Child Health Working Group and Small Airways Study Group Joint Meeting

SMALL AIRWAYS
& CHILD HEALTH
WORKING GROUP MEETING
DATE: Saturday September 3rd
TIME: 4.00–5.00pm
VENUE: Royal College of General Practitioners; 30 Euston
Square, London, UK

Agenda
16.00-16.05 Welcome / Introduction Omar Usmani
16.05–16.15 On-going publications
16.05–16.10 – Chest nomenclature commentary Liz Hillyer
16.10–16.20 – Systematic Review of the comparative Sam Sonnappa
16.20–16.35 Pre-school asthma wheeze Jonathan Grigg
16.35–16.50 New ideas for the group
• Ideas so far Omar Usmani
– Implications of ICS particle size on (on behalf of Nicolas Roche)
• GERD
• ACOS
– Other ideas / Discussion Group
16.50–17.00 Oscillometry – FOT study overview Ron Dandurand

ONGOING PUBLICATIONS
– CHEST PARTICLE SIZE NOMENCLATURE EDITORIAL
– SYSTEMATIC REVIEW OF THE ICS PARTICLE SIZE
COMPARATIVE EFFECTIVENESS EVIDENCE
16.05–16.20PM

Chest Commentary: Nomenclature Update:
Background
•  Need for consensus on aerosol particle nomenclature
•  Terms used in the published literature:
o  Extrafine, ultrafine, small vs. large, standard-size, coarse
•  ERS/ISAM Task Force Report (ERJ 2011) includes:
o  “Fine-particle dose” (FPD) = mass of drug consisting of
particles <5µm in aerodynamic diameter
o  Denotes Qvar and ciclesonide as being “extrafine.”
•  Hence our proposal, submitted to Chest last month:
o  “Extrafine” particle = MMAD <2µm
o  “Fine” particle = MMAD 2-5µm
o  “Coarse” particle = MMAD >5µm

Chest Commentary: Review 29Aug
Reviewer 1: favorable, two suggestions:
1.  Replace the Figure (schematic of lung deposition by particle
size) with a table summarizing evidence basis for nomenclature
proposal:
o  This could be added without deleting the figure.
2.  Add a proposal for use of the terms extrafine- and coarse-particle
fractions, in accordance with “fine-particle fraction”
o  Instead we could propose “extrafine-particle dose” and
“coarse-particle dose,” as per fine-particle dose (FPD)
o  The fine-particle fraction (FPF) is variable depending on how
it’s calculated (FPD/emitted dose vs. FPD/nominal metered
dose) & can be the same for two products with different
delivered doses even if the FPD differs

Chest Commentary: Review 29Aug
Reviewer 2: “…can’t agree with this simplistic
approach”
•  Seven comments, mostly missing the point of our
proposal: ie, it’s strictly about nomenclature.
•  His/her comments are focused on the point that there
are “too many other considerations (inhaler design,
formulation, inhalation pattern, lung disease) that
influence lung deposition”
•  We agree but want to avoid a literature review
•  Plan: address his/her points when possible and push
back when not possible

SYSTEMATIC REVIEW OF THE
COMPARATIVE EFFECTIVENESS LITERATURE
ON ICS PARTICLE SIZE
DR SAM SONNAPPA

Figure : PRISMA flowchart showing the step-by-step process of the application of
inclusion and exclusion criteria to generate the final number of studies included
in the meta-analysis
Literature Review

Figure : Forest plot showing pooled odds ratios (95% CI) for measures of asthma control
Results: Asthma Control

Figure: Forest plot showing pooled relative risk ratios (95% CI)
for measures of asthma exacerbations
Results: Exacerbations

Summary
•  Extra-fine ICS have significantly higher odds of
achieving asthma control with lower exacerbation rates
at significantly lower doses than fine particle ICS
•  There is even a potential to change ICS from fine
particle to extra-fine particle as a step-up therapy
before adding LABAs, which is currently not
recognised in asthma guidelines
•  Physicians must consider the potential benefits of
prescribing extra-fine formulations of ICS to asthmatics

PRE-SCHOOL ASTHMA / WHEEZE
JONATHAN GRIGG
16.20–16.35PM

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.

