Infection as a treatable Infection as a treatable cause for asthma- Where do cause for asthma- Where do

we go from here?we go from here?

David L Hahn, MD MSDavid L Hahn, MD MS

Workshop - September 2012Workshop - September 2012

Conflict of interest disclosureConflict of interest disclosure

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

AgendaAgenda

Goal or purpose:Goal or purpose: Looking towards the future of Looking towards the future of research into azithromycin as a novel treatment for research into azithromycin as a novel treatment for asthmaasthma

Aim#1:Aim#1: Brief background of rationale and research Brief background of rationale and research to dateto date

Aim#2:Aim#2: Open discussion about your perspectives of Open discussion about your perspectives of the possible role(s) for PBRN researchthe possible role(s) for PBRN research

BackgroundBackground Current asthma treatments are palliative, not curativeCurrent asthma treatments are palliative, not curative

– Anti-inflammatory treatmentsAnti-inflammatory treatments Despite treatment, half of patients have uncontrolled Despite treatment, half of patients have uncontrolled

asthmaasthma– Demoly et al 2010Demoly et al 2010

Asthma Control Test (ACT)Asthma Control Test (ACT)

Asthma Control in Five European CountriesAsthma Control in Five European Countries

Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010

Not Well Controlled (ACT≤19)Not Well Controlled (ACT≤19)

• • More activity limitations (40.8% vs 1.5%)More activity limitations (40.8% vs 1.5%) • • More breathlessness ≥3 times weekly (72.5% vs 5.4%)More breathlessness ≥3 times weekly (72.5% vs 5.4%) • • More sleep difficulties ≥1 times weekly (60.3% vs 4.6%)More sleep difficulties ≥1 times weekly (60.3% vs 4.6%) • • More rescue medication ≥2-3 times weekly (77.4% vs 15.9%)More rescue medication ≥2-3 times weekly (77.4% vs 15.9%) • • More healthcare utilization (17.4% vs 9.9%)More healthcare utilization (17.4% vs 9.9%) • • More absenteeism (12.2% vs 5.5%)More absenteeism (12.2% vs 5.5%) • • More work impairment (30.0% vs 15.4%)More work impairment (30.0% vs 15.4%) • • Decreased quality-of-life (P<.001)Decreased quality-of-life (P<.001)

Compared to Controlled (ACT≥20)Compared to Controlled (ACT≥20)

Lack of Asthma Control is CommonLack of Asthma Control is Common

Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010

Well Controlled -Asthma ControlTest (ACT)-Not WellControlled

All asthma

Asthma prevalence = 6.1% (France,Germany, Italy, Spain and UK, 2008)

Treated asthma

BackgroundBackground

A subset of asthma (20%) progresses to COPDA subset of asthma (20%) progresses to COPD– Increasing the burden of morbidity and mortalityIncreasing the burden of morbidity and mortality

Preventive and curative treatments are desirablePreventive and curative treatments are desirable

Macrolides for asthmaMacrolides for asthma Growing interest in second generation macrolides/azalides for Growing interest in second generation macrolides/azalides for

asthmaasthma– To offer greater controlTo offer greater control– Possibly preventive or curativePossibly preventive or curative

Unresolved debate about mechanismsUnresolved debate about mechanisms– Anti-inflammatory v antimicrobial (atypicals)Anti-inflammatory v antimicrobial (atypicals)

10 trials published: mixed results10 trials published: mixed results Methodologic limitationsMethodologic limitations

– Small, short-term, different drug/duration, no post-treatment Small, short-term, different drug/duration, no post-treatment observation period, disease-oriented outcomes, limited external observation period, disease-oriented outcomes, limited external validity (poor generalizability)validity (poor generalizability)

Macrolides for asthmaMacrolides for asthma Growing interest in second generation macrolides/azalides for Growing interest in second generation macrolides/azalides for

asthmaasthma– To offer greater controlTo offer greater control– Possibly preventive or curativePossibly preventive or curative

Unresolved debate about mechanismsUnresolved debate about mechanisms– Anti-inflammatory v antimicrobial (atypicals)Anti-inflammatory v antimicrobial (atypicals)

10 trials published: mixed results10 trials published: mixed results Methodologic limitationsMethodologic limitations

– Small, short-term, different drug/duration, no post-treatment Small, short-term, different drug/duration, no post-treatment observation period, disease-oriented outcomes, observation period, disease-oriented outcomes, limited external limited external validity (poor generalizability)validity (poor generalizability)

Guideline treatment trials: Lacking external validityGuideline treatment trials: Lacking external validity

Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?. Thorax 2007;62:219-223the trials apply?. Thorax 2007;62:219-223

4%

96%

EligibleIneligible

6%

94%

• • Current asthmaCurrent asthma

The proportion of people with asthma eligible for the major RCTs The proportion of people with asthma eligible for the major RCTs (n=17) cited in the Global Initiative for Asthma (GINA) guidelines.(n=17) cited in the Global Initiative for Asthma (GINA) guidelines.

