ATS Symposium session presented by Prof. David Price: Leukotriene Antagonists As First-line Asthma Controller For Step 2 Presented May 2015 at ATS 2015, Denver, Colorado, USA

1. Leukotriene Antagonists As First-line
Asthma Controller For Step 2
David Price
Professor of Primary Care Respiratory Medicine, University of Aberdeen;
Director of Research in Real-Life, Singapore; Member of ARIA and EPOS
Executive; Co-founder of the Respiratory Effectiveness Group;
Community Based Respiratory Specialist Norfolk
Wednesday May 20th; 2:15-2:35 PM
Four Seasons Ballroom 3-4 (lower level), Colorado Convention Center

2. Faculty Disclosures:
ATS 2015 – Denver (I)
 Relevant financial relationships with a commercial interest:
David Price
• Board Membership Company (past and current): Aerocrine Board
Membership, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim,
Chiesi, Meda, Mundipharma, Napp, Novartis, and Teva.
• Consultancy (current): Almirall, Amgen, AstraZeneca, Boehringer
Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp,
Novartis, Pfizer, and Teva;
• Grants and unrestricted funding for investigator-initiated studies
(past and current): UK National Health Service, British Lung Foundation,
Aerocrine, AKL Ltd, Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi,
Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Napp, Novartis,
Orion, Pfizer, Respiratory Effectiveness Group, Takeda, Teva, and
Zentiva; Payments for lectures/speaking: Almirall, AstraZeneca,
Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda,
Merck, Mundipharma, Novartis, Pfizer, SkyePharma, Takeda, and Teva;
• Payment for manuscript preparation (past): Mundipharma and Teva

3. Faculty Disclosures:
ATS 2015 – Denver (II)
 Relevant financial relationships with a commercial interest:
David Price
• Patents (current): AKL Ltd
• Payment for development of Educational Materials (past):
GlaxoSmithKline, Novartis;
• Stock / stock options (current): Shares in AKL Ltd which produces
phytopharmaceuticals; 80% ownership of Research in Real Life Ltd and
its subsidiary social enterprise Optimum Patient Care
• Payment for travel/accommodation/meeting expenses (past):
Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and
Teva;
• Funding for patient enrolment or completion of research (past):
Almirral, Chiesi, Teva, and Zentiva;
• Peer reviewer for Grant committees (past): Medical Research Council
(2014), Efficacy and Mechanism Evaluation programme (2012), HTA
(2014)

4. Current asthma management in the UK
0
5
10
15
20
25
30
35
1 2 3 4 5
Percentageofpatients
GINA treatment stage
N = 29,337
Price D, et al. 2012 Thorax; 67:A186-A187
Stage 1
Beta-
agonist as
necessary
Stage 2
Initiate
ICS
Stage 3
Add
LABA
Increase
ICS
dose
Stage 4
Increase
ICS
dose
Add
further
therapy
Stage 5
High ICS
dose
Oral
steroids
Other
therapie
s
BTS/SIGN. British guideline on the management of asthma (QRG 141); Oct 2014

5. Study Rationale: Guideline recommendations
1. Price D. Asthma. 1999;4:74–8.
• Recognition that airway inflammation is present even in patients with mild
asthma has led to introducing anti-inflammatory therapy earlier in the
management of asthma.
• Many patients with asthma still have considerable symptoms & lifestyle
limitation despite ICS management.1 Possible reasons for this include:
• Lack of disease recognition
• Poor adherence to ICS
• Poor inhaler technique
• Untreated rhinitis
• Smoking
• Failure to optimise treatment

6. Uncertain landscape
• Short-term double-blind double-dummy studies and in patients with
significant asthma severity comparing the use of montelukast vs ICS
at step 2 suggested that leukotriene antagonists were inferior to ICS.
Meta-analysis conclusions:1
• Patients randomised to LTRA had a 60% increased risk of exacerbation
compared with those randomized to ICS
• Those randomised to ICS had a significantly increased FEV1 compared
with LTRA
• Effects of montelukast and beclomethasone on airway function and
asthma control:2
• 400μg BDP significantly improved FEV1 vs LTRA
• No significant difference in exacerbations
Ducharme FM. BMJ 2003;326:621
Israel E, et al. JACI. 2002;110:847–54

7. Studies have shown that efficacy RCTs exclude about 95% of asthma and
90% of COPD routine care populations due to strict inclusion criteria.
Herland K, et al. Respir Med 2005;99:11–19.
Limitations: RCTs inclusions/exclusions
Does it matter…?