•  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

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

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)

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)

Outcomes/Endpoints
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 Endpoints:
•  Acute respiratory event
o  Hospital Admissions OR A&E attendance OR
o  Acute Oral Steroid Prescriptions
o  Antibiotic Prescriptions with LR complaint
•  Risk Domain Asthma Control
•  Overall Asthma Control (OAC)
•  Treatment stability

Outcome Definitions
Risk Domain Asthma Control
(RDAC)
Defined as absence of:
Controlled:
•  Asthma-related: Hospital admission AND A&E
attendance AND out-patient attendance; AND
•  Acute use of oral steroids; AND
•  Antibiotics prescribed with lower respiratory
consultation
Uncontrolled: all others
Treatment stability:
Stable:
•  Achieved Risk Domain Asthma Control; AND
•  No additional therapy defined as no:
•  Increased dose of ICS (≥50% increase
of that prescribed at index date) AND/
OR
•  Use of additional therapy as defined by:
long-acting bronchodilator (LABA),
theophylline, LTRAs
Unstable: all others
Overall Asthma Control
Defined as absence of:
Controlled:
•  RDAC (achievement/non-achievement); plus
•  Average daily dose of SABA ≤200mcg salbutamol
Uncontrolled: all others

Extrafine vs non-extrafine ICS
Treatment Group
P-value*
EF ICS (n=275) NEF ICS (n=1100)
Age (years)
mean (SD)
3.2 (1.2) 3.2 (1.2) NA
Gender, n(%)
female
89 (32.3) 356 (32.3) NA
Comorbidities
Diabetes 1 (0.4) 0 (0) 0.29
Rhinitis 10 (3.6) 41 (3.7) 0.69
Eczema 113 (41.1) 452 (41.1) NA
GERD 11 (4.0) 41 (3.7) 0.83
*conditional logistic regression
Matching criteria: Age, Gender, Index Date Year, Baseline Reliever,
Baseline exacerbations, Antibiotic prescriptions, Eczema

OUTCOME SUMMARY
BASELINE OUTCOMES
EF ICS (n=275) NEF ICS (n=1100) EF ICS (n=275) NEF ICS (n=1100)
Exacerbations
Mean (SD) 0.76 (0.88) 0.77 (0.93) 0.55 (0.85) 0.49 (0.83)
Yes (≥1), n(%) 142 (51.6) 568 (51.6) 99 (36.0) 366 (33.3)
P-value* NA 0.363
Lower respiratory
Hospitalisations
Mean (SD) 0.06 (0.26) 0.05 (0.28) 0.03 (0.16) 0.03 (0.17)
Yes (≥1), n(%) 14 (5.1) 47 (4.3) 7 (2.5)
P-Value* 0.546 0.789
Lower respiratory
A&E Attendances
Mean (SD) 0.02 (0.13) 0.02 (0.16) 0.01 (0.12) 0.02 (0.16)
Yes (≥1), n(%) 5 (1.8) 25 (2.2) 4 (1.4) 16 (1.2)
P-value* 0.643 0.712
Acute oral steroid
prescriptions
Mean (SD) 0.72 (0.88) 0.74 (0.95) 0.53 (0.83) 0.47 (0.83)
Yes (≥1), n(%) 135 (49.1) 535 (48.6) 94 (34.2) 350 (31.8)
P-value* 0.683 0.426
Lower respiratory
antibiotic
prescriptions
Mean (SD) 1.06 (1.29) 1.08 (1.31) 0.61 (1.07) 0.63 (1.0)
Yes (≥1), n(%) 152 (55.3) 608 (55.3) 100 (36.4) 416 (37.8)
P-value* NA 0.639
Acute Respiratory
Events
No, n(%) 133 (48.4) 532 (48.4) 176 (64.0) 734 (66.7)
Yes, n(%) 142 (51.6) 568 (51.6) 99 (36.0) 366 (33.3)
P-value* NA 0.363
Risk Domain Asthma
Control
Controlled, n(%) 68 (24.5) 272 (24.7) 128 (46.5) 523 (47.5)
Uncontrolled, n(%) 207 (75.3) 828 (75.3) 147 (53.5) 577 (52.5)
P-value* NA 0.755
Overall Asthma
Control
Controlled, n(%) 51 (18.3) 209 (17.6) 81 (29.5) 332 (30.2)
Uncontrolled, n(%) 183 (68.3) 709 (66.4) 65 (23.6) 279 (25.3)
Missing 41 (13.3) 182 (16.0) 129 (46.9) 489 (44.5)
P-value* NA 0.904
Treatment Stability
Stable, n (%) – – 115 (41.8) 451 (41.0)
Unstable, n (%) – – 118 (42.9) 439 (39.9)
Missing, n (%) – – 42 (15.3) 210 (19.1)
P-value* – 0.847
No significant differences to suggest
extrafine particle ICS offers benefit over
standard particle ICS

