Slides from Respiratory Effectiveness Group Obstructive Sleep Apnoea (OSA) Working Group Meeting held in London during ERS 2016.

1. OBSTRUCTIVE SLEEP
APNOEA INAUGURAL
WORKING GROUP MEETING
Dr Mihaela Stefan
DATE: Saturday September 3rd
TIME: 5.00–6.15pm
VENUE: Royal College of General Practitioners; 30 Euston
Square, London, UK

2. Agenda
17.00-17.15 Welcome / Introduction
– OSA new area for REG research...?
17.15-17.45 A first research idea
– Clinical and Cost Implications of PAP in patients with OSA
and Obstructive Lung Disease
17.45-18.10 Other potential projects for the group
18.10-18.15 Next Steps & Meeting Close

3. The Respiratory Effectiveness Group (REG)
• Founded in October 2012 by
David Price, Professor of
Primary Care Respiratory
Medicine at the University of
Aberdeen.
• Recognised the growing importance of real-life research and the
need for respiratory experts around the world to come together to:
o De-fragment practice
o Set best practice quality standards
o Set a unified agenda
for future ethical and meaningful real-life research.

4. Evolving landscape: timeline
• Brussels
Declaration on
Asthma: stated
a need to include
evidence from
real world
studies in
treatment
guidelines
• Michael Rawlins
(NICE Chairman):
RCTs should be
complemented
by a diversity of
approaches that
involve analysing
the totality of the
evidence base
2008
ATS/ERS
Large, prospective
studies in ʻreal-
worldʼ settings
(e.g., trials
designed
pragmatically to
reflect everyday
clinical practice) to
ensure they
provide content
validity as well as
reflect clinically
meaningful
outcomes
2009
ARIA / GA2LEN
Proposed the use
of composite
measures when
evaluating asthma
control and called
for the
measurement
properties to be
validated in clinical
trials
2010
NHLBI expert
workshop
Highlighted areas
that need
strengthening in
order to optimize
the potential of
real-life/
comparative
effectiveness
(CER) research in
pulmonary
diseases, sleep,
and critical care.
2011
REG was
founded!
2012

5. • 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
COPD
Asthma
Patient RCT eligibility drop-off with sequential application of
standard inclusion criteria

6. Evidence
Theoretical
Theoretical
model provide
rationale
Classical double-
blind double-
dummy RCTs
Gold standard,
large range of
outcomes.
But not “real-
life” patients,
compliance and
represent <10%
of patients
Pragmatic
trials
More real-life
Broader inclusion
criteria Allow
normal factors to
occur usually
randomised.
Simple outcomes,
but still consent &
rigorous
Observational
Data
Real-life patients
Not randomised
Routine data
Normal decisions
Difficult to ensure
group comparability
Matching of case
controls,
adjustment
Real-life studies
Need for integrated approach
to evidence evaluation

7. Working groups: specialty focus
• Not-for profit,
international research
and advocacy group
• Investigator-led;
5 executive members
providing leadership
• >300 collaborators
spanning 40 countries
• 14 Working groups
to identify research
needs in areas where
real-world research
methodologies have
particular utility

8. RESEARCH IDEA
IMPACT OF POSITIVE AIRWAY PRESSURE ON
HEALTHCARE RESOURCE UTILIZATION IN PATIENTS WITH
OBSTRUCTIVE LUNG DISEASE AND SLEEP-RELATED
BREATHING DISORDERS
17.15–17.45

9. Background: OLDOSA
• “OLD-OSA overlap syndrome” refers to the coexistence of OLD
(obstructive lung disease: COPD and asthma) and OSA
• A broader umbrella term of “OLDOSA syndrome” is proposed1
1. Ioachimescu OC, et al. Respirology. 2013;18:421-31; 2

10. Background: OLDOSA
WHY…?
• Obesity is a growing problem worldwide1
• Obesity predisposes OSA.2
• Possible link between obesity and OLD:
o Positive correlation between baseline BMI and the subsequent development of
asthma3
o Rhinitis4,5 and GERD6–8 are common risk factors to both asthma and OSA
• OSA is an independent risk factor for asthma exacerbations8
• Prevalence of comorbid OSA may be increasing with increasing asthma
severity9
• No population-based studies using polysomnography to identify the prevalence
and severity of OSA in routine care asthma patients
• Patients with COPD and OSA have higher mortality than those with COPD and
Tx with CPAP reduces COPD exacerbations11
1.WHO: http://www.who.int/mediacentre/factsheets/fs311/en/ . 2.Romero-Corral A, et al. Chest. 2010;137:711–719; 3. Delgado J, et al. J
Inv Aller Clin Immunol. 2008;18:420-5; 4. Staevska MT, et al. Curr Allergy Asthma Rep,2004;4:193; 5. Ing AJ, et al. Am J Med. 2000;1
08(Suppl 4a):120S–5S; 6. Avidan B, et al. Gut. 2001;49:767–72; 7. Cibella F, et al. Am J Med. 2001;111(Suppl 8A):31S–6S; 8. Ten Brinke
A, et al. Eur Respir J. 2005;26:812–8; 9. Julien JY, et al. JACI. 2009;124:371-6; 10. Alkhalil M, et al. Clin Sleep Med. 2009; 5: 71–78
11.Marin JM et al. AmJ Respir. Crit, Care. Med. 2010;182:325-31

