The document outlines a planned study comparing the effectiveness of extra-fine particle inhaled corticosteroids (ICS) to non-extra fine ICS, leukotriene receptor antagonists (LTRAs), and short-acting beta agonists (SABAs) as step-up therapy options for preschool children with asthma or wheezing. The study will use data from UK primary care records to conduct a descriptive analysis of treatment patterns and a comparative effectiveness analysis over 1-year and exploratory 5-year outcome periods. The goal is to test if extra-fine ICS achieve better outcomes than alternatives as a step

1. DATE: FRIDAY SEPTEMBER 25TH
VENUE: Wyndham Apollo Hotel, Amsterdam
ROOM: Boardroom
TIME: 17:00-18.30
CHAIR: Professor Doctor Richard J. Martin, Chairman,
Department of Medicine, National Jewish Health,
Denver, Colorado, USA
SMALL AIRWAYS STUDY
GROUP MEETING

2. SASG members
Lead: Richard Martin
• Akki Niimi
• Alan Kaplan
• Alberto Papi
• David Price
• Dirkje Postma
• Elliot Israel
• Emilio Pizzichini
• Hironori Sagara
• Jonathan Grigg
• Nicolas Roche
• Omar Usmani
• Ronald Dundurand
• Theresa Guilbert
• Wanda Phipatanakul
• Wim van Aalderen
Bold = confirmed attendance

3. Agenda

4. Meeting outcomes
• Bring everyone up to date on current:
o Publication status
o Funding status of new research ideas
• Agree:
o Authors & target journals for 3 planned papers
o Next steps for the preschool asthma study
o Study ideas to be submitted for prioritisation for
REG’s 2016 core research grants

5. A brief history

6. Small Airways Study Group:
Focus and rationale
• The group was established 7 years ago to explore the
implications of targeting the small airways on the management
of obstructive lung disease
• Initial focus on EF HFA-BDP; Qvar®: scope has since expanded
to consider:
o Treatment of small airways, in general
o All extrafine particle (mass median aerodynamic diameter
particle size of <2 microns) respiratory therapies
• SASG activities has now moved to sit under REG as one of the
working groups

7. SASG became an REG Working Group in 2014

8. Authors Title Reference
Postma DS, Roche N, Colice G, Israel E,
Martin RJ, van Aalderen WMC, Grigg J,
Burden A, Hillyer EV, von Ziegenweidt J,
Gopalan G, Price D
Comparing the effectiveness of small-particle
versus large-particle inhaled corticosteroid
in COPD
Int J COPD
2014;9:1163-1186.
Colice G, Martin RJ, Israel E, Roche N,
Barnes N, Burden A, Polos P, Dorinsky P,
Hillyer EV, Lee AJ, Chisholm A, von
Ziegenweidt J, Barion F, Price D.
Asthma outcomes and cost of therapy with
extrafine beclomethasone and fluticasone.
J Allergy Clin
Immunol.
2013;132:45-54.
Martin R, Price D, Roche N, Elliot Israel,
Willem MC van Aalderen, Jonathan Grigg,
Dirkje S Postma, Theresa W Guilbert,
Elizabeth V Hillyer, Anne Burden, Julie von
Ziegenweidt & Gene Colice
Cost-effectiveness of initiating extrafine- or
standard size-particle inhaled corticosteroid
for asthma in two health-care systems: a
retrospective matched cohort study
Respir Med. 2014;
24:14081
Price D, Thomas M, Haughney J, Lewis RA,
Burden A, von Ziegenweidt J, Chisholm A,
Hillyer EV, Corrigan CJ.
Real-life comparison of beclometasone
dipropionate as an extrafine- or larger-particle
formulation for asthma
Respir Med.
2013;107:987-1000
Barnes N, Price D, Colice G, Chisholm A,
Dorinsky P, Hillyer EV, Burden A, Lee AJ,
Martin RJ, Roche N, von Ziegenweidt J,
Israel E.
Asthma control with extrafine-particle
hydrofluoroalkane-beclometasone vs. large-
particle chlorofluorocarbon-beclometasone: a
real-world observational study
Clin Exp Allergy.
2011;41:1521-1532
Price D, Martin RJ, Barnes N, Dorinsky P,
Israel E, Roche N, Chisholm A, Hillyer EV,
Kemp L, Lee AJ, von Ziegenweidt J, Colice
G.
Prescribing practices and asthma control
with hydrofluoroalkane-beclomethasone and
fluticasone: a real-world observational study
J Allergy Clin
Immunol.
2010;126:511-518
e511-510.
SASG publications 2010-14

