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Child Health Working Group and Small Airways Study Group Joint Meeting

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Slides from meeting of Respiratory Effectiveness Group Child Health Working Group and Small Airways Study Group joint meeting, held in London during ERS 2016 Congress

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Child Health Working Group and Small Airways Study Group Joint Meeting

  1. 1. 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
  2. 2. 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
  3. 3. ONGOING PUBLICATIONS – CHEST PARTICLE SIZE NOMENCLATURE EDITORIAL – SYSTEMATIC REVIEW OF THE ICS PARTICLE SIZE COMPARATIVE EFFECTIVENESS EVIDENCE 16.05–16.20PM
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. SYSTEMATIC REVIEW OF THE COMPARATIVE EFFECTIVENESS LITERATURE ON ICS PARTICLE SIZE DR SAM SONNAPPA
  8. 8. 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
  9. 9. Figure : Forest plot showing pooled odds ratios (95% CI) for measures of asthma control Results: Asthma Control
  10. 10. Figure: Forest plot showing pooled relative risk ratios (95% CI) for measures of asthma exacerbations Results: Exacerbations
  11. 11. 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
  12. 12. PRE-SCHOOL ASTHMA / WHEEZE JONATHAN GRIGG 16.20–16.35PM
  13. 13. 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.
  14. 14. •  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
  15. 15. 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
  16. 16. 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)
  17. 17. 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)
  18. 18. 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
  19. 19. 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
  20. 20. MATCHED RESULTS SUMMARY
  21. 21. 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
  22. 22. 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 *conditional logistic regression No significant differences to suggest extrafine particle ICS offers benefit over standard particle ICS
  23. 23. 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 *conditional logistic regression Matching criteria: Age, Gender, Index Date Year, Baseline Reliever, Baseline exacerbations, Antibiotic prescriptions, Eczema 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
  24. 24. 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 *conditional logistic regression No significant differences to suggest benefit of ICS versus LTRA
  25. 25. 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 *conditional logistic regression Matching criteria: Age, Gender, Index Date Year, Baseline Reliever, Baseline exacerbations, Antibiotic prescriptions, Eczema
  26. 26. 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 *conditional logistic regression 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
  27. 27. 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 *conditional logistic regression LTRA vs SABA Matching criteria: Age, Gender, Index Date Year, Baseline Reliever, Baseline exacerbations, Antibiotic prescriptions, Eczema
  28. 28. 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 *conditional logistic regression No significant differences to suggest benefit of LTRA versus SABA
  29. 29. ADDITIONAL ANALYSES
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. DISCUSSION
  34. 34. 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
  35. 35. NEW RESEARCH IDEAS INTERACTION OF ICS PARTICLE SIZE AND – ASTHMA, EXCESS WEIGHT AND GERD – ACOS – OTHERS? 16.35–16.50PM
  36. 36. 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)
  37. 37. 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)
  38. 38. OSCILLOMETRY – FOT STUDY RON DANDURAND 16. 50–17.00PM
  39. 39. STANDARDIZATION OF FOT RESULTS ACROSS ALL FIVE COMMERCIALLY MARKETED DEVICES Ron Dandurand 16. 50–17.00PM
  40. 40. 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.
  41. 41. Background
  42. 42. 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.
  43. 43. FOT is Rhino Talk 20-20,000 Hz 300-3000 Hz 5-75 Hz Infrasound receiver
  44. 44. 5 Commercial Devices tremoFlo iOS Quark i2m MostGraph-02 Resmon Pro
  45. 45. McGill U Health Centre FOT Unit
  46. 46. McGill U Health Centre FOT Unit McFOTU
  47. 47. McGill U Health Centre FOT Unit
  48. 48. McGill U Health Centre FOT Unit
  49. 49. 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
  50. 50. 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
  51. 51. 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
  52. 52. Multi-Patient Data
  53. 53. Bland-Altman Matrix i2m MG tF iOS RM i2m MG tF
  54. 54. Bland-Altman Matrix i2m MG tF iOS RM i2m MG tF
  55. 55. 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.
  56. 56. 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
  57. 57. 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
  58. 58. Discussion •  Questions •  Study design suggestions •  Potential sources of funding •  Are other similar initiatives in progress? rdandurand@videotron.ca

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