11. Background: PAP
• Positive airway pressure (PAP) is the most effective treatment
for patients with moderate-to-severe obstructive OSA.1
• Real-life evidence (claims data) suggests PAP is an effective and
cost-effective OSA treatment. Compared with baseline:2
o PAP associated with 41% lower healthcare and disability costs and
fewer missed
o Healthcare costs in controls (diagnosed with OSA but untreated)
decreased by 8%
o Healthcare costs increased by 34% in those without OSA over the
same period
• Small observational studies suggests that PAP Tx may
attenuated the risk of severe asthma in patients with comorbid
OSA, particularly in older patient groups.3
1. Hoffman B, et al. J Occup Environ Med.2010;52:473-7;
2. Teodorescu M, et al. Sleep Disord. 2013; 2013: 251567;
3. Albarrak M et al. Sleep. 2005;28:1306-11.

12. Possible Beneficial Effects of PAP in
Patients with Asthma and OSA

13. • Need to understand the inter-relationship
between OSA-Asthma-COPD and the real-life
implications of undiagnosed or inadequately
treated OSA on OLD, and vice versa.

14. Aim
• To evaluate the impact of a diagnosis of sleep-related
breathing disorder (SBD, including OSA) on clinical
outcomes and healthcare resource utilization in a
representative population of patients with OLD and
comorbid SBD in the United Kingdom.
• Hypothesis: It is assumed that a diagnosis of OSA
(surrogate marker for treatment) will be associated with a
decrease in the use of health care resources.

15. Design & Data source
Design
• Historical matched cohort study using electronic medical records
and linked questionnaire data from the Optimum Patient Care
Research Database (OPCRD)
Data source
• The Optimum Patient Care Research
Database (OPCRD) is a UK primary care
database available to REG:
o Quality-controlled, longitudinal, primary-care database
o Contains anonymous data from ≥550 UK general practices
& ~2.5 million patients
o Captured via the OPC asthma and COPD clinical review service
– Respiratory “enriched” database
o Ethical approval for medical research

16. Study Population
Inclusion criteria Active Population Control Population
Aged: ≥18 years at index date ✔ ✔
A physician diagnosis of SDB
(defined as ≥1 SBD diagnostic codes)
✔
X
≥3 years of continuous data:
• ≥1 year prior to “index date”
• ≥2 years immediately after index date
✔ ✔
OLD Diagnosis, any of:
Asthma subpopulation: asthma diagnosis ever prior to index date,
≥2 asthma prescriptions in the baseline year; no COPD Read
code in the 3-year study period
COPD subpopulation: COPD diagnosis ever prior to index date,
≥2 COPD prescriptions in each of the baseline years; no asthma
Read code in the 3-year study period
Asthma & COPD subpopulation: Asthma & COPD diagnoses
within 2 years of each other ever prior to the index date and ≥2
OLD prescriptions in each of the baseline years; no asthma or
COPD resolved codes within the study period
✔ ✔
Exclusion criteria Active Population Control Population
To optimise the external validity of the study findings no exclusion criteria will be applied

17. Study Period
• The study will consider a three-year continuous
observation period for eligible patients
• 1 baseline year immediately before the index date
(months -12–0)
• Index date (date/month 0) will be:
o Active cohort: the data of first SDB diagnosis
o Control cohort: date of a random primary care consultation in
matched controls
• 2 outcome years immediately following the index date
o Primary analysis: 24-month outcome period, months 0-24 (for
evaluation of all primary and secondary endpoints)
o Secondary analysis: 21-month outcome period, months 0-24 (for
primary endpoint evaluation only)

18. Study Design
Index Date:
Active: Date of first OSA diagnosis
Control Group: healthcare consultation date in patients matched on age,
BMI, sex and OLD diagnosis, OLD severity
Baseline: 1 year
Outcome: 2 years
(primary: months 0-24)
Active Arm
Control Arm
Outcomes:
Primary: Acute respiratory event rate
Secondary:
• Acute care hospital days (total days/period)
• Pharmaceutical dispensations (days supply/period)
• Overall healthcare costs
Outcome: 21 month
(secondary: months 3-24)
Month
0
Month
3

19. Primary endpoint
Acute respiratory event rate
• Defined as the occurrence of any of the following events
coded for a lower respiratory complaint:
o Hospital admission
o Emergency Room / Accident & Emergency attendance
o Acute course of oral steroid prescription
o Antibiotics prescriptions.

