2015 ERS EVENTS

DATE: FRIDAY SEPTEMBER 25TH

VENUE: Wyndham Apollo Hotel, AmsterdamROOM: BoardroomTIME: 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

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

Agenda

Meeting outcomes

• Bring everyone up to date on current:o Publication statuso Funding status of new research ideas

• Agree:o Authors & target journals for 3 planned paperso Next steps for the preschool asthma studyo Study ideas to be submitted for prioritisation for

REG’s 2016 core research grants

A brief history

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:oTreatment of small airways, in generaloAll 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

SASG became an REG Working Group in 2014

Authors Title ReferencePostma 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

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 alIncreased 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

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 sexo Presenter: Marjan Kerkhofo When: Sunday 27th September, 12:50-14:40o Where: Hall 14-32

Publications Update

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

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-agonisto 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.

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.

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

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 confirmedo Intended format: full manuscripto 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

eventso Target journal: for discussion in Amsterdamo Lead author: looking for volunteers…

• 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)

• Publication intention:o Status: to be published; funding being confirmedo Intended format: short reporto 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 Amsterdamo Lead author: looking for volunteers…

Planned papers: Dose Response (II)

• 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

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

algorithmso Inverse Probability of Treatment Weighting (IPTW)o Stratification by PSo Covariate adjustment using PS

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

Planned papers: Matching ApproachesPublication 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

• 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 researcho 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

Possible figure from ERS/ISAM Taskforce Report

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

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 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, oro ≥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

Primary Endpoint:• Exacerbations (ATS/ERS definition) defined as occurrence of an:

o Asthma-related: Hospital admissions OR A&E attendance; ORo 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

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.

Baseline Descriptive Analysis

Final Cohortn=47528

Patients excluded

*No prescriptions for ICS, LTRA or combo in baseline

Patient Selection from OPCRD:

Descriptive Analysis: Sample Size

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

Descriptive Analysis: Demographics

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

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

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

Descriptive Analysis: Asthma Exacerbations and Antibiotics

Baseline Asthma Exacerbations*

Full Cohort(n= 47528)

Treatment Groupp-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 Groupp-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

Descriptive Analysis: Baseline Drugs

Drug Total (n=47528)

Treatment Groupp-value*

NEF ICS (n=10793) EF ICS (n=357) LTRA

(n=335)SABA

(n=35864)

SABAYES n (%) 44798 (94.25) 9588 (87.39) 317 (88.80) 290 (86.57) 34603 (96.48)

<0.001NO n (%) 2730 (5.75) 1384 (12.61) 40 (11.20) 45 (13.43) 1261 (3.52)

SAMAYES n (%) 2970 (6.25) 751 (6.84) 24 (6.72) 32 (9.55) 2163 (6.03)

< 0.001NO n (%) 44558 (93.75) 10221 (93.16) 333 (93.28) 303 (90.45) 33701 (93.97)

LAMAYES n (%) 0 0 0 0 0

NANO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)

LABAYES n (%) 79 (0.17) 17 (0.15) 0 0 62 (0.17)

0.975NO n (%) 47449 (99.83) 10955 (99.85) 744 (100) 335 (100) 35802 (99.83)

ICSYES n (%) 0 0 0 0 0

NANO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)

LTRAYES n (%) 0 0 0 0 0

NANO n (%) 47613 (100) 10670 (100) 744 (100) 335 (100) 35864 (100)

THEOYES n (%) 224 (0.47) 41 (0.37) 1 (0.28) 0 182 (0.51)

0.923NO n (%) 47304 (99.53) 10931 (99.63) 356 (99.72) 335 (100) 35682 (99.49)

*Chi Square

Descriptive Analysis: Baseline Drugs

Drug n (%)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 Groupp-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:MinimumMaximum

0.0710.96

0.273.83

0.273.48

0.0514.21

Descriptive Analysis: IPD Drugs

Drug Full Cohort(n=47528)

Treatment Groupp-value*

NEF ICS (n=10972) EF ICS (n=357) LTRA

(n=335)SABA

(n=35864)

SABAYES n (%) 40710 (85.65) 4638 (42.27) 130 (36.41) 78 (23.28) 35864 (100)

<0.001NO n (%) 6818 (14.35) 6334 (57.73) 227 (63.59) 257 (76.72) 0

SAMAYES n (%) 724 (1.52) 77 (0.70) 4 (1.12) 4 (1.19) 639 (1.78)

<0.001NO n (%) 46504 (97.85) 10895 (99.30) 353 (98.88) 331 (98.81) 35225 (98.22)

LAMAYES n (%) 0 0 0 0 0

NANO n (%) 47528 (100) 10972 (100) 357 (100) 335 (100) 35864 (100)

LABAYES n (%) 66 (0.14) 23 (0.21) 0 0 43 (0.12)

0.064NO n (%) 47462 (99.86) 10949 (99.79) 357 (100) 335 (100) 35821 (99.88)

ICSYES n (%) 11149 (23.46) 10972 (100) 357 (100) 0 0 <0.001

NO n (%) 36379 (76.54) 0 0 335 (100) 35864 (100)

LTRAYES 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)

0.019NO n (%) 47484 (99.91) 10970 (99.98) 357 (100) 335 (100) 35822 (99.88)

*Chi Square

Descriptive Analysis: Patients on ICS

*Chi Square

Type of ICS ICS Cohortn (%)

EF ICS 357 (3.16)

Type of ICS

Drug Substance

Beclometasone Fluticasone Mometasone Budesonide Ciclesonide p value*

EF ICS (n=357) 357 (47.98) 0 0 0 0

<0.001NEF ICS (n=10972) 9861 (89.87) 519 (4.73) 2 (0.02) 590 (5.38) 0

Type of ICS

Mean Drug Dose (mcg) at IPD (SD, Median, Range) p value*

EF ICS 181.06 (141.37, 137, 27.4-1311.5)

0.504NEF 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

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

Thao Le: REG Supporter Liaison

Future funding update

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 discussions1. 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

• 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

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 peoplecan’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

• 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

100

200

300

400

500

600

700

800

900

1000 Patient RCT eligibility drop-off with sequential application of standard inclusion criteria

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umbe

r of s

ubje

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100.0%

38.4%

14.3%5.7% 3.7% 2.1% 1.7% 1.3%

COPD

0

200

400

600

800

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All pat VAS >7.5 No Co-morbidity FEV1 30-70 S or XS Packy > 15 No Hayfever

Num

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s

100.0%

42.1%

15.2%10.1% 9.2% 8.2% 7.2%

Asthma

What sort of evidence do we have …?Po

pula

tion

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…

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

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

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

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

Alison Chisholm & Group Discussion/Decision

REG Core Funding Submissions

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 Committeeby 31 Dec 2015

If insufficient REG Funds, continue to look externally

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 diseaseo Focus on metabolic effects, also consider:

– Pneumonia– Acute respiratory events– Osteoporosis-related risks– Cardiovascular– Obesity

o Subgroup analysis by diagnosis: Asthma, COPD, ACOS

Interaction of particle size and excess weight/obesity and GERD

• Hypothesiso The mechanisms by which high BMI and GERD impair asthma

control could involve increased distal airway inflammationo 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/obesity2. Determine the relationship between overweight/obesity and

GERD as determinants of poor asthma control

Differential role of ICS particle size in ACOS management

• Hypothesiso The mechanisms by which high BMI and GERD impair asthma

control could involve increased distal airway inflammationo 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/obesity2. Determine the relationship between overweight/obesity and

GERD as determinants of poor asthma control