ICS (all) vs LTRA
Treatment Group
P-value*
LTRA (n=104) ICS (n=104)
Age (years)
mean (SD)
2.6 (1.1) 2.6 (1.1) NA
Gender, n(%)
female
41 (39.4) 41 (39.4) NA
Comorbidities
Diabetes 0 (0) 0 (0) NA
Rhinitis 6 (5.8) 7 (6.7) 0.782
Eczema 39 (37.5) 39 (37.5) NA
GERD 9 (8.7) 5 (4.8) 0.258
LTRA = 104
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records
LTRA pa,ent records

OUTCOME SUMMARY
BASELINE OUTCOMES
LTRA (n=104) ICS (n=104) LTRA (n=104) ICS (n=104)
Exacerbations
Mean (SD) 1.13 (1.0) 1.13 (1.0) 0.8 (1.1) 0.6 (0.9)
Yes (≥1), n(%) 75 (72.1) 75 (72.1) 47 (45.2) 41 (39.4)
P-value* NA 0.378
Lower respiratory
Hospitalisations
Mean (SD) 0.13 (0.4) 0.1 (0.3) 0 (0.2) 0.0 (0.2)
Yes (≥1), n(%) 12 (11.5) 7 (6.7) 4 (3.8) 1 (1.0)
P-Value* 0.232 0.215
Lower respiratory
A&E Attendances
Mean (SD) 0.1 (0.3) 0.0 (0.1) 0.0 (0.2) 0.0 (0.1)
Yes (≥1), n(%) 9 (8.7) 2 (1.9) 4 (3.8) 1 (1.0)
P-value* 0.05 0.215
Acute oral steroid
prescriptions
Mean (SD) 1.0 (1.0) 1.1 (1.0) 0.8 (1.1) 0.6 (0.9)
Yes (≥1), n(%) 69 (67.0) 72 (69.2) 44 (42.3) 40 (38.5)
P-value* 0.327 0.556
Lower respiratory
antibiotic
prescriptions
Mean (SD) 1.5 (1.6) 1.6 (1.6) 0.9 (1.2) 0.7 (0.9)
Yes (≥1), n(%) 74 (71.2) 74 (71.2) 49 (47.1) 48 (46.2)
P-value* NA 0.896
Acute Respiratory
Events
No, n(%) 15 (14.4) 15 (14.4) 36 (34.6) 41 (39.4)
Yes, n(%) 89 (85.6) 89 (85.6) 68 (65.4) 63 (60.6)
P-value* NA 0.485
Risk Domain Asthma
Control
Controlled, n(%) 15 (14.4) 15 (14.4) 36 (34.6) 41 (39.4)
Uncontrolled, n(%) 89 (85.6) 89 (85.6) 68 (65.4) 63 (60.6)
P-value* NA 0.485
Overall Asthma
Control
Controlled, n(%) 14 (13.5) 14 (13.5) 18 (17.3) 30 (28.8)
Uncontrolled, n(%) 84 (80.8) 81 (77.9) 28 (26.9) 30 (28.8)
Missing 6 (6.7) 9 (8.6) 58 (55.8) 44 (42.4)
P-value* NA 0.655
Treatment Stability
Stable, n (%) – – 36 (34.6) 38 (36.5)
Unstable, n (%) – – 68 (65.4) 52 (50.0)
Missing, n (%) – – 0 14 (13.5)
P-value* – 0.230
benefit of ICS versus LTRA