9. Authors Title Reference
Roche N, Postma DS, Colice G, et al.
Differential effects of inhaled corticosteroids in
smokers/ex-smokers and nonsmokers with
asthma
Am J Respir Crit Care
Med. 2015;191:960-4.
Israel E, Roche N, Martin RJ, et al
Increased dose of inhaled corticosteroid
versus add-on long-acting β-agonist for step-
up therapy in asthma.
Ann Am Thorac Soc.
2015;12:798-806.
van Aalderen WM, Grigg J, Guilbert TW,
et al.
Small-particle inhaled corticosteroid as first-line
or step-up controller therapy in childhood
asthma
J Allergy Clin Immunol
Pract. 2015;3:721-31.
SASG publications 2015

10. SASG Activities in Amsterdam
• Oral Abstract: Prescribed doses and effect on asthma
treatment outcomes of extrafine (ciclesonide) vs standard
particle inhaled corticosteroids (ICS)
o Presenter: Dirkje Postma
o When: Tuesday September 29th, 8:30-10:30
o Where: Room 5.1
• Poster Abstract: Dose-response effect of small particle vs
standard particle ICS on severe asthma exacerbations by
sex
o Presenter: Marjan Kerkhof
o When: Sunday 27th September, 12:50-14:40
o Where: Hall 14-32

11. Publications Update

12. Papers at/nearing submission (I)
• Real-life effectiveness of extrafine ciclesonide vs fine-particle
inhaled corticosteroids in a Dutch population
o Primary outcomes abstract at the 2015 ATS Conference:
– Presented by Dirkje Postma (primary outcomes)
o Secondary outcomes abstract at the 2015 ERS Conference:
– Dirkje Postma to present oral abstract on Tuesday September
29th, 8:30-10:30 (Room 5.1)
o Manuscript submitted to Allergy:
– Lead Author: Dirkje Postma
– Core Message: In this matched cohort analysis, initiation of ICS
with ciclesonide was associated with better 1-year asthma
outcomes and fewer changes to therapy, despite signs suggesting
difficult-to-control asthma, at one third of the prescribed dose than
with fine-particle ICS.
– History: Rejected in August from ERJ after one peer review

13. Papers at/nearing submission (II)
• Cost-effectiveness of asthma step-up therapy as an
increased dose of small-particle inhaled corticosteroid
or add-on long-acting beta2-agonist
o Rejected by PharmacoEconomics 26 August 2015 after one
peer review.
o Currently reformatting for resubmission to Value in Health.
• ICS or add-on long-acting β-agonist in combination or
separate inhaler as step-up therapy for patients with
uncontrolled asthma receiving ICS
o Draft is in author review.

14. Papers at/nearing submission (III)
• Real-world effectiveness of extrafine vs standard particle ICS:
PHARMO Dataset
o Oral abstract at 2015 REG Rotterdam Summit: Effectiveness of
initiating extra-fine vs standard particle inhaled corticosteroids (ICS)
as asthma therapy.
o Manuscript in preparation:
– Lead author: Thys van der Molen
– Target: BMC Pulmonary Medicine
– Core Message: At significantly lower prescribed doses, extrafine
ICS are associated with better odds of asthma control and
treatment stability than fine-particle ICS in matched patients
prescribed their first ICS.
– Timeline: Final approved version to be ready for journal
submission in early October.

15. Papers at/nearing submission (IV)
• Effect of spacer use in combination with small-particle and non-
small particle ICS in Asthma
o Abstract at the 2015 ATS Conference: Effectiveness of spacers for
the delivery of extra-fine particle (Qvar®) and standard sized
particle (Fluticasone Propionate) inhaled corticosteroid in patients
with asthma.
o Manuscript in preparation:
– Target: Chest
– Core Message: This matched cohort study found no evidence
that prescribing of spacer devices is associated with improved
asthma outcomes, either in terms of decreased exacerbations
or decreased incidence of oral candidiasis.
– Timeline: Manuscript undergoing internal review

16. Planned papers: Metabolic
Consequences of Particle Size
• Analysis complete; publication planning underway
• Extension study proposal developed under review with potential supporter
• Publication intention:
o Status: to be published; funding being confirmed
o Intended format: full manuscript
o Timeline: in manuscript planning phase
o Key message: At the ICS doses consumed in real life, patients
prescribed extrafine-particle ICS, compared with patients prescribed fine-
particle ICS:
– Are less likely to be coded for pneumonia; and
– Record significantly lower relative rates of exacerbations and acute respiratory
events
o Target journal: for discussion in Amsterdam
o Lead author: looking for volunteers…

