Asthma in Children Step Care Stanley J Szefler

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Asthma in Children: Step Care Stanley J. Szefler, MD Helen Wohlberg and Herman Lambert

Asthma in Children: Step 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 Objectives • To review recent studies that impact the approach to asthma therapy.

Learning Objectives • To review recent studies that impact the approach to asthma therapy. • To summarize key findings that differentiate treatment in children. • To indicate methods to select therapy to optimize effect and minimize adverse effects.

Disclosure Advisory Board for Boehringer Ingelheim, Genentech, Glaxo. Smith. Kline and Merck Consultant for

Disclosure Advisory Board for Boehringer Ingelheim, Genentech, Glaxo. Smith. Kline and Merck Consultant for Genentech Investigator for Glaxo. Smith. Kline Grant support: NHLBI Childhood Asthma Management Program, Asthma Clinical Research Network, Childhood Asthma Research and Education Network and Asthma. Net

Disclosure Grant support (continued): NIAID Inner City Asthma Consortium NIEHS/EPA Childhood and Environmental Health

Disclosure Grant support (continued): NIAID Inner City Asthma Consortium NIEHS/EPA Childhood and Environmental Health Center Grant CDPHE Colorado Cardiovascular, Cancer and Pulmonary Disease Program Caring for Colorado Foundation, Glaxo. Smith. Kline Health Outcomes Program.

Primary Goal of Therapy: Achieving and Maintaining Asthma Control • Primary goal of asthma

Primary Goal of Therapy: Achieving and Maintaining Asthma Control • Primary goal of asthma therapy is to enable a patient to achieve and maintain control over their asthma - Eliminate impairments including symptoms, functional limitations, poor quality of life, and other manifestations of asthma - Reduce risk of exacerbations, ED visits, and hospitalizations • Treatment goals are identical for all levels of asthma 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 Population • NAEPP defined three age groups - 12 years and above -

Pediatric Population • NAEPP defined three age groups - 12 years and above - 5 to 11 years of age - Less than 5 years of age • Treatment goals are identical for all age groups • Treatment steps vary by age due to available 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 Adjusting Therapy in Youths 12 Years of Age and Adults

Assessing Asthma Control and Adjusting Therapy in Youths 12 Years of Age and Adults

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

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

Approaches to Personalizing Asthma Management • Early intervention strategies – Who? What treatment? What

Approaches to Personalizing Asthma Management • Early intervention strategies – Who? What treatment? What outcomes? • Biomarkers – Which ones? What application? • Combination therapy – How soon? What type? • Genetics/epigenetics – Are we there yet? • Immunomodulators – benefit-risk?

EPR-3 Recommendations: Step-Up Therapy Preferred: Low-dose ICS Alternative: Either cromolyn, LTRA, nedocromil, or theophylline.

EPR-3 Recommendations: Step-Up Therapy Preferred: Low-dose ICS Alternative: Either cromolyn, LTRA, nedocromil, or theophylline. Step 4 Step 3 Step 2 Step 1 Intermittent Asthma Persistent Asthma Step 6 Step 5

CARE Network CLIC Study Timeline Assessment/ Characterization Randomization Treatment Phase Mt Mt FP FP

CARE Network CLIC Study Timeline Assessment/ Characterization Randomization Treatment Phase Mt Mt FP FP Mt Mt Visit 1 2 3 4 5 6 Week -1 0 4 8 12 16 Consent Asthma Hx e. NO PFTs BD response Biomarkers Genetics Diary and PFM Review diary e. NO PFTs Methacholine Skin testing Review diary e. NO PFTs

>7. 5% Mt Response FEV 1 % Change with Mt CLIC Primary Outcome: FEV

>7. 5% Mt Response FEV 1 % Change with Mt CLIC Primary Outcome: FEV 1 Response Concordance Correlation 0. 55 (0. 43, 0. 65) 50 Mt alone 40 n=6 (5%) 30 20 10 0 -10 -20 ty i t n e d -30 fi o Neither -40 Line n=69 (55%) -50 -40 -30 -20 -10 Ref. Szefler SJ and CARE Network. JACI 2005; 115: 233 -42. Both n=22 (17%) FP alone n=29 (23%) >7. 5% FP Response 0 10 20 30 FEV 1 % Change with FP 40 50

CLIC FEV 1 Response ≥ 7. 5%: Odds Ratio Baseline Characteristic (Categorical) FP Mt

CLIC FEV 1 Response ≥ 7. 5%: Odds Ratio Baseline Characteristic (Categorical) FP Mt FEV 1 < 90% predicted (pre-BD) 4. 16** 1. 78 FEV 1/FVC < 0. 80 (pre-BD) 4. 26** 2. 40* Methacholine PC 20 ≤ 1 mg/ml 2. 62* 1. 17 e. NO > 25 ppb 2. 75* 2. 03 TEC > 350 cells/mm 3 2. 34* 1. 62 Serum ECP > 15 g/L 2. 78** 1. 18 Ig. E > 200 k. U/L 2. 86** 0. 96 u. LTE 4 > 100 pg/mg 2. 03 3. 22* Female 1. 14 2. 30 Minority 0. 84 1. 98 Age ≤ 10 years 0. 64 2. 50* **p ≤ 0. 01; *p ≤ 0. 05 Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005; 115: 233 -42.

CLIC Differential Response Analysis Greater response to fluticasone over montelukast for increased FEV 1

CLIC Differential Response Analysis Greater response to fluticasone over montelukast for increased FEV 1 was associated with: • Higher bronchodilator use • Greater response to bronchodilator • Higher exhaled nitric oxide • Higher serum eosinophilic cationic protein • Lower pre-bronchodilator FEV 1 percent predicted • Lower FEV 1/FVC • Lower methacholine PC 20 Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005; 115: 233 -42.

