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Selection of in Clinical Trials of Antimicrobial Therapy - Acute

Exacerbation of Chronic Bronchitis

Susan D. Thompson, M.D.

February 19, 2002

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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

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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)

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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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Outpatient Antimicrobial Therapy, U.S. (millions of courses in 1992)

McCaig LF and Hughes JM. JAMA 1995; 273:214-9

Otitis media

URI (non-specific)

Bronchitis

Pharyngitis

Sinusitis

All other diagnoses

23.6

17.9

16.3

13.1

12.9

26.5

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

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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%.

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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

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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

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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

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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)

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

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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

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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%

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

% (n) Success Deterioration Success Deterioration

Type 1 43.0 (31) 30.5 (22) 62.9 (44) 14.3 (10)

Type 2 60.0 (45) 10.7 (8) 70.1 (54) 5.2 (4)

Type 3 69.7 (23) 12.1 (4) 74.2 (26) 11.4 (4)

Overall 55.0 (99) 18.0 (34) 68.0(124) # 9.0 (18)

1st Exac 52.5 (31) 17.0 (10) 66.7(38) * 12.3 (7)#p<0.01; *p=0.17

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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

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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

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

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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.

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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

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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

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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

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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

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

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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.

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

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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

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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

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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.

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

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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.”

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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

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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

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AECB study populationsAnthonisen NDA

Mean age (y) 67.3 9.0 59 (range15-88)

Smoking history 93.6% 61.9%

FEV1 (% pred.) 33.9 13.7 N/A

Sputum > 30 mL/d 26.5% N/A

Type 1 or 2 sx 80.9% N/A

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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

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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

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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.

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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.

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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)

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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

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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?