1. 1 Selection of  in Clinical Trials of Antimicrobial Therapy - Acute Exacerbation of Chronic Bronchitis Susan D. Thompson, M.D. February 19, 2002

2. 2 Acute Exacerbation of Chronic Brochitis (AECB) - Outline Definition and scope of the problem Selection of  for AECB trials Review of placebo controlled trials in AECB –Confounding issues Conclusions Unresolved issues and alternatives for future AECB trials

3. 3 AECB 12 million cases of chronic bronchitis (CB) per year in the U.S. - Most common category of chronic obstructive pulmonary disease (COPD) Most cases of CB are due to tobacco use (85- 90%); also environmental pollutants, genetic factors Distinct clinical entity from acute bronchitis (sputum production in absence of underlying lung disease; vast majority of cases have viral etiology)

4. 4 AECB AECB accounts for 5-10% of all antibiotic prescriptions in the U.S. Currently, 17 antibiotics carry the indication of “acute exacerbation of chronic bronchitis” in their label; approved via non-inferiority trials –Older antibiotics carry broader indications: doxycycline labeled for “upper RTI” amoxicillin labeled for “lower RTI”

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6. Bach PB et al, Ann Int Med, 2001; 134:600-620. 6 AECB - Definition Chronic bronchitis: cough and sputum production most days for >3 months in two consecutive years. AECB - Some combination of worsening dyspnea, increased sputum volume, and/or increase in sputum purulence Etiology: Nontypable H. influenzae 50-60%, M. catarrhalis 15-20%, S. pneumoniae 15-20%, Atypicals 5-10%.

7. 7 Selection of  for Clinical Trials  1 : Smallest effect size (if any) that active drug would be reliably expected to have compared with placebo  2 : Largest clinically acceptable loss in efficacy between the experimental drug and the active control The smaller of the two values is 

8. 8 Selection of  - AECB For AECB - –Determination of  1 : estimation of the benefit (if any) of active control over placebo. –Determination of  2 : AECB has very low mortality/morbidity, thus  2 is relatively large, and greater than 20%. –The smaller of the two values (  1 ) is 

9. 9 AECB - Current FDA Guidance Points to Consider (1992): Two trials (or one if CAP/HAP) Organisms: Hemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae 10-20%  for AECB per sliding scale in Points to Consider

10. 10 AECB - Approach to determination of  1 Review results of placebo controlled trials –In past 40 years, <1100 patients enrolled in randomized placebo-controlled trials of antibiotic treatment of AECB, none of identical design Caveats: –Uncertainties in the definition of acute exacerbation –Lack of consistent/reproducible rating system for severity –Lack of standard outcome measures –Role for nonphysiologic outcomes (symptoms, quality of life, time to relapse)

11. Anthonisen NR et al, Ann Int Med, 1987;106:196-204. 11 AECB - Placebo controlled trials: Anthonisen, et al Methods 362 exacerbations in 173 patients with AECB, treated with placebo, TMP/SMX, amoxicillin, or doxycycline Success = Symptoms resolved within 21 days Low FEV 1

12. 12 AECB - Placebo controlled trials: Anthonisen, et al (2) “Winnipeg criteria” Type 1 = Cough, increased sputum production, purulence Type 2 = 2 of these 3 symptoms Type 3 = 1 symptom and 1 of the following: –URI within 5 days –Fever without non-respiratory cause –Increased wheezing –Increased coughing –Increase in respiratory rate or heart rate by 20%

13. 13 AECB - Placebo controlled trials: Anthonisen, et al (3)

14. 14 AECB - Placebo controlled trials: Anthonisen, et al (4) Conclusions: –Antibiotic treatment provided no benefit to Type 3, could probably be justified in Type 2, and demonstrated the greatest benefit in those with the most severe exacerbations (Type 1) –Higher success rate in the antibiotic-treated groups may be less important than the clinical deteriorations

15. 15 AECB - Placebo controlled trials: Anthonisen, et al (5) Conclusions (cont’d): –Subgroups of individual symptoms were no more predictive of outcome. Caveats –No microbiology –All antibiotics assumed to equally effective –Conducted in “pre-resistance” era –Steroid use not controlled –Relatively small numbers

16. Saint, S et al, JAMA, 1995; 273(12):957-960. 16 AECB - Placebo controlled trials: Saint, et al Methods Meta-analysis of 9 placebo-controlled trials of antibiotics in AECB (out of 230 studies screened) Randomized, diagnosis of CB and AECB, at least a 5-day duration of follow-up, and data sufficient to calculate an outcome size Calculated effect sizes: a unitless measure of efficacy.

17. 17 AECB - Placebo controlled trials: Saint, et al (2) Results Trials were combined to yield an overall effect size indicative of a small but statistically significant effect favoring antibiotics over placebo Breakdown: –3/9 statistically significant benefit of antibiotics –3/9 trend favoring antibiotics –3/9 no difference from placebo

18. 18 AECB - Placebo controlled trials: Saint, et al (3) 6 of 9 trials reported PEFR as the most frequently reported outcome measure –2 of these 6 showed a trend or significant improvement in PEFR favoring antibiotic group

19. 19 AECB - Placebo controlled trials: Saint, et al (4) Conclusion: Antibiotics yield a small but statistically significant improvement compared with placebo that may be clinically significant, especially in patients with low baseline flow rates Caveat: Variety of outcomes measures used: PEFR, duration of exacerbation, PaO2, symptom score, overall severity score as determined by a physician

20. 20 AECB - Placebo controlled trials: Allegra, et al Not included in Saint, et al meta-analysis; published in Italian Trial: amoxicillin/clavulanic acid vs placebo (5d) >40 years, cough/sputum, FEV 1 <80% predicted, no steroids 761 screened, 369 exacerbations Failure: 49.7% placebo, 13.6% antibiotics Retrospective review: Low FEV 1 : did worse with placebo Severe functional impairment and higher number of exacerbations - derive greatest benefit

21. Bach PB et al, Ann Intern Med, 2001; 134:600-620 21 AECB - Placebo controlled trials: Bach, et al ACP-ASIM and ACCP developed evidence-based clinical practice guidelines for AECB management Reviewed modalities of diagnostic testing as well as therapeutic interventions Included 11 randomized, placebo-controlled studies of antibiotic treatment Conclusion: Antibiotics are beneficial in the treatment of patients with AECB; patients with more severe exacerbations are more likely to benefit from antibiotics.