8. RCT references
1) Pawels R et al. N Engl J Med 1997
2) Kips J et al. Am J Respir Crit Care 2000
3) Bateman E. Am J Respir Crit Care 2004
4) Papi A et al. Eur Respir J 2007
5) Busse W et al. J Allergy Clin Immunol 2008
Real-life references
1) Partridge Pulm Med 2006
2) De Marco et al. Int Arch Allergy Immunol 2005
3 and 4) Janson et al. Eur Respir J 2001 3=Italy 4=UK
5 and 6) Breekveldt-Postma et al. Pharmaco-epidemiol Drug Saf 2008 5=fixed
combination 6=ICS
7) Stallberg et al. Resp Med 2003
8) Adams et al. J Allergy Clin Immunol 2002
9) Corrigan Prim Care Resp J 2011
Randomised trials
0
20
40
60
80
100
1 2 3 4 5
PercentageofPatients
75-125 75-125
89
>95
>80
45
34
17
49
14.1
8.3
34
21
40
0
20
40
60
80
100
1 2 3 4 5 6 7 8 9
Real-life studies
Adherence

9. Updated for the CRITIKAL patients
population from Price et al, Abstract
presented IPCRG 2014
DPI = dry powder inhaler;
MDI = metered-dose inhaler
Total
patients =
4645
Inhaler errors: common…?

10. *Montelukast 10 mg once daily + budesonide 400 µg twice daily;
**Budesonide 800 µg twice daily
Price DB, et al. Allergy 2006; 61: 737–742.
Price DB,et al. Thorax 2003; 58: 211–216.
Comorbidity interactions: rhinitis can
affect response to medication

11. Chalmers GW et al. Thorax 2002;57:226–
230
Kerstjens HA, et al. Eur Respir J 1993;6(6):868-76.
1: Non-smoker + ICS
4: Non-Smoker + Placebo
3: Smoker + Placebo
2: Smoker + ICS
1
2
3
4
Lifestyle interactions: smoking can affect
response to medication

12. Different types of trial: the evidence paradigmPopulation
Broad
Narrow
Ecology of
care
Free
Constrained
Highly controlled Pragmatically
controlled
Observational
Managed
as...
Clinical
diagnosis
Confirmed
diagnosis Registration RCTs
Long term
phase III
Pragmatic RCTs
Observational
studies
http://www.effectivenessevaluation.org/ Roche N, Price D et. al 2013 Lancet Respir Med; 1(10):e29-30
ELEVATE

13. 0 2 10 26 52 78 104
Week Week:
Tailored treatment as indicated
by guidelines
LTRA
Ideally no ICS use
ICS Ideally no LTRA use
Baseline
V1 V2 V3 V4 V5 V6 V7
SABA
Randomisation
Price et al NEJM 2011;364:1695-1707

14. ELEVATE Rational:
meaningful outcome measures
Objective Measures Patient-reported / perceived
Efficacy Trial Endpoints “Real-life” control assessments
Airway function:
• Spirometry (FEV1)
• Domiciliary PEF
Patient-reported quality of life (QoL)
Airway hyper-reactivity:
• methacholine bronchial
challenge testing
Symptoms
Exacerbations
Rescue medication use
Price et al NEJM 2011;364:1695-1707

15. Eligibility Criteria: Conducted at 53 primary care practices
in the UK. Enrolled patients 12 - 80 y with physician
diagnosis of asthma
Flexibility and Practitioner Expertise: Both treatments,
LTRA and inhaled glucocorticoid, were given according to
normal clinical practice. All PCPs were eligible to
participate
Protocol discouraged treatment changes between
randomization and the 2-month visit. Patients receiving
disallowed asthma medications remained in the study
Study Design
Price et al NEJM 2011;364:1695-1707