17. • ATS Abstract (poster):
o Dose-response effect of small-particle versus
standard size particle formulations of inhaled
corticosteroids on severe asthma exacerbations.
Planned papers: Dose Response (I)
• ERS Abstract (poster):
o Dose-response effect of
small particle vs standard
size particle inhaled
corticosteroids on severe
asthma exacerbations by
sex.
Being presented by: Marjan Kerkhof, Sunday 27th September
(12:50-14:40; Hall 14-32)

18. • Publication intention:
o Status: to be published; funding being confirmed
o Intended format: short report
o Timeline: in manuscript planning phase
o Key message: Increasing doses of extrafine-particle inhaled
corticosteroids were associated with a greater decrease in
the severe exacerbation rate compared with increasing
doses of fine-particle inhaled corticosteroids in adult patients
with asthma receiving a first prescription for ICS.
o Target journal: for discussion in Amsterdam
o Lead author: looking for volunteers…
Planned papers: Dose Response (II)

19. • Real world effectiveness of ciclesonide vs fine-
particle inhaled corticosteroids in a Dutch
population
o Additional analysis: Comparison between exact
matching and propensity score approaches. “Dose-
response effect of small particle vs standard size particle
inhaled corticosteroids on severe asthma exacerbations
by sex.
– Manuscript plan for discussion
Planned papers: Dutch database
& comparison of matching

20. Planned papers: Matching Approaches
Summary of Study Aims / Design
• Four methods of using the propensity score (PS) were applied
to the ciclesonide dataset and compared with exact matching:
o PS matching (PSM), using 2 algorithms: RiRL and Greedy
algorithms
o Inverse Probability of Treatment Weighting (IPTW)
o Stratification by PS
o Covariate adjustment using PS

21. Results Summary:
• Method of matching did not affect overall result
• Stratification by PS is not a suitable method where exacerbation rate is the primary
endpoint.
• The most suitable for the study aims and data available should be selected.
• Exact matching is a powerful method to create similar groups of patients to be
compared, but in this study differences remained in potentially key variables
(especially evidence of GERD) after exact matching.
o Matching on this variable may have helped to reduce residual unmeasured
biases.
Conclusion:
• Propensity score matching should be used in future studies to inform choice of exact
matching criteria as a very powerful strategy to improve the performance of the exact
matching method and minimise biases from treatment assignment.
• Standardised differences should be used, in conjunction with statistical testing, to
assess the balance of treatment groups at baseline.
Planned papers: Matching Approaches

22. Planned papers: Matching Approaches
Publication Plan:
• Target journal: Eur J Epidemiol
• Intended format: Full manuscript
• Lead author: Nicolas Roche
• Key message: We suggest the PS should be used in
future studies to inform choice of exact matching criteria
as a very powerful strategy to improve the performance
of the exact matching method and minimise biases from
treatment assignment. In addition standardised
differences should be used, in conjunction with statistical
testing, to assess the balance of treatment groups at
baseline

23. • The consensus was to use extrafine vs. fine:
o “Fine”: for ICS with particle MMAD <5 microns but ≥2 microns
(thus FP/non-extrafine BDP etc.)
o “Extrafine”: for ICS with particle MMAD <2 microns (thus Qvar
and ciclesonide)
• The cut-point of 2 microns has been questioned and needs
further research
o Consider slightly higher cut-point (2.5?) as per alveolar deposition
curve (see next slide)
• The cut-point may be somewhat arbitrary
• Include ICS & all inhaled particles
• Outline draft scheduled for mid-October
Invited: ERJ Terminology Editorial

24. Possible figure from ERS/ISAM
Taskforce Report

25. Anjan Nibber: Researcher at Research in Real Life,
on behalf of REG
Comparative effectiveness of extra-fine particle ICS
and alternative guideline-recommended step-up
options in pre-school children

26. Background / Rationale
• The particle size (and delivery characteristics of EF HFA BDP)
of the aerosol may be particularly relevant for young children
in whom a greater proportion of airways are classified as
small (i.e. <2mm in diameter)1 and airways resistance is low
• There is evidence to suggest that EF HFA BDP is equivalent
to CFC-FP in terms of efficacy and safety in adults and
children (5–12 years) with mild-to-moderate asthma2,3
• Evidence remains lacking as to the role that ICS particle size
may play in the management of asthma/wheeze in younger,
pre-school (<5 years) children
1. Leach CL, et al. Eur Respir J. 1998;12:1346–1353.
2. Aubier M, et al. Respir Med. 2001;95:212–220.
3. Fairfax A, et al. Ann Allergy Asthma Immunol. 2001;86:575–582.