• • Current asthma on treatmentCurrent asthma on treatment

Guideline treatment trials: Lacking external validityGuideline treatment trials: Lacking external validity

Herland et al. How representative are clinical study patients with asthma or COPD for a larger 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“real life” population of patients with obstructive lung disease?. Respiratory Med 2005; 99:11-19

6%

94%

EligibleIneligible

3%

97%

Additional exclusions:Additional exclusions: • • Being asymptomaticBeing asymptomatic • • No regular use of ICSNo regular use of ICS

Typical exclusions:Typical exclusions: • • ComorbidityComorbidity • • FEV1 not 50-85 %predictedFEV1 not 50-85 %predicted • ≤ • ≤12% reversibility12% reversibility • • Current smokingCurrent smoking • • Past hx >10 pack yearsPast hx >10 pack years

Generalizable studies of macrolides in Generalizable studies of macrolides in asthma are limitedasthma are limited

Two prospective observational (before-after) trialsTwo prospective observational (before-after) trials– Hahn JFP 1995Hahn JFP 1995– Hahn et al. PLoS ONE 2012Hahn et al. PLoS ONE 2012

Two randomized, controlled trials (RCTs)Two randomized, controlled trials (RCTs)– Hahn et al, PLoS Clinical Trials 2006Hahn et al, PLoS Clinical Trials 2006– Hahn et al. JABFM 2012Hahn et al. JABFM 2012

Treatment of Treatment of Chlamydia pneumoniaeChlamydia pneumoniae infection in adult asthma: a infection in adult asthma: a

before-after trial. J Fam Pract before-after trial. J Fam Pract 1995; 41:345-3511995; 41:345-351

Of 46 patients with Of 46 patients with moderate to severe moderate to severe stable asthma symptoms, stable asthma symptoms, 25 25 (54%) had PFT and (54%) had PFT and clinically confirmed clinically confirmed persisting improvementpersisting improvement::• • Prior acute Prior acute C. C. pneumoniae*pneumoniae*4/4: complete response4/4: complete responseo Possible chronic o Possible chronic C. C. pneumoniae*pneumoniae*21/42: 3 complete 21/42: 3 complete responseresponse18 major improvement18 major improvement

Positive response assoc Positive response assoc w/w/Less disease duration Less disease duration (P=.01)(P=.01)Less fixed obstruction Less fixed obstruction (P<.01)(P<.01)

* Dots represent * Dots represent multiple measures for multiple measures for individualsindividuals

Chlamydia pneumoniaeChlamydia pneumoniae-specific IgE is -specific IgE is prevalent in asthma and is prevalent in asthma and is

associated with disease severity. associated with disease severity. PLoS ONE 2012; 7:e35945.PLoS ONE 2012; 7:e35945.

Of 66 uncontrolled Of 66 uncontrolled asthma patients:asthma patients:

• • 33 (50%) were Cp-33 (50%) were Cp-IgE+IgE+• • 16 (24%) were Cp-16 (24%) were Cp-PCR+PCR+

39/66 elected 39/66 elected azithromycin Rx. azithromycin Rx. Of those 39:Of those 39:

• • 33 (85%) reported 33 (85%) reported lasting improvementlasting improvement• • No association with No association with IgE statusIgE status

*P=0.002, **P<0.0001*P=0.002, **P<0.0001

Secondary outcomes of a pilot randomized Secondary outcomes of a pilot randomized trial of azithromycin treatment for trial of azithromycin treatment for asthma. PLoS Clin Trials 2006; 1:e11asthma. PLoS Clin Trials 2006; 1:e11

Overall Asthma Symptoms

0

1

2

3

1 2 3 4 5 6

Study Month

Symptom Score

Azithro

Placebo

45 patients with mostly 45 patients with mostly mild to moderate mild to moderate persistent asthma persistent asthma symptoms:symptoms:

