Asthma in Children: Asthma in Children: Step CareStep Care

Stanley J. Szefler, MD

Helen Wohlberg and Herman Lambert Chair in Pharmacokinetics,Head, Pediatric Clinic Pharmacology,

National Jewish Health&

Professor of Pediatrics and Pharmacology, University of Colorado School of Medicine

Learning ObjectivesLearning Objectives

• • To review recent studies that impact To review recent studies that impact the approach to asthma therapy.the approach to asthma therapy.

• • To summarize key findings that To summarize key findings that differentiate treatment in children.differentiate treatment in children.

• • To indicate methods to select therapy To indicate methods to select therapy to optimize effect and minimize adverse to optimize effect and minimize adverse effects.effects.

DisclosureDisclosure

Advisory Board Advisory Board for Boehringer Ingelheim, for Boehringer Ingelheim, Genentech, GlaxoSmithKline and MerckGenentech, GlaxoSmithKline and Merck

ConsultantConsultant for Genentech for Genentech

Investigator Investigator forfor GlaxoSmithKlineGlaxoSmithKline

Grant support:Grant support:

NHLBI Childhood Asthma Management NHLBI Childhood Asthma Management Program, Asthma Clinical Research Network, Program, Asthma Clinical Research Network, Childhood Asthma Research and Education Childhood Asthma Research and Education Network and AsthmaNetNetwork and AsthmaNet

DisclosureDisclosure

Grant support (continued):Grant support (continued):

NIAID Inner City Asthma Consortium NIAID Inner City Asthma Consortium

NIEHS/EPA Childhood and Environmental NIEHS/EPA Childhood and Environmental Health Center GrantHealth Center Grant

CDPHE Colorado Cardiovascular, Cancer and CDPHE Colorado Cardiovascular, Cancer and Pulmonary Disease ProgramPulmonary Disease Program

Caring for Colorado Foundation, Caring for Colorado Foundation,

GlaxoSmithKline Health Outcomes Program.GlaxoSmithKline Health Outcomes Program.

Primary Goal of Therapy: Achieving Primary Goal of Therapy: Achieving and Maintaining Asthma Controland Maintaining Asthma Control

• • Primary goal of asthma therapy is to enable a Primary goal of asthma therapy is to enable a patient to achieve and maintain patient to achieve and maintain controlcontrol over their over their asthmaasthma

- Eliminate - Eliminate impairmentsimpairments including symptoms, including symptoms, functional limitations, poor quality of life, and functional limitations, poor quality of life, and other manifestations of asthmaother manifestations of asthma

- Reduce - Reduce riskrisk of exacerbations, ED visits, and of exacerbations, ED visits, and hospitalizations hospitalizations

• • Treatment goals are identical for all levels of Treatment goals are identical for all levels of asthma severityasthma severity

NHLBI. National Asthma Education and Prevention Program. Full report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma (EPR-3). Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed August 31, 2007.

Pediatric PopulationPediatric Population

• • NAEPP defined three age groupsNAEPP defined three age groups

- 12 years and above- 12 years and above

- 5 to 11 years of age- 5 to 11 years of age

- Less than 5 years of age- Less than 5 years of age

• • Treatment goals are identical for all age Treatment goals are identical for all age groupsgroups

• • Treatment steps vary by age due to available Treatment steps vary by age due to available studies and disease presentation.studies and disease presentation.

NHLBI. National Asthma Education and Prevention Program. Full report of the Expert Panel: Guidelines for the Diagnosis and Management of Asthma (EPR-3). Available at: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed August 31, 2007.

Assessing Asthma Control and Assessing Asthma Control and Adjusting Therapy Adjusting Therapy

in Youths 12 Years of Age and Adultsin Youths 12 Years of Age and Adults

Stepwise Approach for Managing Asthma Stepwise Approach for Managing Asthma in Youths in Youths >>12 Years of Age and Adults12 Years of Age and Adults

Approaches toApproaches to Personalizing Asthma Management Personalizing Asthma Management

• • Early intervention strategies Early intervention strategies – Who? – Who? What treatment? What outcomes?What treatment? What outcomes?

• • BiomarkersBiomarkers – Which ones? What – Which ones? What application?application?

•• Combination therapy Combination therapy – How soon? – How soon? What type?What type?

• • Genetics/epigeneticsGenetics/epigenetics – Are we there – Are we there yet?yet?

• • ImmunomodulatorsImmunomodulators – benefit-risk? – benefit-risk?