27. • To test the hypothesis that use of EF ICS in pre-school children with
asthma/wheeze will achieve better outcomes than treatment
alternatives (i.e. NEF ICS, LTRA, or SABA)
Study Objectives
• Phase I: a descriptive analysis of treatment patterns in children aged ≤5 years with
wheezing illness
• Phase II: a comparative effectiveness evaluation of guideline-recommended treatment
options in pre-school children newly initiating Step 2 therapy NEF ICS vs EF ICS and
LTRA vs EF ICS over a 1-year outcome period
• Exploratory analysis: an extension of the primary analysis over a 5-year outcome
period to explore whether EF ICS may offer potential disease-modifying effects
compared with alternative treatment options when used in the management of early-life
wheezing illness
Study Phases

28. Data Source
• The UK’s Optimum Patient Care Research Database
(OPCRD)
• Fully anonymised UK primary care data
• Historical medical records for:
o >2.2 million patients, from
o >550 primary care practices across the UK
• Ethical approval for medical research

29. Study Design
Index Date:
Date SABA (control
arm) or of first Step 2
asthma / wheeze
prescription
Baseline year:
12-months prior to index date for Phase I
analysis (mapping prescribing patterns)
and for patient characterisation and
confounder definition
Exploratory 5-year outcome period
Primary 1-year outcome period
REFERENCE ARM
EF ICS
i.e. EF HFA BDP or ciclesonide via pMDI
LTRA
Eligible patients must:
• Have diagnostic evidence of asthma /
wheeze
• be aged ≤5 years
NEF ICS
i.e. FP or NEF BDP via pMDI
Control: SABA
• Index date: date at which patients received their first prescription of ICS via pMDI or
LTRA, or (for the control arm) a repeat prescription for SABA
• Baseline: 1 year before ID
• Outcome: 1 year after ID (and 5-years after ID for exploratory analysis)

30. Inclusion Criteria
• Age: ≤5 years of age at the index date
• Evidence of pre-school wheeze or asthma during the baseline year – defined as either:
o ≥2 wheezing episodes recorded within their primary care records in the baseline year, or
o ≥2 prescriptions (at two different points in time) during the baseline year for any
combination of oral steroids coded for a lower respiratory complaint ± salbutamol
• Active treatment during outcome year:
o Active treatment arms (Step 2 therapy): ≥2 prescriptions (i.e. ≥1 in addition to that
prescribed at index date) for any of the Step 2 treatment options (i.e. any ICS via pMDI or
LTRA)
o Control arm: ≥2 prescriptions for SABA
o Exploratory 5-year outcome analysis: ≥1 prescription of the index date therapy in each of
the outcome years
• At least 2 year’s continuous records: ≥1 year’s continuous baseline records and ≥1 year’s
outcome records
o Eligibility for the exploratory analysis ≥5-years’outcome data
Study Population
Exclusion Criteria
• Have a clinical diagnosis for any chronic respiratory disease, except wheeze or asthma
• Received a combination inhaler in addition to a separate ICS inhaler in baseline;
• Multiple step-up therapies on the same day
• Infants: any child under the age of 1 year (as ≥1 year of baseline data is required)

31. Outcomes
Primary Endpoint:
• Exacerbations (ATS/ERS definition) defined as occurrence of an:
o Asthma-related: Hospital admissions OR A&E attendance; OR
o An acute course of oral steroids (coded for asthma or wheeze)
Secondary Endpoint:
• Acute respiratory event
• Risk Domain Asthma Control
• Overall Asthma Control (OAC)
• Treatment stability
• SABA Usage
• Controller-to-reliever ratio
• Oral Thrush

32. Interaction & exploratory analyses
Interaction Analysis:
• Atopic history
• Gender
• Index date coding
• Maternal smoking
• Age
• Disease severity
• Components of the Asthma Predictive Index (API) before the age of 3
o A study-generated composite of factors associated with persistent
wheeze at 6yrs
Exploratory analyses: 5-year outcome period to evaluate potential
disease-modifying effects of small-particle ICS in early childhood.

