Congreso Latinoamericano de Alergia, Asma e Inmunología 2015 Presidente: Alfonso Mario Cepeda Sarabia Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai: 2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza Buenos Aires, marzo 14-16, 2015

1. XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag
Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza
Buenos Aires, marzo 14-16, 2015 - http://www.slaai2015.com
Programa Congreso Para Todos
XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Recent Advances in the Treatment of Childhood Asthma

2. Robert F. Lemanske, Jr. MD
Professor of Pediatrics and Medicine
University of Wisconsin-Madison
Madison, Wisconsin
Recent Advances in the
Treatment of Childhood Asthma

3. NHLBI Asthma Networks
Childhood Asthma
Research and Education
(CARE) Network
5 centers: 1999, 2004
n National Jewish Medical & Research
Ctr.
n Penn State U. (Data Coordinating
Center)
n U. Arizona
n U. Calif./S.D./Kaiser Perm.
n U. Wisconsin/Madison
n Washington U.

4. Step-wise Approach to
Asthma Therapy
Intermittent
Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
Adjusting therapy based
on asthma CONTROL
Stepping down Stepping up

5. Step-up Approaches in
Asthma
Thomas, Lemanske & Jackson, JACI 128:915, 2011

6. Step-up
Long Term
in Preschool
Children

7. Preventing Early Asthma in Kids:
The PEAK Trial
Can early recognition and
treatment of children at high
risk of developing asthma
prevent the disease process?
Guilbert T et al. NEJM 354:1985, 2006

8. • Randomized, multicenter, double-blind, parallel
group, placebo-controlled trial
• 285 two and three year olds at high-risk for asthma
• Fluticasone 44 µg/puff or placebo (2 puffs b.i.d.)
Year 3
Screening/
Eligibility Run-in
Interim Efficacy Tests
PEAK: Study Design
Years 1 & 21 month
Randomize
Treatment Observation
Guilbert T et al. NEJM 354:1985, 2006

9. Episode-free Days During the
Entire Study
Guilbert T et al. NEJM 354:1985, 2006
Treatment Phase:
↓ Exacerbations
↓ Supplemental
medications (ICS
and LTRA)
= bronchodilator
use and
unscheduled visits
Observation Phase:
= Exacerbations
= Supplemental
medications (ICS
and LTRA)
= Bronchodilator
use and
unscheduled visits

10. Do Baseline Characteristics
Influence Treatment Response?
Percentage of EFDs
Stratifying Variable
ICS Mean
(95% CI)
Placebo Mean
(95% CI)
Difference
(95% CI)
P-value
(ICS vs
Placebo)
Male 93 (92, 95) 86 (83, 89) 7.3 (3.9, 11.1) 0.0005
Female 92 (89, 94) 92 (89, 94) 0.1 (-3.4, 3.5) 0.9
Caucasian 93 (91, 95) 84 (80, 88) 9.1 (4.8, 13.9) 0.0001
Non-Caucasian 92 (89, 94) 93 (91, 94) -1.0 (-3.9, 1.7) 0.6
Run-In EFD <80% 92 (90, 94) 84 (79, 87) 8.6 (4.2, 13.2) 0.0009
Run-In EFD >=80% 93 (91, 95) 93 (91, 95) 0.0 (-2.5, 2.5) 0.9
ED/Hospitalization History 95 (93, 96) 87 (83, 90) 7.7 (3.9, 11.6 0.0004
No ED/Hospitalization History 90 (87, 92) 91 (89, 93) -1.1 (-4.4, 2.1) 0.6
≥1 Positive Aeroallergen Skin Test 93 (91, 94) 86 (83, 89) 6.5 (3.2, 10.0) 0.0027
Negative Aeroallergen Skin Test 93 (90, 95) 92 (89, 94) 0.9 (-2.5, 4.4) 0.6
Bacharier LB and the NHLBI CARE Network. J Allergy Clin Immunol 2009; 123:1077-82.

11. Safety-Growth

12. All participants
Linear Growth Not Different Two
Years After Treatment Discontinuation
Guilbert, JACI 2011 Nov;128(5):956-63

13. 0 4 8 12 16 20 24 28 32 36 48
Months
Heightchangefrombaseline(cm)
Differencebetweentreatmentandplacebogroup
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
†
† †
‡
† †
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
† † † † †
3 years
2 years
Age at baseline
All Subjects
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
† †
‡
‡ ‡ † †
‡
>= 15kg
< 15kg
Weight at baseline
2 years old at baseline
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
‡ †
‡ † †
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0 >= 15kg
< 15kg
Weight at baseline
3 years old at baseline
on treatment off treatment
Linear Growth Differs by Age and Weight