EPR-3 Recommendations:EPR-3 Recommendations:Step-Up TherapyStep-Up Therapy

Intermittent Asthma Persistent Asthma

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

Preferred:Low-dose ICS

Alternative:Either cromolyn, LTRA, nedocromil, or theophylline

CARE Network CLIC Study Timeline

Assessment/Assessment/CharacterizationCharacterization

MtMt

Treatment PhaseTreatment Phase

FPFP

MtMt

FPFP

FPFP FPFP

MtMt MtMt

ConsentConsentAsthma HxAsthma HxeNOeNOPFTsPFTsBD responseBD responseBiomarkersBiomarkersGeneticsGeneticsDiary and PFMDiary and PFM

Review diaryReview diaryeNOeNOPFTsPFTsMethacholineMethacholineSkin testingSkin testing

Visit Visit 11 22 33 44 55 66

Week Week -1-1 00 44 88 1212 1616

Review diaryReview diaryeNOeNOPFTsPFTs

Ran

do

miz

atio

nR

and

om

izat

ion

CLIC Primary Outcome: CLIC Primary Outcome: FEVFEV11 Response Response

FEVFEV11 % Change with FP % Change with FP

FE

VF

EV

11 %

Ch

an

ge

wit

h M

t %

Ch

an

ge

wit

h M

t

Mt alonen=6 (5%)

Neithern=69 (55%)

FP alonen=29 (23%)

Bothn=22 (17%)

Line of identity

Concordance Correlation 0.55 (0.43, 0.65)Concordance Correlation 0.55 (0.43, 0.65)

>>7.

5% M

t7.

5% M

t R

esp

on

seR

esp

on

se

>>7.5% FP Response7.5% FP Response

Ref. Szefler SJ and CARE Network. JACI 2005;115:233-42.

-50-40-30-20-10

01020304050

-50 -40 -30 -20 -10 0 10 20 30 40 50

Baseline Characteristic (Categorical)Baseline Characteristic (Categorical) FPFP MtMt

FEVFEV11 < 90% predicted (pre-BD) < 90% predicted (pre-BD) 4.16**4.16** 1.781.78

FEVFEV11/FVC < 0.80 (pre-BD)/FVC < 0.80 (pre-BD) 4.26**4.26** 2.40*2.40*

Methacholine PCMethacholine PC2020 ≤≤ 1 mg/ml 1 mg/ml 2.62*2.62* 1.171.17

eNO > 25 ppbeNO > 25 ppb 2.75*2.75* 2.032.03

TEC > 350 cells/mmTEC > 350 cells/mm33 2.34*2.34* 1.621.62

Serum ECP > 15 Serum ECP > 15 g/Lg/L 2.78**2.78** 1.181.18

IgE > 200 kU/LIgE > 200 kU/L 2.86**2.86** 0.960.96

uLTEuLTE44 > 100 pg/mg > 100 pg/mg 2.032.03 3.22*3.22*

FemaleFemale 1.141.14 2.302.30

MinorityMinority 0.840.84 1.981.98

Age Age ≤≤ 10 years 10 years 0.640.64 2.50*2.50*

**p **p ≤≤ 0.01; *p 0.01; *p ≤≤ 0.05 0.05

CLIC FEVCLIC FEV11 Response ≥ 7.5%: Response ≥ 7.5%:

Odds RatioOdds Ratio

Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005;115:233-42.

CLIC Differential CLIC Differential Response AnalysisResponse Analysis

• Higher bronchodilator useHigher bronchodilator use

• Greater response to bronchodilatorGreater response to bronchodilator

• Higher exhaled nitric oxideHigher exhaled nitric oxide

• Higher serum eosinophilic cationic proteinHigher serum eosinophilic cationic protein

• Lower pre-bronchodilator FEVLower pre-bronchodilator FEV11 percent predicted percent predicted

• Lower FEVLower FEV11/FVC/FVC

• Lower methacholine PCLower methacholine PC2020

Greater response to fluticasone over montelukast Greater response to fluticasone over montelukast for increased FEVfor increased FEV11 was associated with: was associated with:

Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005;115:233-42.

CLIC ConclusionsCLIC Conclusions

• Children with lower pulmonary function or higher Children with lower pulmonary function or higher levels of markers associated with allergic levels of markers associated with allergic inflammation should receive ICS therapy.inflammation should receive ICS therapy.

• Children without these indicators could receive a Children without these indicators could receive a therapeutic trial of either ICS or LTRA.therapeutic trial of either ICS or LTRA.

How does the asthma-related phenotype influence the choice of medication selected to improve pulmonary function?

Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005;115:233-42.

Follow-up StudyFollow-up Study

• LTELTE44/FE/FENONO ratios were associated with a greater response to ratios were associated with a greater response to montelukast than FP for FEVmontelukast than FP for FEV11 and for asthma control days. and for asthma control days.

• Children with high LTEChildren with high LTE44/FE/FENONO ratios were likely to be younger ratios were likely to be younger and female and exhibit lower levels of atopic markers and and female and exhibit lower levels of atopic markers and methacholine reactivity.methacholine reactivity.

Can we predict who would have a better response to montelukast over ICS?

Ref. Rabinovitch N and the CARE Network. J Allergy Clin Immunol 2010;126:545-51 and 959-61.

EPR-3 RecommendationsEPR-3 Recommendations

Intermittent Asthma Persistent Asthma

Step 1

Step 2

Step 3

Step 4

Step 5

Step 6

BADGER Protocol: BADGER Protocol: OverviewOverview

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

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

*Ref. Lemanske RF and CARE Network. NEJM 2010;362:975-985.

