Childhood Asthma Prevention Study CAPS

1
Stanley J. Szefler, MD
2
Early Intervention in Childhoood Asthma
Stanley J. Szefler, MD Helen Wohlberg Herman
Lambert Chair in Pharmacokinetics, National
Jewish Medical and Research Center Professor of
Pediatrics and Pharmacology, University of
Colorado Health Sciences Center
3
Disclosure

• Presenter Stanley J. Szefler, MD has documented
  that he/she is a consultant for Astra Zeneca,
  Genentech, Glaxo Smith Kline, MAP, Merck,
  Novartis, Ross, Sanofi Aventis, Schering, Verus
  and has resolved any identified conflicts of
  interest
• Presenter Stanley J. Szefler, MD has documented
  that his/her presentation will not involve
  discussion of unapproved or off-label,
  experimental or investigational use.

4
Improving Asthma Control

• Goals of long-term control therapy
• Prevent symptoms
• Improve pulmonary function
• Reduce inflammation
• Resolve and prevent progression

5
Potential Approaches to Improving Asthma Control

• Early intervention
• Combination therapy
• Biomarkers
• Genetics
• Immunomodulators

6
Asthma Pathways
Environment
Normal Airway
GeneticPredisposition
Function
Remodeling
Asthma
Origins
Epithelial Injury
Injury
Matrix Deposition
Repair
Remission, Persistence Progression or Regression?
Angiogenesis
Genetic Predispositionfor Remodeling
Smooth MuscleHypertrophy/Hyperplasia
Lazaar AL, Panettieri R. Am J Med.
2003115652-659.
7
Pulmonary Function Over TimeFEV1 Percent
Predicted
110
Mild, wheezy bronchitis
Control
Wheezy bronchitis
100
Asthma
FEV1 ( predicted)
90
Severe Asthma
80
70
7
10
14
21
28
35
Age (years)
Oswald H, et al. Pediatr Pulmonol. 19972314-20.
8
Models of Disease Progression from Childhood to
Adulthood
100
A. Normal remains normal B. Begins normal steep
slope resulting in severe obstruction over
time C. Begins normal rapid decline early on
resulting in severe obstruction D. Begins with
low values and continues with low lung function
90
A
B
80
C
FEV1 ( Predicted)
70
D
60
50
40
5
10
15
20
30
40
50
60
70
0
Age (Years)
Szefler SJ. J Allergy Clin Immunol.
2005115685-688.
9
The Natural History Asthma Phenotype
Age at Assessment (Years)
Classification
Persistent wheezing from9 years of age
Persistent wheezingfrom onset
Remission Relapse Intermittent Transient NO
wheezing ever
Sears MR, et al. N Engl J Med. 20033491414-1422.
10
Outcomes in Pulmonary Function Based on Natural
History Asthma Phenotype
Mean (?SE) FEV1FVC ratios measured at 9, 11, 13,
15, 18, 21, and 26 years in male and female study
members, according to the pattern of wheezing.
Sears MR, et al. N Engl J Med. 20033491414-1422.
11
Airway Remodeling InflammationRBM Thickness in
Infants
plt0.05 plt0.01 plt0.001 RBM, reticular
basement membrane RV, reversibility Saglani S,
et al. Am J Respir Crit Care Med.
2005171722-727.
12
Question 1
What medication has the potential to alter the
natural history of asthma?
1. Inhaled corticosteroids 2. Omalizumab 3.
Sublingual immunotherapy 4. Specific subcutaneous
immunotherapy
13
Study Design
Follow-up Phase
Screening Baseline Phase
Treatment Phase
Transition Phase
Routine Care
3 visits per year
2 visits per year
2 visits
5 visits
2-4 months
4 months
8 years
4 6 years
Randomize
Discontinue Study Rx
Enroll in CAMPCS
Bud
Ned
Plbo

• Randomized, multicenter, double-masked
  placebo-controlled study
• Budesonide and Nedocromil compared to masked
  placebo

CAMP, NEJM 343(15) 2000
14
Childhood Asthma Management Program

• Clinical measures of control strongly favored
  Budesonide over Placebo
• Symptoms
• Rescue medication use and prednisone courses
• Episode-free days
• Hospitalizations and urgent care
• Initiation of beclomethasone or additional asthma
  medication