ICS (all) vs SABA
Treatment Group
P-value*
SABA (n=3960) ICS (n=990)
Age (years)
mean (SD)
3.19 (1.3) 3.19 (1.3) NA
Gender, n(%)
female
1552 (39.2) 388 (39.2) NA
Comorbidities
Diabetes 6 (0.2) 0 (0) 1.000
Rhinitis 170 (4.3) 36 (3.6) 0.351
Eczema 1488 (37.6) 372 (37.6) NA
GERD 149 (3.8) 36 (3.6) 0.850

OUTCOME SUMMARY
BASELINE OUTCOMES
SABA (n=3960) ICS (n=990) SABA (n=3960) ICS (n=990)
Exacerbations
Mean (SD) 0.50 (0.78) 0.53 (0.84) 0.41 (0.81) 0.42 (0.83)
Yes (≥1), n(%) 1420 (35.9) 335 (35.9) 1042 (26.3)
P-value* NA 0.378
Lower respiratory
Hospitalisations
Mean (SD) 0.05 (0.26) 0.05 (0.26) 0.02 (0.16) 0.02 (0.15)
Yes (≥1), n(%) 157 (4.0) 36 (3.7) 76 (1.9) 15 (1.5)
P-Value* 0.614 0.396
Lower respiratory
A&E Attendances
Mean (SD) 0.01 (0.13) 0.02 (0.15) 0.01 (0.11) 0.03 (0.2)
Yes (≥1), n(%) 52 (1.3) 13 (1.3) 39 (1.0) 21 (2.1)
P-value* 1.000 0.004
Acute oral steroid
prescriptions
Mean (SD) 0.46 (0.77) 0.50 (0.82) 0.40 (0.83) 0.40 (0.83)
Yes (≥1), n(%) 1303 (32.9) 334 (33.7) 987 (24.9) 259 (25.2)
P-value* 0.135 0.822
Lower respiratory
antibiotic
prescriptions
Mean (SD) 0.89 (1.21) 0.92 (1.27) 0.56 (1.00) 0.57 (1.00)
Yes (≥1), n(%) 1920 (48.5) 480 (48.5) 1370 (34.6) 344 (34.7)
P-value* NA 0.924
Acute Respiratory
Events
No, n(%) 1492 (37.7) 373 (37.7) 2099 (53.0) 523 (52.8)
Yes, n(%) 2468 (62.3) 617 (62.3) 1861 (47.0) 467 (47.2)
P-value* NA 0.915
Risk Domain Asthma
Control
Controlled, n(%) 1492 (37.7) 373 (37.7) 2099 (53.0) 523 (52.8)
Uncontrolled, n(%) 2468 (62.3) 617 (62.3) 1861 (47.0) 467 (47.2)
P-value* NA 0.915
Overall Asthma
Control
Controlled, n(%) 1,179 (29.8) 302 (30.5) 1054 (26.6) 338 (34.1)
Uncontrolled, n(%) 2516 (63.5) 631 (63.7) 2906 (73.4) 597 (60.3)
Missing 265 (6.7) 57 (5.8) 0 55 (5.6)
P-value* NA 0.043
Treatment Stability
Stable, n (%) – – 2052 (51.8) 448 (45.3)
Unstable, n (%) – – 1908 (48.2) 542 (54.7)
Missing, n (%) – – 0 0
P-value* – 0.317
Little significant differences to suggest
benefit of ICS versus SABA
– possible ICS benefit in terms of overall asthma control
– Difference in A&E attendances favours SABA

Treatment Group
P-value*
SABA (n=1036) LTRA (n=259)
Age (years)
mean (SD)
2.6 (1.2) 2.6 (1.2) NA
Gender, n(%)
female
364 (35.1) 91(35.1) NA
Comorbidities
Diabetes 3 (0.3) 0 (0) 1.000
Rhinitis 35 (3.4) 11 (4.3) 0.496
Eczema 388 (37.5) 97 (37.5) NA
GERD 59 (5.7) 24 (9.3) 0.038
LTRA vs SABA