LABA step-up was more than 1.5 times as likely to produce the best response

(p = 0.002)

(p = 0.004)

BADGER Study: ConclusionsBADGER Study: Conclusions

• • Significant variability in treatment response was Significant variability in treatment response was noted at the Step-3 level.noted at the Step-3 level.

•• LABA step-up therapy was more than 1.5 times LABA step-up therapy was more than 1.5 times as likely to produce the best response.as likely to produce the best response.

• Many children demonstrated a best response to Many children demonstrated a best response to either step-up ICS or LTRA.either step-up ICS or LTRA.

• Several characteristics, such as baseline ACTSeveral characteristics, such as baseline ACT®®, , eczema,eczema, and race could be useful in selecting and race could be useful in selecting medication treatment for best response.medication treatment for best response.

Ref. Lemanske RF and CARE Network. NEJM 2010;362:975-985.

Summary PointsSummary Points

• • Inhaled corticosteroids are the preferred long-term Inhaled corticosteroids are the preferred long-term controller therapy at Step 2 level.controller therapy at Step 2 level.

•• At Step 3 Level, LABA step-up therapy was more than At Step 3 Level, LABA step-up therapy was more than 1.5 times as likely to produce the best response.1.5 times as likely to produce the best response.

• LTRA are alternative choices for Step 2 long-term LTRA are alternative choices for Step 2 long-term controller and supplementary Step 3.controller and supplementary Step 3.

• Variable response can occur at either Step 2 or Step 3 Variable response can occur at either Step 2 or Step 3 therapy and alternative treatments may be selected therapy and alternative treatments may be selected within each Step before stepping up therapy.within each Step before stepping up therapy.

Inner-City Anti-IgE Therapy for Inner-City Anti-IgE Therapy for Asthma (ICATA)Asthma (ICATA)

Published by Busse et al, New Published by Busse et al, New Eng J Med 2011;364:1005-1015Eng J Med 2011;364:1005-1015Published by Busse et al, New Published by Busse et al, New

Eng J Med 2011;364:1005-1015Eng J Med 2011;364:1005-1015

A Randomized Trial to Evaluate the Impact of the Addition of Omalizumab to Guidelines Based Therapy of Inner-City Children and

Adolescents with Asthma

A Randomized Trial to Evaluate the Impact of the Addition of Omalizumab to Guidelines Based Therapy of Inner-City Children and

Adolescents with Asthma

Enrollment characteristicsEnrollment characteristics• 6 to 20 years of age with a diagnosis 6 to 20 years of age with a diagnosis

of persistent asthmaof persistent asthma

• Allergy to a perennial allergenAllergy to a perennial allergen

• Inner-city residentInner-city resident

• At recruitment, participants had At recruitment, participants had uncontrolled asthma uncontrolled asthma

• Weight and total serum IgE levels Weight and total serum IgE levels were suitable for omalizumab dosingwere suitable for omalizumab dosing

Study DesignStudy Design

• Enrollment (4 weeks)Enrollment (4 weeks)

– Asthma control assessedAsthma control assessed

– Using a Guidelines-based algorithm, treatment Using a Guidelines-based algorithm, treatment was begun or adjusted to achieve asthma was begun or adjusted to achieve asthma controlcontrol

• Randomization and treatment (60 weeks)Randomization and treatment (60 weeks)

– Following an adjustment of asthma Following an adjustment of asthma medications during enrollment, participants medications during enrollment, participants were randomized to receive omalizumab or were randomized to receive omalizumab or placebo every 2 to 4 weeks for 60 weeksplacebo every 2 to 4 weeks for 60 weeks

The effect of omalizumab on exacerbationsThe effect of omalizumab on exacerbations

Difference of -16.5% with an exacerbation (p<0.001)

(n=211)(n=208)

Effect of Omalizumab on Asthma Exacerbations

Effect of Omalizumab on Asthma Exacerbations

% o

f P

artic

ipan

ts w

ith E

xace

rbat

ions

(n=211)(n=208)

Asthma Management

• Utilize asthma characteristics, biomarkers, and genetics to “profile” asthma severity and prognosis.

• Select medications based on driving factors of disease presentation and predictors of response.

• Monitor response and assess reasons for treatment failure.

• Develop proactive approach and adjust therapy accordingly.

Individualized or “Personalized” Approach

Where Do We Go From Here?Where Do We Go From Here?

• Improve process of asthma management to Improve process of asthma management to apply step-care approachapply step-care approach

• Identify alternative biomarker for Step 3Identify alternative biomarker for Step 3• Assess “step-up” treatment strategies to Assess “step-up” treatment strategies to

improve control and reduce exacerbationsimprove control and reduce exacerbations• Environment control measuresEnvironment control measures• Reduce impact of viral infectionReduce impact of viral infection• Immune-based therapy to reduce impact of Immune-based therapy to reduce impact of

allergen-induced inflammation.allergen-induced inflammation.

Possibilities to improve asthma control

Future Approaches toFuture Approaches to Improving Asthma Management Improving Asthma Management

• • GeneticsGenetics• • Early interventionEarly intervention• • ImmunomodulatorsImmunomodulators• • BiomarkersBiomarkers• • Combination therapyCombination therapy