2015 ERS EVENTS

DATE: SATURDAY SEPTEMBER 26TH

VENUE: Wyndham Apollo Hotel, AmsterdamROOM: BoardroomTIME: 17:00-18.30

CHAIRS: Steve Turner: Paediatric Consultant and Clinical Senior Lecturer, Child Health, Royal Aberdeen Children's Hospital, Aberdeen, UK

CHILD HEALTH WORKINGGROUP MEETING

Agenda

Real-life MASCOT study (“paediatric step-up”)

Steve Turner: Paediatric Consultant and Clinical Senior Lecturer, Child Health, Royal Aberdeen Children's Hospital, Aberdeen, UK

Completed Work

Abstracts presented• RCPCH (Royal College of Paediatrics and Child Health) 2014:

o Paed Step-Up: baseline descriptive analysis– Presented by Steve Turner

• ERS 2014:o Poster: Predictors of BTS Step 3 paediatric asthma prescribingo Oral abstract: Comparative effectiveness of paediatric asthma step-

up options: increasing ICS dose vs adding separate LABA– Both presented by Clare Murray

• ERS 2015:o Predicting asthma exacerbations in children – an observational study

in real life– Poster discussion to be presented by Steve Turner, 29th

September 2015; 14:45–16:45, Room E104-106

Publication Status: Paper 1

AIMS: To determine the proportion of initial ‘step-up’ episodes where LABAs were prescribed and to describe characteristics of individuals not stepped up with LABA.CONCLUSIONS: One-third of initial step-up episodes in children with asthma treated with ICS are to add LABA. Different characteristics of children prescribed therapies other than LABA suggest that prescribers tailor treatment in some clinical settings.

Turner SW, Richardson K, Burden A, Thomas M, Murray C, Price D. npj Primary Care Respiratory Medicine. 2015; 25:15041

Published 11 June 2015

Publication Status: Paper 2

• Focus of papers: Matched cohort analyses analyses with FDC ICS/LABA as the reference group:1. FDC ICS/LABA vs LTRA add-on

2. FDC ICS/LABA vs ICS dose increase

• Status: Underway (Clare Murray as lead author)

Publication Status: Paper 3

• Focus of paper: matched analyses of ICS/LABA step-up therapy delivered as a fixed dose combination or as separates

• Status: Submitted to Thorax 5 August 2015, rejected 20th Sept 2015

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 preschool 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, preschool (<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 preschool 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 preschool 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 preschool 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

Study Protocol in DevelopmentNikolaos G. Papadopoulos: Professor of Allergy and Pediatric Allergy, Center for Pediatrics and Child Health, Institute of Human Development, The University of ManchesterRoyal Manchester Children's Hospital, Manchester, UKClare Murray: University of Manchester and Royal Manchester Children's Hospital, Manchester, UK

Addition of antimicrobials to usual asthma exacerbation care (pediatric analysis)

Background / Rationale• Respiratory viruses are the most common causes of asthma

exacerbations (and may also be involved in the pathogenesis of chronic asthma in children),1 but other factors can increase the risk/severity of exacerbations.

• Increasing evidence suggests atypical bacterial infections contribute to exacerbation severity and in a small proportion of cases have been implicated in pneumonia.2

• There are evidence to suggest that macrolide antibiotics and the ketolide antibiotic telithromycin may have an effect on asthma exacerbations through their antibacterial and/or anti-inflammatory properties.2

1. Korppi M. Management of bacterial infections in children with asthma. Expert Rev Anti Infect Ther. 2009;7:869-77.2. Johnston SL. Macrolide antibiotics and asthma treatment. J Allergy Clin Immunol. 2006;117:1233-6.

Background / RationaleRecent RCT Data:• In adult patients (n=278) with acute exacerbations of asthma found a significant

reduction in asthma symptoms among patients receiving add-on telithromycin compared with placebo.1

o The mechanism or mechanisms of action was/were not determined.

• 40 children with acute asthma addition of (15mg/kg) clarithromycin for 21 days in addition to their regular (GINA-guided) exacerbation treatment resulted in:2

o Increase in number of symptom-free dayso Reduction in the number and severity of days with loss of control following index

episodeo Decrease in the duration of the initial asthma exacerbation.o Lung function did not differ between groups.