CAMP, NEJM 343(15) 2000
15
FEV1 After Bronchodilator
CAMP, NEJM 343(15) 2000
16
Mean post-bronchodilator FEV1
Study visits (months since randomization)
Covar et al. Am J Respir Crit Care Med
2004170234-241
17
Question 2
What is the appropriate time to begin long-term
controller therapy for asthma in young children?
1. Prior to first wheezing episode with risk
profile? 2. After first wheezing episode? 3.
After second wheezing episode? 4. After third
wheezing episode with appropriate risk factors?
18
Can ICS Change the Natural History of Asthma?
Chronic Asthma
Inhaled Steroids?
Progression
Protection
Asthma, Not Chronic
Asthma Initial Phase
Remission
Exacerbation
No Asthma
19

• Prevention of
• Early Asthma
• In Kids
• (PEAK)

Funded by the National Heart, Lung, and Blood
Institute
20
What Is The PEAK Trial?
PEAK investigated the question whether inhaled
corticosteroids (ICS), when initiated in
preschool-aged children at high risk for
asthma, can alter the natural history of asthma
after ICS are discontinued

21
Rationale

• Asthma Predictive Index identifies high-risk
  children that will have continuation of
  asthma-like symptoms in school years1.
• ICS have been reported to reduce symptoms in
  high-risk young children with intermittent
  wheezing2,3.
• No effect after discontinuation of ICS on the
  natural course of asthma in school aged children
  may be due to the initiation of ICS after the
  occurrence of critical injurious events4.

1Castro-Rodriguez, AJRCCM, 2000 3Bisgaard,
AJRCCM, 1999 2Teper, Ped Pulm, 2004
4CAMP Research Group, NEJM, 2000
22
PEAK Study Design
Screening/ Eligibility
Run-in
Year 3
Years 1 2
1 month
Interim Efficacy Tests
Randomize

• Randomized, multicenter, double-blind,
  parallel group, placebo-controlled trial
• 285 two and three year olds at high-risk for
  asthma
• Fluticasone 44 ?g/puff or placebo (2 puffs
  b.i.d.)

23
Inclusion Criteria

• Children 24-47 months of age
• Positive asthma predictive index
• At least 36 weeks at birth
• No systemic illnesses apart from asthma or
  allergic rhinitis
• gt 10 for height
• lt 4 months of inhaled corticosteroid and lt 4
  courses of systemic steroid in last year

24
Asthma Predictive Index

• Identify high risk children (ages 2 3)
  
• gt 4 wheezing episodes in the past year (at
  least one must be MD diagnosed)
  PLUS
• One major criteria OR - Two minor criteria
• Parent with asthma ? Food sensitivity
• Atopic dermatitis ? Peripheral
  eosinophilia (?4)
• Aero-allergen sensitivity ? Wheezing not
  related to infection

Modified from Castro-Rodriguez, AJRRCM, 2000
25
PEAK Primary Outcome

• Episode-free days during the observation-year
• No cough or wheeze
• No unscheduled clinic, urgent care, ER
  or hospital visits
• No use of asthma medications including
  bronchodilator
  pre-treatment before exercise

26
Methods

• Episode-free days (EFD) are
• Annualized from the 14 day parental recall on the
  Treatment Contact Form
• Corrected by the coordinator record
• All outcomes adjusted by
• Sex, age, race, center, aeroallergen SPT
• Baseline symptom duration severity,
  eosinophils, eczema.

27
Addition of Controllers
Persistent Symptoms OR gt 4 courses of oral
steroids in 12 mos
Montelukast
Open label fluticasone
Other supplementary asthma medications
Taper after 2 months based on specific protocols
28
Treatment Failure Status

• 2 hospitalizations in a 12-month period
• Hypoxic seizure or intubation due to asthma

29
Study Population Enrollment and Disposition
285 Randomized Participants
143 in ICS group
142 in placebo group
132 included in Year 1 2 analyses
131 included in Year 3 analysis
130 included in Year 1 2 analyses
125 included in Year 3 analysis
Guilbert TW and CARE Network. NEJM
20063541985-97.
30
Baseline Characteristics

• No significant differences seen between groups in
  the following characteristics
• Demographic
• Atopic except for higher percentage of
  eosinophils in ICS group
• Symptom burden
• Emergency room visits
• Hospitalizations
• Albuterol use
• Nocturnal awakening