16. Patient population
• INCLUSION CRITERIA
• Aged 12–80 year
• Capable of understanding study and
procedures
• A diagnosis of asthma:
• Documented reversibility after
inhaled SABA, and/or
• PEF variability on PEF diary, and/or
• Physician diagnosed asthma and/or
• Physician diagnosis of asthma +
history of response to treatment
• Not currently receiving, and had not
received, inhaled steroid or LTRA
within the previous 12 weeks.
• EXCLUSION CRITERIA
• Other clinical trial involvement
within 90 days.
• Change in asthma medication
within previous 12 weeks.
• Abuser of alcohol or illicit drugs.
• Other pulmonary disorder
or unresolved respiratory
infection in previous
12 weeks.
• A history of life-threatening
illness
• Systemic, intramuscular or
intra-articular corticosteroids in
previous 2 weeks
Price et al NEJM 2011;364:1695-1707

17. Blinding…..
• General practitioners (GPs)/practice asthma nurses and
participants were aware of the randomisation
• Study research assistants were blinded to the randomisation.
• Random allocation given directly to GPs / practice nurses by
independent automated telephone system
• GPs / practice nurses had minimal involvement in data collection
and continued with normal management following allocation
• Study research assistants collected resource use information,
prescribing record data, and clinical resource utilisation data at the
end of the study period
• When collecting resource data research assistants were blind to
the randomised allocation of the participants

18. Outcome measures
Primary:
• Asthma Quality of Life Questionnaire (AQLQ) at 2 months
The trial was designed to test for equivalence wrt the MiniAQLQ
Secondary outcome measures included (at 2 months and 2 years):
• Asthma Quality of Life Questionnaire (AQLQ) at 2 years
• Adherence (based on prescription records)
• Asthma Control Questionnaire (ACQ)
• Royal College of Physicians 3-item asthma questionnaire (RCP3)
• 14-item Mini Rhinoconjunctivitis Quality of Life Questionnaire
(MiniRQLQ)
• Severe asthma exacerbations - course of oral steroids or hospitalization for
asthma
Price et al NEJM 2011;364:1695-1707

19. Statistical Methods
• Primary analysis: intention-to-treat analysis of the
MiniAQLQ score at 2 months.
• Criterion for equivalence: 95% confidence interval
for the difference in the MiniAQLQ score would be
between –0.3 and 0.3.
• Conservative approach in selecting 0.3 (min.
clinically important difference for MiniAQLQ = 0.5)
Price et al NEJM 2011;364:1695-1707

20. ELEVATE: demographics and drop out rates
Comparison to other studies (ELEVATE Step 2, GOAL)
1. Bateman ED, et al. Am. J. Respir. Crit. Care Med. 2004; 170: 836-844. 170. p.836, (2004)
Characteristic
ELEVATE
Step 2; N=306
GOAL1
Strata 1; N=1098
Sex (% Female) 51% 57%
Age * 45.8 (16.4) 36.3 (15.6)
Quality of Life
(Juniper AQLQ 1, worst, to 7)
4. 74 (1.04) 4.4 (1.00)
Lung Function *
86
%PPEF
77
%PFEV1
Percent reversibility * 8.9% (9.86) 22% (12.2)
Smokers – current 21.9% 9.5%
Drop out rate 4.0% 15.4%

21. Months
ELEVATE:
main results
Price et al. N Engl J Med. 2011 May 5;364(18):1695-707
Months

22. Adjusted Mean Difference
2 mo -0.02 (-0.24, 0.20)
2 yr -0.11 (-0.35, 0.13)
Price et al. N Engl J Med. 2011 May 5;364(18):1695-707
Main results: primary outcome

23. WHY THE DIFFERENCE…?

24. Different types of trial: the evidence paradigmPopulation
Broad
Narrow
Ecology of
care
Free
Constrained
Highly controlled Pragmatically
controlled
Observational
Managed
as...
Clinical
diagnosis
Confirmed
diagnosis Registration RCTs
Long term
phase III
Pragmatic RCTs
Observational
studies
http://www.effectivenessevaluation.org/ Roche N, Price D et. al 2013 Lancet Respir Med; 1(10):e29-30
ELEVATE
Long term
phase III
`
Different
population
Different Management`

25. The PRECIS Wheel
• The Pragmatic–Explanatory Continuum Indicator Summary
(PRECIS) wheel provides a structured approach to assessing the
extent to which studies may provide direct/indirect evidence
• 9 “spokes,” each representing a different element of the study
design (e.g., study eligibility criteria, expertise of individuals applying
the intervention).
• Each spoke, or axis, represents an explanatory– pragmatic (i.e.,
efficacy–effectiveness) continuum, and aspects of a trial are
scored/positioned along each respective axis depending on the
extent to which they reflect the characteristics of an explanatory
(efficacy) RCT or a pragmatic effectiveness trial
Thorpe KE, et al. CMAJ 2009;180:E47–E57.