OUTCOME SUMMARY
BASELINE OUTCOMES
SABA (n=1036) LTRA (n=259) SABA (n=1036) LTRA (n=259)
Exacerbations
Mean (SD) 0.72 (0.91) 0.90 (1.21) 0.53 (0.87) 0.71 (1.10)
Yes (≥1), n(%) 500 (48.3) 125 (48.3) 354 (34.2) 102 (39.4)
P-value* NA 0.097
Lower respiratory
Hospitalisations
Mean (SD) 0.08 (0.34) 0.12 (0.45) 0.04 (0.23) 0.04 (0.23)
Yes (≥1), n(%) 64 (6.2) 21 (8.1) 14 (1.4) 7 (2.7)
P-Value* 0.245 0.130
Lower respiratory
A&E Attendances
Mean (SD) 0.02 (0.17) 0.10 (0.41) 0.02 (0.14) 0.03 (0.22)
Yes (≥1), n(%) 20 (2.0) 19 (7.3) 14 (1.4) 7 (2.7)
P-value* <0.0001 0.130
Acute oral steroid
prescriptions
Mean (SD) 0.64 (0.88) 0.76 (1.09) 0.50 (0.86) 0.70 (1.14)
Yes (≥1), n(%) 454 (43.8) 112 (43.2) 333 (32.1) 95 (37.3)
P-value* 0.676 0.142
Lower respiratory
antibiotic
prescriptions
Mean (SD) 1.15 (1.34) 1.29 (1.53) 0.76 (1.12) 0.82 (1.28)
Yes (≥1), n(%) 616 (59.5) 154 (59.5) 464 (44.6) 112 (43.2)
P-value* NA 0.677
Acute Respiratory
Events
No, n(%) 264 (25.5) 66 (25.5) 430 (41.5) 105 (40.5)
Yes, n(%) 772 (74.5) 193 (74.5) 606 (58.5) 154 (59.5)
P-value* NA 0.767
Risk Domain Asthma
Control
Controlled, n(%) 264 (25.5) 66 (25.5) 430 (41.5) 105 (40.5)
Uncontrolled, n(%) 772 (74.5) 193 (74.5) 606 (58.5) 154 (59.5)
P-value* NA 0.767
Overall Asthma
Control
Controlled, n(%) 214 (20.7) 54 (20.9) 225 (21.7) 66 (25.4)
Uncontrolled, n(%) 822 (79.3) 192 (74.1) 811 (78.3) 169 (65.3)
Missing 0 (0) 13 (5.0) 0 24 (9.3)
P-value* NA 0.901
Treatment Stability
Stable, n (%) – – 412 (39.8) 104 (40.2)
Unstable, n (%) – – 624 (60.2) 155 (59.8)
Missing, n (%) – – 0 (0) 0 (0)
P-value* – 0.523
benefit of LTRA versus SABA

Explore interaction of switch to ICS (I)
•  50-60% of patients in SABA and LTRA arms
received ICS in the outcome year
•  Implications…?
•  Explore:
o  Time to treatment failure
–  Addition of new therapy (i.e. ICS) or ≥50% dose
increase in index date therapy
o  Time to first exacerbation

Time to first exacerbation
& treatment stability
OUTCOME SUMMARY
Time to First Exacerbation
(days)
Time to Treatment Failure
(days)
EF vs NEF ICS
(n=275 v n=1100)
Mean (SD) 61.0 (92.1) 70.2 (100.3) 115.0 (97.3) 129.8 (100.5)
P-value* 0.165 0.145
ICS vs SABA
(n=990 v n=3960)
Mean (SD) 62.7 (97.4) 60.4 (96.7) 128.4 (101.8) 110.0 (99.9)
P-value* 0.489 0.183
ICS vs LTRA
(n=104 v n=104)
Mean (SD) 87.2 (114.3) 83.9 (99.7) 134.8 (110.9) 107.7 (88.7)
P-value* 0.992 0.959
LTRA vs SABA
(n=259 v n=1036)
Mean (SD) 72.0 (97.4) 68.5 (96.9) 104.6 (93.7) 99.5 (94.5)
P-value* 0.594 0.046
No clinically meaningful differences seen
between any choice of treatment