20. Endpoints: secondary
Healthcare resource utilization
• Primary care consultations:
o All
o For SDB
o For a lower respiratory complaint
o For a lower respiratory code resulting in a course of antibiotics
o For a lower respiratory code resulting in a course of oral steroids
• Secondary Care:
o Hospitalizations with a lower respiratory code
o Hospitalizations with a SDB code
o Out patient department attendances with a lower respiratory code
o All out patient department attendances with a SDB code

21. Endpoints: secondary
Pharmaceutical dispensations
(days supply/period)
• OLD treatment– Days supplied
o ICS daily dose
o LABA daily dose
o LAMA daily dose
o SABA daily dose
• Total Prescriptions
o Oral steroid courses for lower
respiratory complaints
o Antibiotics courses for lower
respiratory complaints
o Theophylline prescriptions
Overall healthcare cost
o Drug-related
– OLD
– SDB
– OLD + SDB
o Encounter-related
– OLD
– SDB
– OLD + SDB
o Total: Encounter + Drug
related
– OLD
– SDB
– OLD + SDB

22. Within-population analysis
• Primary endpoint outcome comparison for baseline -12–0 months vs versus outcome periods (0–
24 months; primary and 3–21 months; secondary), for:
o All Active Patients, All Active OLD sub-populations
o All Control Patients, All Control OLD sub-populations
• Predictors / key independent variables of HRU
Index Date:
Baseline: 1 year
Active Arm
Primary Analysis 1 – Active Cohort:
OSA + OLD pre vs post OSA diagnosis
Subanalyses:
OSA + Asthma pre vs post OSA diagnosis
OSA + COPD pre vs post OSA diagnosis
OSA + Asthma + COPD pre vs post OSA diagnosis
Outcomes:
Primary: Acute respiratory events
Secondary:
• Acute care hospital days (total days/period)
• Pharmaceutical dispensations (days supply/period)
• Overall healthcare costs
Control Arm
Primary Analysis 1 – Control Cohort:
OLD pre vs post OSA diagnosis
Subanalyses:
Asthma pre vs post OSA diagnosis
COPD pre vs post OSA diagnosis
Asthma + COPD pre vs post OSA diagnosis
Secondary Outcome: 21 month
(months 3-24)
Primary Outcome: 2 years
(months 0-24)

23. Matched outcome analysis
• Comparative analysis of active patients and matched controls over 1 year (primary) and 21
months (secondary), stratified by comorbid OLD diagnosis
• Controls matched to active patients based on:
o Key demographic (age, sex, BMI) and clinical (OLD diagnosis, index year,) characteristics; OR,
Propensity score matching (probability of being diagnosed with OSA)
Index Date:
Active: Date of first OSA diagnosis
Control Group: healthcare consultation date in
patients matched on age, BMI, sex and OLD
diagnosis and baseline OLD severity
Baseline: 1 year
Active Arm
Primary Analysis = All patients
Sub analysis by OLD diagnosis
Control Arm
Primary Analysis = All patients
Sub analysis by OLD diagnosis
Subanalysis: Asthma + OSA vs Asthma
Subanalysis: COPD + OSA vs COPD
Subanalysis:
Asthma + COPD + OSA vs Asthma + COPD
Outcomes:
Primary: Acute respiratory events
Secondary:
• Acute care hospital days (total days/
period)
• Pharmaceutical dispensations
(days supply/period)
• Overall healthcare costs
Secondary Outcome: 21 month
(months 3-24)
Primary Outcome: 2 years
(months 0-24)

24. Questions for the group
• SDB or OSA?
• Time period before and after the index date
• We assume that OSA diagnosis is a surrogate
for PAP treatment. If the dataset has information
about the CPAP delivered we can also do a
secondary analysis in the group that we know
that they got the machine.

25. OTHER RESEARCH IDEAS
GROUP DISCUSSION / BRAINSTORM
17.45–18.10

26. NEXT STEPS
FUTURE MEETINGS
18.10–18.15

27. Systematic Review of the Comparative
Effectiveness Literature on ICS Particle Size
• TBC