22. Nouira S et al, Lancet, 2001;2020- 2025. 22 AECB - Placebo controlled trials: Nouira et al Randomized placebo-controlled trial of ofloxacin 400 mg/d vs placebo x 10 days 90 patients with AECB requiring mechanical ventilation; pneumonia excluded; aminophylline but no steroids Mortality: 2 (4%) ofloxacin, 10 (22%) placebo More abx: 3 (6%) ofloxacin, 16 (35%) placebo Decreased duration of ventilation and hospital stay in ofloxacin group

23. 23 AECB - Placebo controlled trials: Agency for Healthcare Research and Quality(AHRQ) AHRQ Evidence Report/Technology Assessment: prepared by Duke University Evidence-based Practice Center (EPC). The EPCs systematically review the relevant scientific literature on assigned topics and conduct additional analyses when appropriate. Examined 11 placebo-controlled studies of antibiotic treatment - included 2 trials not in Saint et al meta-analysis

24. 24 AECB - Placebo controlled trials: AHRQ (2) –Sachs, et al 1995: 71 outpatients with COPD, increasing dyspnea treated with TMP/SMX, amoxicillin, or placebo; all received steroids. No differences were observed in recovery rate or changes in symptom score, PEFR, temperature, or sputum. –Caveats: Role of corticosteroid anti- inflammatory effect; patients had relatively high PEFR and low proportion of patients with purulent sputum.

25. McCrory DC et al, AHRQ Publication No. 01-E003:March 2001, 48-53. 25 AECB - Placebo controlled trials: AHRQ (3) Conclusion: “Randomized controlled trials of antibiotic treatment of acute exacerbation of chronic bronchitis show overall evidence of a relatively small benefit in pulmonary function. These trials suggest that patients with more evidence of bacterial infection (sputum purulence) and more severe illness (worse PEFR) benefit most from antibiotics; however, this has not been conclusively demonstrated. Likewise, a hypothesized interaction between corticosteroids and antibiotic use cannot be addressed by existing trial data.”

26. 26 Confounding Issues in AECB Trials Concurrent effective therapies or exogenous factors that may diminish treatment group differences –Inhaled short acting  agonists and bronchodilators –Systemic corticosteroids –Oxygen therapy-Cigarette smoking

27. 27 Confounding Issues in AECB Trials Difficulty in defining appropriate patient population –sputum colonization with pathogens in COPD –Unclear role of viruses, atypical pathogens, environmental exposure, and other clinical problems (e.g., CHF, nonpulmonary infections, PE, pneumothorax, etc.) in AECB causation –Severity criteria not validated: the assumption that the AECB severity can be judged by a combination of clinical features which have a less good prognosis

28. 28 AECB study populations

29. 29 AECB - “Old” versus “new” antibiotics Resistance increasing: H. influenzae - amoxicillin, TMP/SMX; S. pneumoniae - PCN, amoxicillin, cephalosporins, TMP/SMX, macrolides; M. catarrhalis - most are ampicillin resistant. Most placebo controlled AECB studies were conducted before the emergence of respiratory pathogens that are resistant to multiple antibiotics No randomized, controlled trials have shown superiority of newer, broad-spectrum antibiotics, and no data to suggest increased failures with increases in antibiotic resistance

30. 30 AECB - Can  1 be determined? Perform meta-analysis and calculate  Limitations: –patient population in placebo controlled studies is not uniform. –studies used different designs and endpoints, none ideal –studies have varying outcomes –most studies not recent

31. 31 AECB - Selection of  Conclusion: Performance of a meta- analysis with subsequent selection of delta would not yield a meaningful value due to the differences in study design including heterogeneous patient populations and diverse endpoints.

32. 32 Conclusions A review of placebo controlled trials of antibiotic treatment of AECB does not allow a definitive estimation of the benefit of active control over placebo Patients with more severe (?definition) illness may benefit most from antibiotics, but this has not been conclusively demonstrated, nor have validated severity criteria been demonstrated.

33. 33 AECB - Options for Future Trials Non-inferiority trials in all patients (current practice) - but what should delta be? Placebo-controlled trials with early escape in all patients with AECB Placebo-controlled trials only in patients who are perceived to be low risk (e.g., Winnipeg mild/moderate Groups 2 and 3)

34. 34 AECB - Options for Future Trials Non-inferiority trials in “severely ill” AECB patients –?control for smoking, concurrent therapies –definition of severe AECB 3 Arm studies: Placebo, new drug, old drug Prophylaxis/interval pulsed phase therapy

35. 35 AECB - Unresolved Issues Are placebo controlled trials with an early escape option acceptable in AECB studies? –Should only patients with less severe disease be enrolled in these trials? If non-inferiority trials are conducted in AECB, what should  be? Should future AECB trials include only patients with “severe” AECB?