14. PEAK Conclusions:
Efficacy
n In preschool children at increased risk of developing
asthma (+ API), regular treatment with an ICS:
n Significantly reduces days with asthma symptoms and reduces
exacerbations requiring prednisone
n Improves pulmonary function
n When the daily therapy is stopped:
n Symptoms return and pulmonary function is no longer improved
compared to placebo treatment
n ICS treatment clearly can control asthma disease
burden, but it does not appear to alter its natural
history or expression
Guilbert TW et al. NEJM 354:1985, 2006

15. Peak Conclusions:
Safety
n In the study cohort as a whole, linear growth was
not significantly different in preschool age children
treated with ICS compared to placebo 2 years after
ICS is stopped
n In a post-hoc analysis, those children treated with
ICS who are younger in age and of lesser weight
had less linear growth, possibly due to a higher ICS
exposure. Consider keeping dose under 10-12mcg/
kg/day to avoid growth effects in 2-3 year olds
n Different medication formulations, devices, or
spacers could alter these findings

16. Step-up
Short Term in
Preschool
Children

17. Acute Intermittent Management
Strategies (AIMS)
Placebo LTRA + Placebo ICS + b-agonist
Montelukast 4 mg daily + Placebo ICS + b-agonist
At first sign of RTI symptoms x 7 days
Study Overview
Budesonide 1 mg bid + Placebo LTRA + b-agonist
RandomizationRun in
• Randomized, multicenter, double-blind, placebo-controlled trial
• 238 children 12-59 months w/ recurrent episodes of intermittent wheezing
-2 episodes in the previous year
-2 urgent care visits, 2 oral steroid courses, or 1 of each
• Primary outcome = episode free days
• Secondary outcomes = symptoms scores during illnesses & OCS use
Bacharier L. et al. JACI 122:1127, 2009

18. AIMS Results
n ~3.5 respiratory tract illnesses per child in the year
long study
n No difference in primary outcome (EFDs) or in oral
corticosteroid use
EFDs (95% CI) OCS courses (95% CI)
Conventional Therapy 74% (65% to 81%) 0.9 (0.6-1.4)
Montelukast 73% (66% to 79%) 1.0 (0.7-1.3)
Budesonide 76% (70% to 81%) 0.7 (0.5-1.0)
Bacharier L. et al. JACI 122:1127, 2009

19. Differences in Symptoms
• Significant differences seen in API+ but not API-
children
• Greater differences seen in children with a history of
OCS use in the past year
• No growth effects of intermittent high-dose ICS
Bacharier L. et al. JACI 122:1127, 2009

20. Step-up
Long vs Short
Term

21. ICS Options for Preschool
Children with Recurrent
Wheeze and Past Year
Exacerbations
Long Short
Zeiger R et al. NEJM 365:1990, 2011

22. MIST Protocol: Overview
Treatment Phase: 52 Weeks
Randomized
Treatment
Group
Nightly EXCEPT
During Respiratory
Tract Illnesses
During Respiratory
Tract Illnesses
ONLY for 7 days
Daily
low-dose
Budesonide
Budesonide
0.5 mg PM
Placebo AM
Budesonide
0.5 mg PM
Intermittent
high-dose
Budesonide
Placebo PM
Budesonide
1.0 mg AM
1.0 mg PM
Cohort (N=278): Ages 12-53 mo, frequent wheeze,
modified API, past year exacerbation, intermittent illnesses
Run-in: placebo respule nightly + albuterol prn

23. Intermittent
Daily
p-value=0.87
0 50 100 150 200 250 300 350 400
0
20
40
60
80
100
B.
Days
%ofPatientswithouta
CourseofPrednisolone
139 114 100 89 78 71 64 50
139 114 93 84 74 66 54 40
Number at Risk
Intermittent
Daily
23
Time to 1st Exacerbation Similar
with Daily vs Intermittent ICS
(Rate 0.95/person yr)
(Rate 0.97/person yr)
Zeiger R et al. NEJM 365:1990, 2011

24. Lessons from MIST
In API positive preschoolers
with frequent wheeze & prior year exacerbations
n Illness burden is substantial despite ICS therapy
n Intermittent high-dose budesonide started early during
predefined respiratory tract illnesses and continued for 7 days,
may be an alternative option to daily low-dose budesonide given
its
ü similar outcomes
ü less frequent use
ü lower ICS exposure
Zeiger R et al. NEJM 365:1990, 2011

25. Step-up
Long Term
in School-aged
Children

26. BADGER: Research Question
n In children not satisfactorily controlled on
low dose ICS (fluticasone 100 µg BID)
therapy, what is the next best treatment
approach?
n Increased doses of ICS (fluticasone 250 µg BID)?
n Add a LABA (salmeterol/fluticasone combination)?
n Add a LTRA (montelukast)?
Lemanske RF et al. NEJM 362:975, 2010