33. Baseline Descriptive Analysis

34. Final Cohort
n=47528
Patients excluded
*No prescriptions for ICS,
LTRA or combo in baseline
Patient Selection from OPCRD:
OPCRD Patients –
Initiated on ICS or
LTRA & Age: ≤5
years
n=84848
Valid period
n=51627
Evidence of pre-
school wheeze or
asthma
n=15066
No other chronic
respiratory disease
n=15060
Single step up
therapy
n=14646
Patients received
≥2 therapy scripts
n=11664
OPCRD Patients
–Initiated on
SABA & Age: ≤5
years
n=604566
Valid period
n=409267
On Step 1*
n=169959
Evidence of pre-
school wheeze
or asthma
n=48323
No other chronic
respiratory
disease
n=48317
No step-up
therapy
n=48317
Patients
received ≥2
therapy scripts
n=35864
n=33221
n=36561
n=6
n=414
n=2982
n=195299
n=360944
n=115636
n=6
n=6194
n=6259

35. Descriptive Analysis: Sample Size
Full Cohort
Treatment Group
NEF ICS EF ICS LTRA SABA
n (%) 47529 (100)
10972
(23.84) 357 (0.75) 335 (0.70) 35864 (75.45)
Full Cohort
(n=47528)
ICS
(n=11329)
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
Given at IPD

36. Descriptive Analysis: Demographics
Full Cohort
(n=47528)
Treatment Group
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
p-value*
Age
categorised
1-year n(%) 4198 (8.83) 962 (8.77) 32(8.96) 73(21.79) 3131(8.73)
<0.0001
2-year n(%) 10622 (22.35) 2564 (23.37) 90(25.21) 121(36.12) 7832(21.84)
3-year n(%) 11521 (24.24) 2804 (25.56) 83(23.25) 64(19.10) 8656(24.14)
4-year n(%)
11429 (24.05) 2600 (23.70) 81(22.69) 48(14.32) 8693(24.24)
5-year n(%)
9758 (20.53) 2042 (18.61) 71(19.89) 29(8.65) 7643(21.31)
Gender, n
(% male)
29906 (62.92) 6793 (61.91) 238(66.67) 213(63.58) 22662(63.19) 0.094
*Chi Square

37. Descriptive Analysis: Comorbidities
Evidence of comorbidities
(in study period), n (%)
Full Cohort
(n=47528)
Treatment Group
p-value*
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
Other Chronic Respiratory
Diseases
0 0 0 0 0 NA
Diabetes 148 (0.31) 10 (0.09) 0 0 138 (0.40) <0.0001
Rhinitis 1991 (4.19) 456 (4.16) 13 (3.64) 15 (4.47) 1507 (4.20) 0.431
Eczema 7365 (15.50) 1819 (16.58) 60 (16.81) 66 (19.70) 5420 (9.50)
<0.0001
*Chi Square

38. Descriptive Analysis: Asthma Consultations
Baseline Asthma
Consultations
Full Cohort
(n=47529)
Treatment Group
p-value*
NEF ICS
(n=10793)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
0 27703 (58.29 4647 (42.35) 169 (47.34) 178 (53.13) 22709 (63.32)
<0.0001
1-5 19058 (40.10) 6073 (55.35) 185 (51.82) 150 (44.77) 12643 (35.25)
6-10 638 (1.34) 213 (1.94) 2 (0.56) 6 (1.80) 424 (1.18)
11-15 93 (0.20) 28 (0.26) 1 (0.28) 0 64 (0.2)
16-20 30 (0.06) 10 (0.09) 0 0 20 (0.05)
21-25 3 (0.01) 1 (0.01) 0 0 2 (0)
26-30 3 (0.01) 0 0 1 (0.30) 2 (0)
*Chi Square

39. Descriptive Analysis: Asthma Exacerbations
and Antibiotics
Baseline Asthma
Exacerbations*
Full Cohort
(n= 47528)
Treatment Group
p-value **
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
YES n (%) 27745 (58.38) 7600 (69.27) 255 (71.42) 256 (76.42) 19634 (54.75)
<0.0001NO n (%) 19783 (41.62) 3372 (30.73) 102 (28.57) 79 (23.58) 16230 (45.25)
Mean (SD),
Median (IQR)
1.96 (1.18)
2 (11, 1)
2.02 (1.68)
2 (8, 1)
1.48 (1.42)
1 (7,1)
2.35 (1.40),
2 (7,1)
1.93 (1.18),
2 (11,1)
*Count of exacerbation events (acute oral steroids, antibiotics with respiratory event, emergency and inpatient respiratory
admissions). Events within 2 weeks are assumed to be the same exacerbation
**Chi Square
Baseline Antibiotic
Courses*
Full Cohort
(n= 47528)
Treatment Group
p-value **
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
YES n (%) 26526 (55.81) 5629 (51.30) 196 (54.90) 197 (58.81) 20504 (57.17)
<0.0001
NO n (%) 21002 (44.19) 5343 (48.70) 161 (45.10) 138 (41.19) 15360 (42.83)
*Antibiotics courses in baseline with evidence of a lower respiratory event
**Chi Square