31
Episode-free Days During Observation Year
Treatment Ends
Observation (Year 3)
Guilbert TW and CARE Network. NEJM
20063541985-97.
32
Time to Any Supplementary Asthma Controller
Medication
Treatment Ends
Observation (Year 3)
Proportion not on controller
p 0.998
Guilbert TW and CARE Network. NEJM
20063541985-97.
33
Outcomes During Observation Phase

• No differences between groups seen for
• Number of exacerbations requiring systemic
  corticosteroid bursts
• Unscheduled physician visits
• Hospitalizations
• Bronchodilator use
• Montelukast use
• Respiratory system impedance
• Average of days of supplemental ICS use 26
  less in ICS group (p0.007) during first 3
  months
• There were no significant differences in
  adherence, completed visits, drop-outs, treatment
  failures or serious adverse events between study
  groups.

34
Question 3
During the PEAK study, what outcomes indicated
that the inhaled corticosteroid had an effect?
1. Reduction in episode free days during the
treatment period 2. Reduction in linear growth
velocity during the entire treatment period 3.
Reduction in bone density during the treatment
period 4. None of the above.
35
Was any effect seen during treatment?
36
Episode-free Days During the Entire Study
Guilbert TW and CARE Network. NEJM
20063541985-97.
37
ICS Effect During Treatment Phase
Asthma Exacerbations
Plt0.001
Guilbert TW and CARE Network. NEJM
20063541985-97.
38
ICS Effect During Treatment Phase
Supplementary Controller Use
Plt0.001
Plt0.001
39
Time to Any Supplementary Asthma Controller
Medication
Months p-value 0-12 0.02 0-24
0.01 0-36 0.34
Guilbert TW and CARE Network. NEJM
20063541985-97.
40

• Based on the impact on symptom control, lung
  function parameters and growth, it does appear
  that treatment group received an effective dose
  of ICS

41
Summary Clinical Implications

• Based on the results of the PEAK study
• ICS are effective in improving asthma-like
  symptom burden, exacerbations, and lung function
  in high-risk toddlers.
• Continuous ICS therapy for 2 years once
  discontinued does not modify the natural history
  of asthma in early childhood

42
Why was there no effect on the natural history of
asthma after the discontinuation of ICS?
43
Possible Reasons

• Intervention not started early enough
• Treating children younger than age 2 would
  include many who will outgrow their disease
• Children may not have received a sufficient dose
  of ICS
• ICS may not alter the natural history of asthma
  regardless of the time they are initiated

44
Improving Asthma Control
Possible approaches

• Maintenance therapy with escalation of
  combination therapy based on asthma control.
• Maintenance combination therapy with as needed
  combination therapy.
• Individualized approach based on asthma
  characteristics, biomarkers and genetics.

45
Monitoring ICS Use

• Are there ways to optimize the use of ICS
• Targeting biologic markers in asthma
• Airway hyperresponsiveness
• Sputum eosinophils
• Exhaled nitric oxide (eNO)

46
Asthma Management
Possible approaches

• Maintenance therapy with escalation of
  combination therapy based on asthma control.
• Maintenance combination therapy with as needed
  combination therapy.
• Individualized approach based on asthma
  characteristics, biomarkers and genetics.
• Hybrid of these approaches based on best features
  of each approach.

47
Improving Asthma Control

• Goals of long-term control therapy
• Prevent symptoms
• Improve pulmonary function
• Reduce inflammation
• Resolve and prevent progression

48
Question 4
Asthma progression can be measured by the
following
1. Reduction in FEV1 predicted over time 2.
Reduction in FEV1/FVC 3. Prednisone courses over
time 4. Increase in FVC predicted over time
49
Mean post-bronchodilator FEV1
Study visits (months since randomization)
SRP (no.)
NSRP (no.)
Covar et al. Am J Respir Crit Care Med
2004170234-241
50
Potential Approaches to Improving Asthma Control

• Early intervention
• Combination therapy
• Biomarkers
• Genetics
• Immunomodulators

51
What is an AsthmaImmunomodulator?

• Mechanism(s)?
• Measure of effect?
• Duration of effect?
• Risk-benefit?

52
Asthma Management
Current status of asthma medications

• Inhaled corticosteroids are the preferred
  long-term control therapy for persistent asthma
• Effect of ICS is lost once treatment is stopped
• LABA and LTRA are not considered to be
  immunomodulators
• Anti-IgE is viewed as blocking IgE effect.

53
Asthma Management
Individualized Approach

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