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

Robert F. Lemanske, Jr. MD Professor of Pediatrics and Medicine

University of Wisconsin-Madison

Madison, Wisconsin

Recent Advances in the Treatment of Childhood Asthma

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.

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

Step-up Approaches in Asthma

Thomas, Lemanske & Jackson, JACI 128:915, 2011

Step-up Long Term

in Preschool Children

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

•  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 & 2 1 month

Randomize

Treatment Observation

Guilbert T et al. NEJM 354:1985, 2006

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

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.

Safety-Growth

All participants

Linear Growth Not Different Two Years After Treatment Discontinuation

Guilbert, JACI 2011 Nov;128(5):956-63

0 4 8 12 16 20 24 28 32 36 48

Months

Hei

ght c

hang

e fro

m b

asel

ine

(cm

)D

iffer

ence

bet

wee

n tre

atm

ent a

nd p

lace

bo g

roup

-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 years2 years

Age at baselineAll Subjects

-2.0

-1.5

-1.0

-0.50.0

0.5

1.0

-2.0

-1.5

-1.0

-0.50.0

0.5

1.0

† †‡

‡ ‡ † †‡

>= 15kg< 15kg

Weight at baseline2 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 baseline3 years old at baseline

on treatment off treatment

Linear Growth Differs by Age and Weight

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

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

Step-up Short Term in

Preschool Children

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

Randomization Run 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

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

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

Step-up Long vs Short

Term

ICS Options for Preschool Children with Recurrent Wheeze and Past Year

Exacerbations

Long Short

Zeiger R et al. NEJM 365:1990, 2011

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

IntermittentDaily

p-value=0.87

0 50 100 150 200 250 300 350 4000

20

40

60

80

100

B.

Days

% o

f Pat

ient

s with

out a

Cour

se o

f Pre

dniso

lone

139 114 100 89 78 71 64 50139 114 93 84 74 66 54 40

Number at RiskIntermittentDaily

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

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

Step-up Long Term

in School-aged Children

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

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

BADGER Protocol: Overview

Period 1 Period 2 Period 3 Run-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

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

Step-up Intermittent in School-aged

Children

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

TREXA Protocol: Overview

Daily Therapy Relief Group

Treatment Groups

Run-in to demonstrate

control on low dose ICS

8 weeks 44 weeks

Randomize

Major outcome measure:

Asthma exacerbations ICS + Alb ICS BID A

Combined ICS ICS BID

Placebo ICS + Alb B

Daily ICS

ICS + Alb Placebo ICS BID C

Rescue ICS Placebo ICS

+ Alb Placebo ICS BID D

“Placebo”

TREXA: Regimens on Exacerbations Requiring Oral Corticosteroids

Tim

e to

1st E

xace

rbat

ion

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)

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)

Trea

tmen

t Fai

lure

(2

ora

l ste

roid

cou

rses

)

N=71 N=71 N=71 N=74

TREXA: Regimens on Linear Growth

Rescue ICS

Combined ICS

Daily ICS

1.1 cm

Placebo P < 0.001

(Martinez F, Lancet 2011;377:650-7)

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

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

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