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Selection of D in Clinical Trials of Antimicrobial Therapy - Acute Exacerbation of Chronic Bronchitis

Selection of D in Clinical Trials of Antimicrobial Therapy - Acute Exacerbation of Chronic Bronchitis. Susan D. Thompson, M.D. February 19, 2002. Acute Exacerbation of Chronic Brochitis (AECB) - Outline. Definition and scope of the problem Selection of D for AECB trials

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Selection of D in Clinical Trials of Antimicrobial Therapy - Acute Exacerbation of Chronic Bronchitis

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

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

  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. 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”

  5. 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%. Bach PB et al, Ann Int Med, 2001; 134:600-620.

  6. Selection of D for Clinical Trials • D1: Smallest effect size (if any) that active drug would be reliably expected to have compared with placebo • D2: Largest clinically acceptable loss in efficacy between the experimental drug and the active control • The smaller of the two values is D

  7. Selection of D - AECB • For AECB - • Determination of D1: estimation of the benefit (if any) of active control over placebo. • Determination of D2: AECB has very low mortality/morbidity, thus D2 is relatively large, and greater than 20%. • The smaller of the two values (D1) is D

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

  9. AECB - Approach to determination of D1 • 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)

  10. 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 FEV1 Anthonisen NR et al, Ann Int Med, 1987;106:196-204.

  11. 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%

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

  13. 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

  14. 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

  15. 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. Saint, S et al, JAMA, 1995; 273(12):957-960.

  16. 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

  17. 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

  18. 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

  19. 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, FEV1<80% predicted, no steroids • 761 screened, 369 exacerbations • Failure: 49.7% placebo, 13.6% antibiotics • Retrospective review: Low FEV1: did worse with placebo • Severe functional impairment and higher number of exacerbations - derive greatest benefit

  20. 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. Bach PB et al, Ann Intern Med, 2001; 134:600-620

  21. 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 Nouira S et al, Lancet, 2001;2020-2025.

  22. 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

  23. 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.

  24. 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.” McCrory DC et al, AHRQ Publication No. 01-E003:March 2001, 48-53.

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

  26. 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

  27. AECB study populations

  28. 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

  29. AECB - Can D1 be determined? • Perform meta-analysis and calculate D • 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

  30. AECB - Selection of D • 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.

  31. 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.

  32. 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)

  33. 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

  34. 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 D be? • Should future AECB trials include only patients with “severe” AECB?

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