Workshop - September 2012
Infection as a treatable
cause for asthma- Where do
we go from here?
David L Hahn, MD MS
Conflict of interest disclosure

I have no conflicts of interest that relate to
this presentation
Agenda



Goal or purpose: Looking towards the future of
research into azithromycin as a novel treatment for
asthma
Aim#1: Brief background of rationale and research
to date
Aim#2: Open discussion about your perspectives of
the possible role(s) for PBRN research
Background

Current asthma treatments are palliative, not curative
– Anti-inflammatory treatments

Despite treatment, half of patients have uncontrolled
asthma
– Demoly et al 2010
Asthma Control Test (ACT)
Asthma Control in Five European Countries
Not Well Controlled (ACT≤19)
• 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 (P<.001)
Compared to Controlled (ACT≥20)
Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010
Lack of Asthma Control is Common
Asthma prevalence = 6.1% (France,Germany, Italy, Spain and UK, 2008)
Well Controlled Asthma Control
Test (ACT)Not Well
Controlled
All asthma
Treated asthma
Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010
Background

A subset of asthma (20%) progresses to COPD
– Increasing the burden of morbidity and mortality

Preventive and curative treatments are desirable
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)
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)
Guideline treatment trials: Lacking external validity
The proportion of people with asthma eligible for the major RCTs
(n=17) cited in the Global Initiative for Asthma (GINA) guidelines.
• Current asthma
• Current asthma on treatment
4%
6%
Eligible
Ineligible
96%
94%
Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of
the trials apply?. Thorax 2007;62:219-223
Guideline treatment trials: Lacking external validity
Typical exclusions:
• Comorbidity
• FEV1 not 50-85 %predicted
• ≤12% reversibility
• Current smoking
• Past hx >10 pack years
Additional exclusions:
• Being asymptomatic
• No regular use of ICS
6%
3%
Eligible
Ineligible
94%
97%
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; 99:11-19
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
Treatment of Chlamydia pneumoniae
infection in adult asthma: a before-after trial.
J Fam Pract 1995; 41:345-351
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 (P<.01)
* Dots represent multiple measures
for individuals
Chlamydia pneumoniae-specific IgE is prevalent
in asthma and is associated with disease
severity. PLoS ONE 2012; 7:e35945.
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
*P=0.002, **P<0.0001
Secondary outcomes of a pilot randomized trial of
azithromycin treatment for asthma. PLoS Clin Trials
2006; 1:e11
Symptom Score
Ov erall Asthma Symptoms
45 patients with mostly mild to
moderate persistent asthma
symptoms:
*
3
• Baseline Cp IgA antibodies
predicted worsening asthma
symptoms at end study (P=.04)
2
• Symptom improvement
attributable to AZ was 28% in
high IgA v 12% in low IgA
subjects (interaction P=0.27)
Azithro
Placebo
1
• Binary measure for improvement
(≥1 unit increased AQLQ and/or
≥50% decreased rescue BD) was:
0
1
2
3
Study Month
*P=0.04 by linear regression analysis
4
5
6
53% AZ v 13% PLA (P=0.03)
NNT=3
Azithromycin for bronchial asthma in adults: An
effectiveness trial. J Am Bd Fam Med 2012;
25:442-459


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
Asthma severity
Randomized
N=75
Open Label
N=22
P-value
3%
9%
0.02
64%/28%/
8%
32%/36%/
32%
0.01
Night Severity 51%/37%/
Mild/Mod/Severe 12%
50%/18%/
32%
0.02
Symptom
score
1.44
2.06
0.01
QOL score
4.98
4.12
0.02
Hospitalized
Previous 2y
Day Severity
Mild/Mod/Severe
Asthma
Symptoms
(5-point scale)
AQL: Asthma
Quality of
Life (Juniper)
Asthma
Control
(Juniper)
Change From Baseline in AQL
48 Weeks Post-Enrolment
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
AQL <0
AQL 0<.5
AQL .5<1
AQL 1<2
AQL >2
Rand Pla
Rand Azithro
Open-label
Summary

Randomized trial was negative
– Underpowered (Potential NNT=7)

Open-label subjects reported significant
prolonged benefit compared to placebo
group
– NNT = 2-3 for AQL improvement ≥ 2 units
at one year
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

Open for Discussion
What kinds of asthma?
 What study designs?
 What role for PBRNs?

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