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

Loading...

PPT – Selection of D in Clinical Trials of Antimicrobial Therapy Acute Exacerbation of Chronic Bronchitis PowerPoint presentation | free to download - id: 52e83-MTI5O



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

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

Description:

doxycycline labeled for 'upper RTI' amoxicillin labeled for 'lower RTI' 5 ... patients with AECB, treated with placebo, TMP/SMX, amoxicillin, or doxycycline ... – PowerPoint PPT presentation

Number of Views:34
Avg rating:3.0/5.0
Slides: 36
Provided by: cde43
Learn more at: http://www.fda.gov
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

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


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
(No Transcript)
6
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.

7
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

8
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

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 D for AECB per sliding scale in Points to
    Consider

10
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)

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 FEV1

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

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
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
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
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
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

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
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
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
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
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
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

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
AECB study populations
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
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

31
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.

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
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
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
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?
About PowerShow.com