Explore interaction of switch to ICS (II)
•  In the unmatched population, evaluate the change in
acute respiratory events between baseline and outcome
as a function of consumed ICS dose in the outcome year
(i.e. total mcg prescribed)
•  Other possible additional analyses to explore markers for
ICS response:
o  Explore whether there is any benefit in ICS treatment in
patients stratified by blood eosinophil threshold (<300 and ≥300)
o  Data available for ~9000 patients

Discussion
•  Key messages:
o  Robustly negative study
o  The study design works – proven in other age groups
o  The results reflect clinical practice observations and results from large trials:
–  Pre-school wheeze is a heterogeneous entity
–  Variable, often little, treatment response
o  There may be some subgroups of patients that are responding to therapy,
but there are no markers for potential response
o  New therapeutic modalities are required
o  In the absence of better tools to help target treatments, the data suggest a
"wait-and-see approach" in this pre-school population may be sound
•  Timeline:
o  Statistical adjustments & additional analyses: by October
o  Manuscript development over the autumn; submission by December

NEW RESEARCH IDEAS
INTERACTION OF ICS PARTICLE SIZE AND
– ASTHMA, EXCESS WEIGHT AND GERD
– ACOS
– OTHERS?
16.35–16.50PM

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
•  Apparent link between obesity and asthma
•  Positive correlation BMI and development of asthma.
•  GERD is a risk factor for asthma and shares common
pathophysiologic mechanisms that lead to worsening of
asthma symptoms, including mechanical effects and local
and systemic anti-inflammatory effects.
•  High BMI and GERD may impair asthma control through:
– Obeisty: 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
Proposed by Nicolas Roche; May 2015
Asthma, GERD, Obesity & extra-fine particle ICS
Therapeutic area(s)

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
Proposed by Nicolas Roche; May 2015 Asthma, COPD & extra-fine particle ICS
Therapeutic area(s)

OSCILLOMETRY – FOT STUDY
RON DANDURAND
16. 50–17.00PM

STANDARDIZATION OF FOT
RESULTS ACROSS ALL FIVE
COMMERCIALLY MARKETED
DEVICES
Ron Dandurand
16. 50–17.00PM

Background
•  Small airways are an important site of
pathophysiology in obstructive lung diseases.
•  Therapeutic targeting of the small airways is
desirable.
•  Easy bedside/clinic technique to evaluate the small
airways remains elusive.
•  FOT potentially, may fill this need.

Background
•  Small amplitude, subsonic, high frequency pressure
waves i.e. infrasound applied at the mouth.
•  Acoustic energy absorption estimates lung
mechanics.
•  Leverages infrasound’s frequency dependence of
lung penetration.
•  Localizes site of airflow limitation to small or large
airways.

FOT is Rhino Talk
20-20,000 Hz
300-3000 Hz 5-75 Hz
Infrasound receiver

5 Commercial Devices
tremoFlo iOS Quark i2m
MostGraph-02 Resmon Pro

McGill U Health Centre FOT Unit

McGill U Health Centre FOT Unit
McFOTU

Single Patient Data
iOS tremoFlo
R5 4.25 2.44
R5-19 or 20 0.87 0
X5 -1.20 -0.83
Fres 9.96 10.53
AX 2.20 2.29

Bland-Altman Matrix
i2m
MG
tF
iOS
RM i2m MG tF

Objectives
•  Establish magnitude of problem
•  Propose potential solutions
o  Data based devise specific software modifications
o  Modify choice of filtre/mouth piece used
•  Explore FOT based pharmacotherapy free of
confounding technical issues.

Proof-of-Concept (in progress)
•  30 pediatric patients
o  Asthma
o  BPD
o  Healthy Controls
•  3 FOT devises
o  iOS
o  tremoFlo
o  MostGraph-02
•  Data for power calculation of larger study
•  $20 K or 14 K euros

Potential Study
•  300-500 adult and pediatric patients
o  Asthma
o  COPD
o  BPD
o  Healthy Controls
•  5 FOT devises
o  iOS
o  tremoFlo
o  MostGraph-02
o  i2m
o  Resmon
•  Based on power calculation from proof-of-concept
•  $200 K or 140 K euros

Discussion
•  Questions
•  Study design suggestions
•  Potential sources of funding
•  Are other similar initiatives in progress?
rdandurand@videotron.ca

Child Health Working Group and Small Airways Study Group Joint Meeting

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