Infection as a treatable cause for asthma- Where do we go from here?

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Infection as a treatable cause for asthma- Where
do we go from here?
Workshop - September 2012

• David L Hahn, MD MS

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Conflict of interest disclosure

• I have no conflicts of interest that relate to
  this presentation

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Agenda

• Goal or purpose Looking towards the future of
  research into azithromycin as a novel treatment
  for asthma
• Aim1 Brief background of rationale and research
  to date
• Aim2 Open discussion about your perspectives of
  the possible role(s) for PBRN research

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Background

• Current asthma treatments are palliative, not
  curative
• Anti-inflammatory treatments
• Despite treatment, half of patients have
  uncontrolled asthma
• Demoly et al 2010

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Asthma Control Test (ACT)
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Asthma Control in Five European Countries
Not Well Controlled (ACT19) More activity
limitations (40.8 vs 1.5) More
breathlessness 3 times weekly (72.5 vs 5.4)
More sleep difficulties 1 times weekly (60.3
vs 4.6) More rescue medication 2-3 times
weekly (77.4 vs 15.9) More healthcare
utilization (17.4 vs 9.9) More absenteeism
(12.2 vs 5.5) More work impairment (30.0
vs 15.4) Decreased quality-of-life
(Plt.001) Compared to Controlled (ACT20)
Demoly et al. Update on asthma control in five
European countries. Eur Respir Rev 2010
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Lack of Asthma Control is Common
Asthma prevalence 6.1 (France,Germany, Italy,
Spain and UK, 2008)
All asthma
Treated asthma
Demoly et al. Update on asthma control in five
European countries. Eur Respir Rev 2010
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Background

• A subset of asthma (20) progresses to COPD
• Increasing the burden of morbidity and mortality
• Preventive and curative treatments are desirable

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Macrolides for asthma

• Growing interest in second generation
  macrolides/azalides for asthma
• To offer greater control
• Possibly preventive or curative
• Unresolved debate about mechanisms
• Anti-inflammatory v antimicrobial (atypicals)
• 10 trials published mixed results
• Methodologic limitations
• Small, short-term, different drug/duration, no
  post-treatment observation period,
  disease-oriented outcomes, limited external
  validity (poor generalizability)

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Macrolides for asthma

• Growing interest in second generation
  macrolides/azalides for asthma
• To offer greater control
• Possibly preventive or curative
• Unresolved debate about mechanisms
• Anti-inflammatory v antimicrobial (atypicals)
• 10 trials published mixed results
• Methodologic limitations
• Small, short-term, different drug/duration, no
  post-treatment observation period,
  disease-oriented outcomes, limited external
  validity (poor generalizability)

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Guideline treatment trials Lacking external
validity
The proportion of people with asthma eligible for
the major RCTs (n17) cited in the Global
Initiative for Asthma (GINA) guidelines.
Current asthma
Current asthma on treatment
Travers et al. External validity of randomised
controlled trials in asthma to whom do the
results of the trials apply?. Thorax
200762219-223
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Guideline treatment trials Lacking external
validity
Additional exclusions Being asymptomatic
No regular use of ICS
Typical exclusions Comorbidity FEV1
not 50-85 predicted 12 reversibility
Current smoking Past hx gt10 pack years
Herland et al. How representative are clinical
study patients with asthma or COPD for a larger
real life population of patients with
obstructive lung disease?. Respiratory Med 2005
9911-19
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Generalizable studies of macrolides in asthma are
limited

• Two prospective observational (before-after)
  trials
• Hahn JFP 1995
• Hahn et al. PLoS ONE 2012
• Two randomized, controlled trials (RCTs)
• Hahn et al, PLoS Clinical Trials 2006
• Hahn et al. JABFM 2012

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Treatment of Chlamydia pneumoniae infection in
adult asthma a before-after trial. J Fam Pract
1995 41345-351
Of 46 patients with moderate to severe stable
asthma symptoms, 25 (54) had PFT and clinically
confirmed persisting improvement Prior acute
C. pneumoniae 4/4 complete response o Possible
chronic C. pneumoniae 21/42 3 complete
response 18 major improvement Positive response
assoc w/ Less disease duration (P.01) Less fixed
obstruction (Plt.01) Dots represent multiple
measures for individuals
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Chlamydia pneumoniae-specific IgE is prevalent in
asthma and is associated with disease severity.
PLoS ONE 2012 7e35945.
Of 66 uncontrolled asthma patients 33 (50)
were Cp-IgE 16 (24) were Cp-PCR 39/66
elected azithromycin Rx. Of those 39 33
(85) reported lasting improvement No
association with IgE status
P0.002, Plt0.0001
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Secondary outcomes of a pilot randomized trial of
azithromycin treatment for asthma. PLoS Clin
Trials 2006 1e11

• 45 patients with mostly mild to moderate
  persistent asthma symptoms
• Baseline Cp IgA antibodies predicted worsening
  asthma symptoms at end study (P.04)
• Symptom improvement attributable to AZ was 28
  in high IgA v 12 in low IgA subjects
  (interaction P0.27)
• Binary measure for improvement (1 unit
  increased AQLQ and/or 50 decreased rescue BD)
  was
• 53 AZ v 13 PLA (P0.03)
• NNT3

• P0.04 by linear regression analysis

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Azithromycin for bronchial asthma in adults An
effectiveness trial. J Am Bd Fam Med 2012
25442-459

• 97 subjects enrolled
• 3 months Rx, 9 months post-Rx observation
• Open-label cohort, n 22 (23)
• Declined randomization after learning of a 50
  chance of receiving placebo
• IRB approval for an open-label (OL) observational
  arm
• More severe asthma than randomized subjects

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Asthma severity
Randomized N75 Open Label N22 P-value
Hospitalized Previous 2y 3 9 0.02
Day Severity Mild/Mod/Severe 64/28/ 8 32/36/ 32 0.01
Night Severity Mild/Mod/Severe 51/37/ 12 50/18/ 32 0.02
Symptom score 1.44 2.06 0.01
QOL score 4.98 4.12 0.02
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Asthma Symptoms (5-point scale)
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AQL Asthma Quality of Life (Juniper)
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Asthma Control (Juniper)
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Change From Baseline in AQL
48 Weeks Post-Enrolment
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Summary

• Randomized trial was negative
• Underpowered (Potential NNT7)
• Open-label subjects reported significant
  prolonged benefit compared to placebo group
• NNT 2-3 for AQL improvement 2 units at one
  year

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Unanswered questions

• Are the open label results spurious, or did these
  subjects correctly self-identify themselves as
  good candidates?
• Was the RCT biased towards a null effect due to
  self- exclusion of subjects most likely to
  benefit?
• Results support further azithromycin trials

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Open for Discussion

• What kinds of asthma?
• What study designs?
• What role for PBRNs?

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What kinds of asthma?

• New-Onset
• Well-controlled
• Uncontrolled and/or treatment resistant
  (refractory)

What study designs?

• Before-After (Registries)
• RCTs
• Including large simple trials