# Presentation: 437927

## Selection of  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  for AECB trials
- Review of placebo controlled trials in AECB
- Confounding issues
- Conclusions
- Unresolved issues and alternatives for future AECB trials

## 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)

## 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”

## Slide 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.

## 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 

## 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 

## 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

## 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)

## 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.

## 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%

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

## 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

## 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

## 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.

## 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

## 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

## 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

## 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

## 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

## 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.

## 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

## 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.

## 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.

## 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

## 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

## AECB study populations

## 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

## 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

## 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.

## 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.

## 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)

## 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

## 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?