40. Descriptive Analysis: Baseline Drugs
Drug
Total
(n=47528)
Treatment Group
p-value*
NEF ICS
(n=10793)
EF ICS (n=357)
LTRA
(n=335)
SABA
(n=35864)
SABA
YES n (%) 44798 (94.25) 9588 (87.39) 317 (88.80) 290 (86.57) 34603 (96.48)
<0.001
NO n (%) 2730 (5.75) 1384 (12.61) 40 (11.20) 45 (13.43) 1261 (3.52)
SAMA
YES n (%) 2970 (6.25) 751 (6.84) 24 (6.72) 32 (9.55) 2163 (6.03)
< 0.001
NO n (%) 44558 (93.75) 10221 (93.16) 333 (93.28) 303 (90.45) 33701 (93.97)
LAMA
YES n (%) 0 0 0 0 0
NA
NO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)
LABA
YES n (%) 79 (0.17) 17 (0.15) 0 0 62 (0.17)
0.975
NO n (%) 47449 (99.83) 10955 (99.85) 744 (100) 335 (100) 35802 (99.83)
ICS
YES n (%) 0 0 0 0 0
NA
NO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)
LTRA
YES n (%) 0 0 0 0 0
NA
NO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)
THEO
YES n (%) 224 (0.47) 41 (0.37) 1 (0.28) 0 182 (0.51)
0.923
NO n (%) 47304 (99.53) 10931 (99.63) 356 (99.72) 335 (100) 35682 (99.49)
*Chi Square

41. Descriptive Analysis: Baseline Drugs
Treatment Group
NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
p-value*
None 604 (5.50) 16 (4.48) 13 (3.88) 1101 (3.07)
<0.001
SABA 9588 (87.39) 317 (88.80) 290 (85.57) 32541 (90.73)
SAAC 70 (0.64) 0 3 (0.90) 151 (0.42)
SAAC+SABA 681 (6.21) 24 (6.72) 29 (8.66) 2000 (5.58)
LABA+/-SAAC+/-
SABA
17 (0.15) 0 0 62 (0.17)
Other 12 (0.11) 0 0 9 (0.03)
*Chi Square
Baseline SABA Daily
Dose (mcg)
Treatment Group
p-value*NEF ICS
(n=10972)
EF ICS
(n=357)
LTRA
(n=335)
SABA
(n=35864)
Sample Size (n)
(% Non-missing)
9588 (87.39) 317 (88.80) 290 (85.57) 32541 (90.73)
<0.0001
Mean (SD) 0.77 (0.60) 0.73 (0.55) 0.74 (0.55) 1.15 (0.98)
Median (IQR) 0.55 (7.12, 0.15) 0.55 (3.29, 0.27)
0.55 (2.47,
0.27)
0.82 (12.02, 0.11)
Range:
Minimum
Maximum
0.07
10.96
0.27
3.83
0.27
3.48
0.05
14.21

42. Descriptive Analysis: IPD Drugs
Drug
Full Cohort
(n=47528)
Treatment Group
p-value*
NEF ICS
(n=10972)
EF ICS (n=357)
LTRA
(n=335)
SABA
(n=35864)
SABA
YES n (%) 40710 (85.65) 4638 (42.27) 130 (36.41) 78 (23.28) 35864 (100)
<0.001
NO n (%) 6818 (14.35) 6334 (57.73) 227 (63.59) 257 (76.72) 0
SAMA
YES n (%) 724 (1.52) 77 (0.70) 4 (1.12) 4 (1.19) 639 (1.78)
<0.001
NO n (%) 46504 (97.85) 10895 (99.30) 353 (98.88) 331 (98.81) 35225 (98.22)
LAMA
YES n (%) 0 0 0 0 0
NA
NO n (%) 47528 (100) 10972 (100) 357 (100) 335 (100) 35864 (100)
LABA
YES n (%) 66 (0.14) 23 (0.21) 0 0 43 (0.12)
0.064
NO n (%) 47462 (99.86) 10949 (99.79) 357 (100) 335 (100) 35821 (99.88)
ICS
YES n (%) 11149 (23.46) 10972 (100) 357 (100) 0 0
<0.001
NO n (%) 36379 (76.54) 0 0 335 (100) 35864 (100)
LTRA
YES n (%) 335 (0.70) 0 0 335 (100) 0
<0.001
NO n (%) 47193 (99.30) 10972 (100) 357 (100) 0 35864 (100)
THEO
YES n (%) 44 (0.09) 2 (0.02) 0 0 42 (0.12)
0.019
NO n (%) 47484 (99.91) 10970 (99.98) 357 (100) 335 (100) 35822 (99.88)
*Chi Square