• • Baseline Cp IgA Baseline Cp IgA antibodies predicted antibodies predicted worsening asthma worsening asthma symptoms at end study symptoms at end study (P=.04)(P=.04)

• • Symptom improvement Symptom improvement attributable to AZ was attributable to AZ was 28% in high IgA v 12% 28% in high IgA v 12% in low IgA subjects in low IgA subjects (interaction P=0.27)(interaction P=0.27)

• • Binary measure for Binary measure for improvementimprovement (≥1 unit (≥1 unit increased AQLQ and/or increased AQLQ and/or ≥50% decreased rescue ≥50% decreased rescue BD) was:BD) was:

53% AZ v 13% PLA 53% AZ v 13% PLA (P=0.03)(P=0.03)NNT=3NNT=3

*

*P=0.04 by linear regression analysis*P=0.04 by linear regression analysis

Azithromycin for bronchial asthma Azithromycin for bronchial asthma in adults: An effectiveness trial. in adults: An effectiveness trial. J Am Bd Fam Med 2012; 25:442-459J Am Bd Fam Med 2012; 25:442-459

97 subjects enrolled97 subjects enrolled

– 3 months Rx, 9 months post-Rx observation 3 months Rx, 9 months post-Rx observation Open-label cohort, n = 22 (23%)Open-label cohort, n = 22 (23%)

– Declined randomization after learning of a 50% Declined randomization after learning of a 50% chance of receiving placebochance of receiving placebo

– IRB approval for an open-label (OL) observational IRB approval for an open-label (OL) observational armarm

– More severe asthma than randomized subjectsMore severe asthma than randomized subjects

Asthma severityAsthma severityRandomizedRandomized

N=75N=75

Open LabelOpen Label

N=22N=22

P-valueP-value

HospitalizedHospitalized

Previous 2yPrevious 2y 3%3% 9%9% 0.020.02

Day SeverityDay SeverityMild/Mod/Mild/Mod/SevereSevere

64%/28%/64%/28%/

8%8%

32%/36%/32%/36%/

32%32% 0.010.01

Night SeverityNight SeverityMild/Mod/Mild/Mod/SevereSevere

51%/37%/51%/37%/

12%12%

50%/18%/50%/18%/

32%32% 0.020.02

Symptom Symptom scorescore 1.441.44 2.062.06 0.010.01

QOL scoreQOL score 4.984.98 4.124.12 0.020.02

Asthma Asthma SymptomsSymptoms (5-point (5-point scale)scale)

AQL: AQL: Asthma Asthma Quality Quality of Life of Life (Juniper)(Juniper)

AsthmaAsthmaControControl l (Junip(Juniper)er)

Change From Baseline in AQLChange From Baseline in AQL

48 Weeks Post-Enrolment48 Weeks Post-Enrolment

0%

5%

10%15%

20%

25%30%

35%

40%45%

50%

Rand Pla Rand Azithro Open-label

AQL <0AQL 0<.5AQL .5<1AQL 1<2AQL >2

SummarySummary Randomized trial was negativeRandomized trial was negative

– Underpowered (Potential NNT=7) Underpowered (Potential NNT=7) Open-label subjects reported significant Open-label subjects reported significant

prolonged benefit compared to placebo prolonged benefit compared to placebo groupgroup– NNT = 2-3 for AQL improvement ≥ 2 units NNT = 2-3 for AQL improvement ≥ 2 units

at one yearat one year

Unanswered questionsUnanswered questions

Are the open label results spurious, or did Are the open label results spurious, or did these subjects correctly self-identify these subjects correctly self-identify themselves as good candidates?themselves as good candidates?

Was the RCT biased towards a null effect Was the RCT biased towards a null effect due to self- exclusion of subjects most due to self- exclusion of subjects most likely to benefit?likely to benefit?

Results support further azithromycin trialsResults support further azithromycin trials

Open for DiscussionOpen for Discussion

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

What kinds of asthma?What kinds of asthma? New-OnsetNew-Onset Well-controlledWell-controlled Uncontrolled and/or treatment Uncontrolled and/or treatment

resistant (refractory)resistant (refractory)

What study designs?What study designs? Before-After (Registries)Before-After (Registries) RCTsRCTs

– Including large simple trialsIncluding large simple trials