aerosol Med Pulm Drug Del

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

Asthma state of treatment: asthma control and metabolic consequences (REG_RES1506) Working title 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 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   Proposed methodology Split out into more than one protocol? Overlap with other studies 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

Metabolic implications of particle size (REG_RES1512) Working title Rationale HEALTH CONSEQUENCES ASSOCIATED WITH CHOICE OF INHALED CORTICOSTEROID PARTICLE SIZE IN THE LONG-TERM MANAGEMENT OF OBSTRUCTIVE LUNG DISEASE 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 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.   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

Asthma & GERD ± Obesity Research Concept (REG_PO23) Working title Proposed methodology Implications of inhaled corticosteroid particle size in the management of asthma in patients excess weight/obesity and/or GERD 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. Objective Evaluate the comparative effectiveness of extra-fine and non extra- fine inhaled corticosteroid (ICS) treatment in patients with asthma and comorbid GERD ± obesity 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 by Nicolas Roche; May 2015

ACO Research Concept (REG_P035) Working title Proposed methodology Implications of inhaled corticosteroid particle size in the management of patients with a mixed asthma-COPD phenotype 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. Objective Evaluate the comparative effectiveness of extra-fine and non extra-fine inhaled corticosteroid treatment in patients with ACO (vs asthma vs COPD) Evaluate the consistency of outcomes across different research definitions of ACO Rationale Outputs from the research 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 Do we know enough about what ACO is? 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 by Nicolas Roche; May 2015

Other research ideas?

Setting priorities Are these projects still: Relevant? Feasible? Valid? 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? Lots of ideas, but how do we priortise?

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

Any other business?