26. The PRECIS Wheel
Pragmatic (A) vs Classical RCT mapped on the PRECIS wheel domains. The
visual representation shows the clear gaps in the efficacy trial design
B. Malmstrom K, et al. Ann Intern Med
1999;130:487–495.
A. Price D, et al.
Health. Technol Assess 2011;15:1–132
Wong GW, et al. Ann Am Thorac Soc. 2014;11:472
• Choice of a Clinically Relevant Endpoint
• Duration of Follow-up Relevant to
Patient Care
• LTRA and ICS given according to normal
clinical practice.
• Patients receiving disallowed asthma
medications remained in the study

27. Call the detective…
ELEVATE adherence
Price et al. N Engl J Med. 2011 May 5;364(18):1695-707

28. Drivers of the ELEVATE trial resutls:
smoking subgroup
Price et al. N Engl J Med. 2011 May 5;364(18):1695-707

29. Drivers of the ELEVATE trial results: rhinitis
subgroup?
Price et al. N Engl J Med. 2011 May 5;364(18):1695-707
• MiniRQLQ score was significantly better at 2
months but not at 2 years for patients receiving
LTRA

30. Crossover implications
• Non-adherence in a non-inferiority trial can
create a bias toward a finding of equivalence.
• Substantial crossover can result in greater
similarity between the treatment regimens that
are ultimately followed, yielding similar
outcomes in comparator arms

31. Changes in Treatment According to
Assigned Treatment
Bias away from the Null:
Number of patients
LTRA
n(%)
ICS
n(%)
Total in group 145 155
Changes at 2 months 8 (6%) 5 (3%)
Changes at 2 years 45 (31%) 32 (21%)

32. Other drivers…?
The subgroups of patients:
• Smoke and have non-eosinophilic disease?
• With/without evidence for a mixture of chronic and reactive
obstructive pulmonary disease?
• With rhinitis versus:
• Diagnosed vs Managed vs Self-reported
• With reversibility/without (limited) reversibility?
• Staying with assigned randomised therapy versus those going
off that therapy/those going to other therapy
• With higher vs lower ACQ cut points?
• Duration since diagnosis versus response

33. Strengths
• UK Government Funded
• Choice of a Clinically
Relevant Endpoint
• Relevant Comparison of
Alternative Treatments
• Duration of Follow-up
Relevant to Patient Care
• Intensive Monitoring of
Adverse Events
• Open-label Design with
Patient-Reported Primary
Outcome
• Equivalence Design with
Flexible Treatment
Regimens Allowing Bias
Away from the Null
• Equivalence design with
substantial cross-over
• Un-blinded design with
primary endpoint based
on patient self-
assessment
Limitations

34. CONCLUSIONS

35. Conclusions: ELEVATE
The question asked by ELEVATE was:
“In a broad primary are population who have been
considered for commencement of regular anti-inflammatory
therapy, is initiation of therapy via LTRA non-inferior to
ICS?”
The results suggest that starting anti-inflammatory therapy
as LTRA is non-inferior to initiating as ICS:
• In this new-initiation patient population
• Treated in a less onerous ecology of care than is
used in a classical RCT

36. Real-life studies
Clinical drivers: representative data
Characteristics of routine care populations (clinical, demographic,
lifestyle) can interact with “pure” classical RCT efficacy results

37. Slides courtesy of Dr Dermot Ryan, first presented at the REG Rotterdam Summit, 2015
Haldar et al Am J Respir Crit Care Med. 2008;178:218–224
RCT &
Guideline
Patients
Broad Spectrum of
Routine Care
Patients
In this age of “targeted therapies” to better target our
patients with the treatments we have available.
The Clinician’s Challenge
Asthma Phenotypes

38. Thank you for your attention…
david@rirl.org
http://www.effectivenessevaluation.org