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

MATCHED RESULTS SUMMARY

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


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 *conditional logistic regression

No significant differences to suggest extrafine particle ICS offers benefit over

standard particle ICS

ICS (all) vs LTRA


LTRA (n=104) ICS (n=104)

Age (years) mean (SD) 2.6 (1.1) 2.6 (1.1) 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

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

LTRApa,entrecords

OUTCOME SUMMARY BASELINE OUTCOMES LTRA (n=104) ICS (n=104) LTRA (n=104) ICS (n=104)


Yes (≥1), n(%) 75 (72.1) 75 (72.1) 47 (45.2) 41 (39.4) P-value* NA 0.378


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


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


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





P-value* NA 0.485



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)


No significant differences to suggest benefit of ICS versus LTRA

ICS (all) vs SABA


SABA (n=3960) ICS (n=990)

Age (years) mean (SD) 3.19 (1.3) 3.19 (1.3) 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)


Yes (≥1), n(%) 1420 (35.9) 335 (35.9) 1042 (26.3) P-value* NA 0.378


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


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


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)



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





P-value* NA 0.915


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


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


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)


Yes (≥1), n(%) 500 (48.3) 125 (48.3) 354 (34.2) 102 (39.4) P-value* NA 0.097


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


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


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)



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





P-value* NA 0.767



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)


No significant differences to suggest benefit of LTRA versus SABA

ADDITIONAL ANALYSES

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

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

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

20-20,000Hz300-3000Hz 5-75Hz

Infrasoundreceiver

5 Commercial Devices

tremoFloiOSQuarki2m

MostGraph-02ResmonPro

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

Single Patient Data


Single Patient Data


Multi-Patient Data

Bland-Altman Matrix

i2m

MG

tF

iOS

RM i2m MG tF

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?

[email protected]

Health & Medicine

Child Health Working Group and Small Airways Study Group Joint Meeting