CLIC Conclusions How does the asthma-related phenotype influence the choice of medication selected to

CLIC Conclusions How does the asthma-related phenotype influence the choice of medication selected to improve pulmonary function? • Children with lower pulmonary function or higher levels of markers associated with allergic inflammation should receive ICS therapy. • Children without these indicators could receive a therapeutic trial of either ICS or LTRA. Ref. Szefler SJ and the CARE Network. J Allergy Clin Immunol 2005; 115: 233 -42.

Follow-up Study Can we predict who would have a better response to montelukast over

Follow-up Study Can we predict who would have a better response to montelukast over ICS? • LTE 4/FENO ratios were associated with a greater response to montelukast than FP for FEV 1 and for asthma control days. • Children with high LTE 4/FENO ratios were likely to be younger and female and exhibit lower levels of atopic markers and methacholine reactivity. Ref. Rabinovitch N and the CARE Network. J Allergy Clin Immunol 2010; 126: 545 -51 and 959 -61.

EPR-3 Recommendations Step 6 Step 5 Step 4 Step 3 Step 2 Step 1

EPR-3 Recommendations Step 6 Step 5 Step 4 Step 3 Step 2 Step 1 Intermittent Asthma Persistent Asthma

BADGER Protocol: Overview Three Treatment Period, Double blind, 3 way cross-over Run-in period on

BADGER Protocol: Overview Three Treatment Period, Double blind, 3 way cross-over Run-in period on 1 x. ICS to demonstrate lack of control Run-in Period -8 weeks 2 Period 1 Evaluation Period 2 Evaluation Period 3 Evaluation Period 2. 5 x ICS or 1 x ICS + LABA or 1 x ICS + LTRA 16 weeks 1 x. ICS = fluticasone DPI 100 µg BID Randomization 2. 5 x ICS = fluticasone DPI 250 µg BID 1 x. ICS+LABA = fluticasone/salmeterol DPI 100/50 BID 1 x. ICS+LTRA = fluticasone DPI 100 µg BID + montelukast

Primary Outcome: Probability of BEST Response Based on Composite Outcome* LABA step-up was more

Primary Outcome: Probability of BEST Response Based on Composite Outcome* LABA step-up was more than 1. 5 times as likely to produce the best response LABA ICS (p = 0. 002) (p = 0. 004) LTRA *Ref. Lemanske RF and CARE Network. NEJM 2010; 362: 975 -985.

BADGER Study: Conclusions • Significant variability in treatment response was noted at the Step-3

BADGER Study: Conclusions • Significant variability in treatment response was noted at the Step-3 level. • LABA step-up therapy was more than 1. 5 times as likely to produce the best response. • Many children demonstrated a best response to either step-up ICS or LTRA. • Several characteristics, such as baseline ACT®, eczema, and race could be useful in selecting medication treatment for best response. Ref. Lemanske RF and CARE Network. NEJM 2010; 362: 975 -985.

Summary Points • Inhaled corticosteroids are the preferred longterm controller therapy at Step 2

Summary Points • Inhaled corticosteroids are the preferred longterm controller therapy at Step 2 level. • At Step 3 Level, LABA step-up therapy was more than 1. 5 times as likely to produce the best response. • LTRA are alternative choices for Step 2 longterm controller and supplementary Step 3. • Variable response can occur at either Step 2 or Step 3 therapy and alternative treatments may be selected within each Step before stepping up therapy.

Inner-City Anti-Ig. E Therapy for Asthma (ICATA) A Randomized Trial to Evaluate the Impact

Inner-City Anti-Ig. E Therapy for Asthma (ICATA) A Randomized Trial to Evaluate the Impact of the Addition of Omalizumab to Guidelines Based Therapy of Inner-City Children and Adolescents with Asthma Published by Busse et al, New Eng J Med 2011; 364: 1005 -1015

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

Enrollment characteristics • 6 to 20 years of age with a diagnosis of persistent asthma • Allergy to a perennial allergen • Inner-city resident • At recruitment, participants had uncontrolled asthma • Weight and total serum Ig. E levels were suitable for omalizumab dosing

Study Design • Enrollment (4 weeks) – Asthma control assessed – Using a Guidelines-based

Study Design • Enrollment (4 weeks) – Asthma control assessed – Using a Guidelines-based algorithm, treatment was begun or adjusted to achieve asthma control • Randomization and treatment (60 weeks) – Following an adjustment of asthma medications during enrollment, participants were randomized to receive omalizumab or placebo every 2 to 4 weeks for 60 weeks

The effect of omalizumab on exacerbations Difference of -16. 5% with an exacerbation (p<0.

The effect of omalizumab on exacerbations Difference of -16. 5% with an exacerbation (p<0. 001) (n=211) (n=208)

% of Participants with Exacerbations Effect of Omalizumab on Asthma Exacerbations (n=211) (n=208)

% of Participants with Exacerbations Effect of Omalizumab on Asthma Exacerbations (n=211) (n=208)

Asthma Management Individualized or “Personalized” Approach • Utilize asthma characteristics, biomarkers, and genetics to

Asthma Management Individualized or “Personalized” Approach • 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.

Where Do We Go From Here? Possibilities to improve asthma control • Improve process

Where Do We Go From Here? Possibilities to improve asthma control • Improve process of asthma management to apply step-care approach • Identify alternative biomarker for Step 3 • Assess “step-up” treatment strategies to improve control and reduce exacerbations • Environment control measures • Reduce impact of viral infection • Immune-based therapy to reduce impact of allergen-induced inflammation.

Future Approaches to Improving Asthma Management • Genetics • • Early intervention Immunomodulators Biomarkers

Future Approaches to Improving Asthma Management • Genetics • • Early intervention Immunomodulators Biomarkers Combination therapy