• These RCT findings warrant further exploration in in larger more representative routine care populations.

1. Johnston SL, Blasi F, Black PN, et al. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med. 2006;354:1589-600.2. Koutsoubari I, Papaevangelou V, Konstantinou GN, et al. Effect of clarithromycin on acute asthma exacerbations in children: an open randomized study.

Pediatr Allergy Immunol. 2012;23:385-90. 

Aim• Primary: to evaluate the effect of antimicrobial

prescribing on asthma exacerbation outcomes.

• Secondary: to explore the differential use of, and outcomes associated with, different classes of antibmicrobials in asthma exacerbation management.

• The study will be conducted in adults and children, but evaluated will include a paediatric subgroup analysis.

Data source

• The anonymised EMRs captured through the OPC service are curated in the OPC Research Database (OPCRD).

• The OPCRD:o Contains anonymised, research-quality data for

approximately 3 million patients who have received ≥1 prescription for) obstructive lung disease from more than 525 practices across the UK

o Has ethical approval for medical research.

Study Design

Index date/event: date of an acute asthma exacerbation. Baseline period: patients will be characterised over a one-year baseline period (immediately prior to index date)Outcome period: 2 week; 6 weeks and 12 weeks following the index date.

Study period: 10-year evaluation period (1 January 2004–31 December 2014). 

Patient eligibilityInclusion criteriaTo be eligible for inclusion in the study, patients must meet the following criteria:• Have physician-diagnosed asthma • Received ≥2 asthma prescriptions (including ≥1 ICS prescription) in the

(baseline year) immediately prior to the index event (exacerbation)• Be aged between 5–65 years at the time of the index event (exacerbation) • ≥54 weeks continuous records: 52 prior to index date and ≥2 after index

date 

Exclusion criteriaIn order to provide the fullest picture of UK primary care prescribing practice possible, there will be no additional exclusion criteria applied to the dataset.

OutcomesPrimaryTime to next exacerbation: Where an exacerbation is defined:• Prescription of systemic steroids; OR• Hospitalization of A&E Attendance for asthma; OR • Unscheduled GP visit coded for asthma / wheeze

Secondary1. Time to disaggregated components of an exacerbation:

a) Time to a prescription of systemic steroids

b) Time to a hospitalization or A&E attendance for asthma;

c) Time to unscheduled GP visit coded for asthma / wheeze

2. Number of exacerbations

3. Number of prescriptions for short-acting beta2-agonists (SABA)

4. Average daily dose of SABA  

Design questions• Option 1

o 2-way matched cohort analysiso To avoid biasing the population towards the younger ages,

use every exacerbation following a baseline characterization year as an index event and repeat measuring analysis?– Each exacerbation experienced by a patient will be

treated as a separate index event providing it occurs ≥7 days after the initial index event.   

o Challenge: Selecting all the exacerbation events within patients as index date with potential overlap of baseline and outcome years is an extremely complex study design

Design questions (continued…)

Option 2: Use the time to an event (a prescription of oral corticosteroids) after each previous event as the outcome parameter in a multilevel survival analysis, analysing all the events that occur within patients and taking the correlation of events within patients into account by including a random effect. A concomitant prescription of antibiotics at time zero would be the exposure under study.• Option 1: time to first exacerbation; matched analysis

would then only look at unique patients. • Option 2: at all exacerbations but without matching and

adjust for baseline imbalance.

Design questions (continued…)

Option 3• Divide the individual patient's follow up into age periods (for example

periods of 3 years) and randomly select one exacerbation if any from every age period within patients to cover the whole range of ages.

• Matching could be performed within age groupso Allow unique matches within time period (may have repeated

patients but unique within a time period)• The amount of overlap of baseline and outcome periods within

patients may then be limitedo Challenge: The issue of matched pairs not being completely

independent in conditional logistic regression would need to be addressed, when analysing all measurements within patients together. This could perhaps be achieved by including a random effect on the patients involved in the pairs.

Steve Turner: Paediatric Consultant and Clinical Senior Lecturer, Child Health, Royal Aberdeen Children's Hospital, Aberdeen, UK

BLF grant submission: outcomes in under 5s after treatment with oral steroids or antibiotics

Group Discussion

Terms of reference for / Aims of the group

Group Discussion

Other ideas / AOB…