Infection as a treatable cause for asthma- Where do we go from here? David L Hahn, MD MS Workshop - September 2012

Conflict of interest disclosure l I have no conflicts of interest that relate to this presentation

Agenda l Goal or purpose: Looking towards the future of research into azithromycin as a novel treatment for asthma l Aim#1: Brief background of rationale and research to date l Aim#2: Open discussion about your perspectives of the possible role(s) for PBRN research

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

Asthma Control Test (ACT)

Asthma Control in Five European Countries Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010 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)

Lack of Asthma Control is Common Demoly et al. Update on asthma control in five European countries. Eur Respir Rev 2010 All asthma Asthma prevalence = 6.1% (France,Germany, Italy, Spain and UK, 2008) Treated asthma

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

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

Macrolides for asthma l Growing interest in second generation macrolides/azalides for asthma –To offer greater control –Possibly preventive or curative l Unresolved debate about mechanisms –Anti-inflammatory v antimicrobial (atypicals) l 10 trials published: mixed results l 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 Travers et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply?. Thorax 2007;62: Current asthma Current asthma The proportion of people with asthma eligible for the major RCTs (n=17) cited in the Global Initiative for Asthma (GINA) guidelines. Current asthma on treatment Current asthma on treatment

Guideline treatment trials: Lacking external validity 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 Additional exclusions: Being asymptomatic Being asymptomatic No regular use of ICS No regular use of ICS Typical exclusions: Comorbidity Comorbidity FEV1 not %predicted FEV1 not %predicted ≤12% reversibility ≤12% reversibility Current smoking Current smoking Past hx >10 pack years Past hx >10 pack years

Generalizable studies of macrolides in asthma are limited l Two prospective observational (before-after) trials –Hahn JFP 1995 –Hahn et al. PLoS ONE 2012 l 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: Of 46 patients with moderate to severe stable asthma symptoms, 25 (54%) had PFT and clinically confirmed persisting improvement: Prior acute C. pneumoniae* 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:e Of 66 uncontrolled asthma patients: 33 (50%) were Cp-IgE+ 33 (50%) were Cp-IgE+ 16 (24%) were Cp-PCR+ 16 (24%) were Cp-PCR+ 39/66 elected azithromycin Rx. Of those 39: 33 (85%) reported lasting improvement 33 (85%) reported lasting improvement No association with IgE status 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 45 patients with mostly mild to moderate persistent asthma symptoms: Baseline Cp IgA antibodies predicted worsening asthma symptoms at end study (P=.04) 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 P=0.27) Symptom improvement attributable to AZ was 28% in high IgA v 12% in low IgA subjects (interaction P=0.27) Binary measure for improvement (≥1 unit increased AQLQ and/or ≥50% decreased rescue BD) was: Binary measure for improvement (≥1 unit increased AQLQ and/or ≥50% decreased rescue BD) was: 53% AZ v 13% PLA (P=0.03)  NNT=3 * *P=0.04 by linear regression analysis

Azithromycin for bronchial asthma in adults: An effectiveness trial. J Am Bd Fam Med 2012; 25: l 97 subjects enrolled – 3 months Rx, 9 months post-Rx observation l 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 RandomizedN=75 Open Label N=22P-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 QOL score

Asthma Symptoms (5-point scale) (5-point scale)

AQL: Asthma Quality of Life (Juniper)

Asthma Control (Juniper)

Change From Baseline in AQL 48 Weeks Post-Enrolment

Summary l Randomized trial was negative –Underpowered (Potential NNT=7) l Open-label subjects reported significant prolonged benefit compared to placebo group –NNT = 2-3 for AQL improvement ≥ 2 units at one year

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

Open for Discussion l What kinds of asthma? l What study designs? l What role for PBRNs?

What kinds of asthma? l New-Onset l Well-controlled l Uncontrolled and/or treatment resistant (refractory) What study designs? l Before-After (Registries) l RCTs –Including large simple trials