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

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Selection of D 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 D 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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AECB - Definition

• Chronic bronchitis cough and sputum production
  most days for gt3 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 D for Clinical Trials

• D 1 Smallest effect size (if any) that active
  drug would be reliably expected to have compared
  with placebo
• D 2 Largest clinically acceptable loss in
  efficacy between the experimental drug and the
  active control
• The smaller of the two values is D

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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

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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 D for AECB per sliding scale in Points to
  Consider

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AECB - Approach to determination of D1

• Review results of placebo controlled trials
• In past 40 years, lt1100 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)

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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)
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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 (contd)
• 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

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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)
• gt40 years, cough/sputum, FEV1lt80 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

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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.

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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.

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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 b-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 populations
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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 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

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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.

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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 D be?
• Should future AECB trials include only patients
  with severe AECB?