27. BADGER: Novel Trial Design
n Each participant would receive all 3 treatment
options
n Determine the presence or absence of a
differential response among those treatments
using a composite outcome that evaluated 3
components in defining asthma control:
n Impairment domain
n Asthma control days
n Pulmonary function (FEV1)
n Risk domain
n Asthma exacerbations
Lemanske RF et al. NEJM 362:975, 2010

28. BADGER Protocol: Overview
Period 1 Period 2 Period 3Run-in period
on 1xICS to
demonstrate
lack of
control
16 weeks 16 weeks 16 weeks
Run-in Period
2-8 weeks
Randomization
Three Treatment Period, Double blind, 3 way cross-over
2.5 x ICS = fluticasone DPI 250 µg BID
1xICS+LABA = fluticasone/salmeterol DPI 100/50 BID
1xICS+LTRA = fluticasone DPI 100 µg BID + montelukast
1xICS = fluticasone DPI
100 µg BID
2.5 x ICS or
1x ICS +
LABA or
1 x ICS +
LTRA
2.5 x ICS or
1x ICS +
LABA or
1 x ICS +
LTRA
2.5 x ICS or
1x ICS +
LABA or
1 x ICS +
LTRA
Evaluation Period Evaluation Period Evaluation Period

29. LABA
ICS
Primary Outcome: Probability of BEST
Response Based on Composite Outcome*
LTRA
*Covariate adjusted model
LABA step-up was more than 1.5 times as
likely to produce the best response
(p = 0.002)
(p = 0.004)LTRA
LABA
ICS
Lemanske RF et al. NEJM 362:975, 2010

30. Step-up
Intermittent in
School-aged
Children

31. Research Question: Children
n In patients receiving daily low dose ICS
treatment who are well controlled, can
ICS doses be reduced and, if possible,
what is the best strategy for doing so?
TREXA
TReating Children to Prevent
EXacerbations of Asthma

32. TREXA Protocol: Overview
Daily Therapy ReliefGroup
Treatment Groups
Run-in to
demonstrate
control on low
dose ICS
8 weeks 44 weeks
Randomize
Major outcome measure:
Asthma exacerbations
ICS + AlbICS BIDA
Combined ICS
ICS BID
Placebo ICS
+ AlbB
Daily ICS
ICS + AlbPlacebo ICS BIDC
Rescue ICS
Placebo ICS
+ AlbPlacebo ICS BIDD
“Placebo”

33. TREXA: Regimens on Exacerbations
Requiring Oral Corticosteroids
Timeto1stExacerbation
Daily ICS
p=0.03
Combined ICS
p=0.07
Rescue ICS
p=0.07
Placebo
p values adjusted for
multiple comparisons
(Hochberg-Bonferroni) (Martinez F, Lancet 2011;377:650-7)

34. 8.5%
23.0%
5.6%
2.8%
0%
10%
20%
30%
40%
Entire +API Cohort
TREXA: Regimens on
Treatment Failures
Rescue
P=0.024
Placebo
Combined
P=0.012 Daily
P=0.009
(Martinez F, Lancet 2011;377:650-7)
TreatmentFailure
(2oralsteroidcourses)
N=71 N=71 N=71 N=74

35. TREXA: Regimens on
Linear Growth
Rescue ICS
Combined ICS
Daily ICS
1.1
cm
PlaceboP < 0.001
(Martinez F, Lancet 2011;377:650-7)

36. TREXA - Conclusions
n Discontinuing ICS causes an unacceptable
increase in exacerbations in children with
well-controlled, mild persistent asthma
n Daily ICS is the most effective treatment for
preventing exacerbations; adding rescue ICS
to daily ICS does not add benefit
n Rescue ICS with albuterol (step-up
intermittent therapy) demonstrates benefits
over albuterol alone and avoids daily ICS
administration and its growth effects

37. CARE Pediatric Asthma Trials:
Summary
Intermittent
Asthma Persistent Asthma
Step 1
Step 2
Step 3
Step 4
Step 5
Step 6
PEAK
BADGER
TREXA
MIST
AIMS

38. XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología 2015
Presidente: Alfonso Mario Cepeda Sarabia
Comité Organizador Local: Edgardo Jares, Anahí Yañez, Estrella Asayag
Presidentes Sociedad Latinoamericana de Alergia, Asma e Inmunología, Slaai:
2013-2015: Alfonso Mario Cepeda Sarabia - 2015-2017: Juan Carlos Sisul Alvariza
Buenos Aires, marzo 14-16, 2015
http://www.slaai2015.com/comites-del-congreso/
Información Slaai: www.slaai.org
Programa Congreso Para Todos
Conferencias XVIII Congreso Latinoamericano de Alergia, Asma e Inmunología
Sociedad Latinoamericana de Alergia, Asma e Inmunología, SLaai