43. Descriptive Analysis: Patients on ICS
*Chi Square
ICS Cohort
n (%)
EF ICS 357 (3.16)
NEF ICS 10972 (96.84)
Drug Substance
Beclometasone Fluticasone Mometasone Budesonide Ciclesonide p value*
EF ICS
(n=357)
357 (47.98) 0 0 0 0
<0.001
NEF ICS
(n=10972)
9861 (89.87) 519 (4.73) 2 (0.02) 590 (5.38) 0
Mean Drug Dose (mcg) at
IPD (SD, Median, Range)
p value*
EF ICS
181.06 (141.37, 137, 27.4-
1311.5)
0.504
NEF ICS
186.26 (153.83, 137, 16.4-
3304.9)
• 744 patients (6.52%) were started on EF ICS at IPD
*Mann-Whitney U test

44. Next Steps
• Investigate spacer and device use
• Discuss number of patients in each treatment groups
• Patient matching: based on demographics and baseline treatments
• Phase II: a comparative effectiveness evaluation of NEF ICS vs EF ICS
and LTRA vs EF ICS over a 1-year outcome period
• Exploratory analysis: an extension of the primary analysis over a 5-
year outcome period to explore whether EF ICS may offer potential
disease-modifying effects compared with alternative treatment options
when used in the management of early-life wheezing illness

45. Thao Le: REG Supporter Liaison
Future funding update

46. New study idea updates (I)
• Systematic review and meta-analysis of the real-life
effectiveness evidence for extra-fine vs standard
particle ICS
• Motivation: responding to a meta-analysis of RCTs
looking at the impact of particle size on efficacy1 – the
findings conflicted
• PI: Dirkje Postma
• Funding: multiple funders sought to maximise impact
• Update: one funder confirmed; second funder at
advanced stage discussions
1. Suarez E, et al. Effect of inhaled corticosteroid (ICS) particle size on asthma
efficacy and safety outcomes: A systematic literature review. Presented at the British
Thoracic Society (BTS) Winter Meeting, London, England, 3–5 December 2014

47. • Systematic review and meta-analysis of the effect of ICS
particle size on asthma efficacy and safety presented the
2014 Winter BTS concluded:1
o There are no overall differences in efficacy and no
appreciable differences in safety between FP-containing
medications and small particle size ICS medications for
the treatment of asthma.
o ICS-containing medications with a small particle size do
not confer additional clinical benefits over those with a
standard particle size.
• These conclusions conflict with (some of) the published
literature, including the SASG’s real-life studies
1. Suarez E, et al. Effect of inhaled corticosteroid (ICS) particle size on asthma efficacy and
safety outcomes: A systematic literature review. Presented at the British Thoracic Society
(BTS) Winter Meeting, London, England, 3–5 December 2014
Concept & Background

48. Effect
‘efficacy’ Safety
High ‘internal’ validity feasible in
clear-cut trial populations
APPROVAL
Real ‘external’ validity
& generalisability by mirroring
real populations and healthcare practices
Medicines won’t work if people
can’t or don’t take them
Needs of Regulators
Effectiveness/
Outcomes
Device
‘to train, or not
to train?’
Adherence
CAN IT WORK IN AN
IDEAL POPULATION
OPTIMALLY MANAGED?
DOES IT WORK IN REAL PATIENTS
MANAGED IN ROUTINE CARE
SETTINGS?
Needs of Patients, Physicians, Payers
Efficacy vs Effectiveness

49. • Studies have shown
that efficacy RCTs
exclude about 95%
of asthma and 90%
of COPD routine
care populations due
to strict inclusion
criteria.1
1. Herland K, et al. Respir
Med 2005;99:11–19.
Limitations: RCTs inclusions/exclusions
0
200
400
600
800
1000
Numberofsubjects
Patient RCT eligibility drop-off with sequential
application of standard inclusion criteria
All pat VAS <2.5 FEV 50-80% Historical Rev 12%
No Co-morbidity Packy <10 Regular 1CS Symptoms
100.0%
38.4%
14.3%
5.7% 3.7% 2.1% 1.7% 1.3%
COPD
0
200
400
600
800
1000
Numberofsubjects
All pat VAS >7.5 No Co-morbidity FEV1 30-70
S or XS Packy > 15 No Hayfever
100.0%
42.1%
15.2%
10.1% 9.2% 8.2% 7.2%
Asthma

50. What sort of evidence do we have …?Population
Broad
Narrow
Ecology of care
FreeConstrained
Highly controlled Pragmatically
controlled
Observational
Managed
as...
Clinical
diagnosis
Confirmed
diagnosis
Registration RCTs
Long term
phase III
Pragmatic RCTs
Observational
studies
Roche N, Price D et. al 2013 Lancet Respir Med; 1(10):e29-30
Different sources of evidence; different questions…

51. Improving guidelines: evidence appraisal
• Sir Michael Rawlins, the former chairman of the UK’s
National Institute for Health and Care Excellence:1
o Hierarchies of evidence are over-simplistic and offer a
pseudoquantitative assessment of the available
evidence.
o All forms of evidence should be considered, while taking
into account the limitations and strengths of their
respective designs
o Differently designed studies should be considered as
complementary and should be used in combination by
guideline developers to help inform their judgments and
recommendations.
1. Rawlins M. De testimonio: on the evidence for decisions about the use of therapeutic
interventions. Lancet 2008;372:2152–2161.
Different research questions
need different research
approaches to answer them

52. Systematic review: Aims & Objectives
• Aim, to:
o Summarise the comparative effectiveness of ICS
medications of different particle sizes as assessed in
real-life studies
o Compare real-life effectiveness and safety outcomes
to the RCT systematic review of the efficacy and safety
outcomes.
o Identify key similarities / differences between the
real-life and RCT evidence
o Consider apparent conflicts in the context of the original
research question asked

53. Systematic review: design / approach
• Literature review – CER literature from the last sixteen years
(1 January 1998 to 13 February 2014)* focussing on:
o Fluticasone propionate vs EF particle ICS and fine particle
ICS (HFA BDP or ciclesonide)
o FP/SAL vs. ICS small particle size combination
comparators (HFA BDP or BDP/FOR HFA)
• Meta-analysis endpoints – consider:
o Efficacy & safety points used in the RCT review (if/where
available)
o Effectiveness measures: exacerbations; MPR, OCS
prescriptions, asthma consults, LRTI abx
*As per RCT review/meta-analysis & extended ~current date

54. New study idea updates (II)
• Health consequences associated with choice of inhaled
corticosteroid particle size in the long-term management of
obstructive lung disease
• Motivation: build on prior metabolic study
• High-level summary: Long-term effects of ICS particle size – focus on:
o Metabolic effects, also consider:
– Pneumonia
– Acute respiratory events
– Osteoporosis-related risks
– Cardiovascular
– Obesity
o Subgroup analysis by diagnosis: Asthma, COPD, ACOS
• PI: David Price
• Funding: under consideration by one funder

55. Alison Chisholm & Group Discussion/Decision
REG Core Funding Submissions

56. REG Support & Research Funding
RESEARCH IDEA
GENERATION
Working Groups
Identify Research
Priorities in their
respective fields of
expertise
SECURING FUNDING
Nature of funding dictates future study course:
• Single commercial funding source: an investigator
initiated study conducted external to REG
• Non-product/brand specific grant(s): an REG
Collaboration carried by REG or in partnership with
REG
REG
Supporters
Non-supporter
& wider
institutional
grants
OR
REG develops
idea in
collaboration
with WG
&
seeks dedicated
research grant
REG Grants
awarded
at start of FY16/17
REG Core Grants
Awarded to Top
Priority Ideas
(subject to
available funding)
31 October Core
Grant submission
deadline
Ideas prioritised
by REG
Research
Committee
by
31 Dec 2015
If insufficient REG Funds, continue to look externally

57. Studies under review by possible funders
• Systematic review and meta-analysis of the real-life
effectiveness evidence for extra-fine vs standard particle ICS
• Health consequences associated with choice of inhaled
corticosteroid particle size in the long-term management of
obstructive lung disease
o Focus on metabolic effects, also consider:
– Pneumonia
– Acute respiratory events
– Osteoporosis-related risks
– Cardiovascular
– Obesity
o Subgroup analysis by diagnosis: Asthma, COPD, ACOS

58. Interaction of particle size and excess
weight/obesity and GERD
• Hypothesis
o The mechanisms by which high BMI and GERD impair asthma
control could involve increased distal airway inflammation
o Differential effect of EF and standard-size ICS may help
exploring this involvement of small airways.
• Objectives
1. Evaluate the comparative effectiveness of EF and NEF ICS in
asthma patients ± GERD ± overweight/obesity
2. Determine the relationship between overweight/obesity and
GERD as determinants of
poor asthma control

59. Differential role of ICS particle size
in ACOS management
• Hypothesis
o The mechanisms by which high BMI and GERD impair asthma
control could involve increased distal airway inflammation
o Differential effect of EF and standard-size ICS may help
exploring this involvement of small airways.
• Objectives
1. Evaluate the comparative effectiveness of EF and NEF ICS in
asthma patients ± GERD ± overweight/obesity
2. Determine the relationship between overweight/obesity and
GERD as determinants of
poor asthma control