SUPPLEMENT ARTICLE
Scenario 1: A Patient with Mild Community-
Acquired Pneumonia—Introduction
to Clinical Trial Design Issues
David N. Gilbert
Providence Portland Medical Center and Oregon Health and Sciences University, Portland, Oregon
A prototypical patient is presented to introduce important design issues for clinical trials of antibacterials in
the treatment of community-acquired pneumonia.
Of the 4 million or more patients in the United States
treated annually for community-acquired pneumonia
(CAP), ∼80% are cared for on an outpatient basis [1,
2]. Admittedly, the patient population is heterogeneous.
However, 2 subgroups constitute a significant percent-
age of the total.
The first subgroup consists of young, otherwise-
healthy individuals who are nonsmokers aged !40
years. “Atypical” pathogens, such as Mycoplasma pneu-
moniae or Chlamydia pneumoniae, are identified fre-
quently as the etiologic organism. Streptococcus pneu-
moniae may be the etiologic organism, especially during
or after viral tracheobronchitis.
In contrast, individuals in the second group are older.
Often, they have used tobacco products for years and
meet clinical criteria for chronic bronchitis and/or
emphysema.
To focus on clinical trial design issues pertinent to
the population of patients with mild pneumonia, a typ-
ical clinical-trial candidate patient is described below.
CASE PRESENTATION
Present illness. A 35-year-old male resident of Bos-
ton, Massachusetts, presents with fever and cough. He
was well until 3 days earlier, when he suffered the onset
of nasal stuffiness, mild sore throat, and a cough pro-
Reprints or correspondence: Dr. David N. Gilbert, 5050 NE Hoyt, Ste. 540,
Portland, OR 97213 (david.gilbert@providence.org).
Clinical Infectious Diseases 2008; 47:S121–2
 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4711S3-0003$15.00
DOI: 10.1086/591391
Downloaded from http://cid.oxfordjournals.org/ at University of California Santa Barbara/Davidson Library on July 8, 2015
ductive of small amounts of clear sputum. Today, he
decided to seek physician assistance because of an in-
crease in temperature to 38.3C and spasms of coughing
that produce purulent secretions. On one occasion, he
noted a few flecks of bright-red blood in his sputum.
Other pertinent history. It is March. He lives in a
home in the city with his wife and 3 children, aged 7,
9, and 11 years. The children are fully immunized. The
11-year-old child is recovering from a “nagging” cough
that has persisted for 10–14 days.
The family has a pet parakeet who is 5 years old and
appears to be well. The patient has not traveled outside
the city in the past year. He is an office manager.
The patient smokes 1 pack/day and has done so since
the age of 15 years. Several times a month, especially
during the winter, on arising from sleep, he produces
∼1 tablespoon of purulent sputum.
Medical history. The patient has no history of fa-
milial illness, hospitalizations, or trauma. There are no
drug allergies or intolerance. The only medication he
takes is acetaminophen occasionally, for headaches. He
drinks beer or wine in moderation.
Physical examination. His body temperature is
38.9C (100F), his pulse is 110 beats/min and regular,
and his respiratory rate is 18 breaths/min. His oxygen
saturation is 93% while breathing room air. There is
mild erythema of the mucosa of the nose and posterior
oropharynx. Inspiratory “rales” are heard at the right
lung base.
Laboratory and radiographic findings. His he-
moglobin level is 12.5 g/dL, with a hematocrit of 36%.
His WBC count is 13,500 cells/mL, with 82% poly-
Scenario 1 • CID 2008:47 (Suppl 3) • S121
morphonuclear cells, 11% band forms, and 7% lymphocytes.
His platelet count is 180,000 cells/mL. The results of a multi-
chemistry screen are unremarkable.
Chest radiography documents bilateral lower lobe infiltrates
that are more pronounced on the right side. There are no
pleural effusions.
Management questions. A validated prediction rule fore-
casts that this patient’s risk of death from his CAP is !1% [3].
Therefore, he is a candidate for outpatient therapy.
What is the likely microbiological diagnosis? On the basis of
the cough of 2 weeks’ duration in the patient’s 11-year-old
child, the pneumonia could be due to M. pneumoniae or an-
other atypical pathogen. However, this illness could represent
pneumococcal pneumonia superimposed on a viral upper re-
spiratory tract infection.
Clinical trial design questions. These are the hard ques-
tions and illustrate some of the many reasons for this workshop:
Is the patient of sufficient reliability to participate in an out-
patient clinical trial of antibacterials for mild CAP? Is it ethical
or, from a practical standpoint, feasible to conduct a placebo-
controlled trial? If an active comparator drug is used, how does
one generate a valid and defensible margin of noninferiority?
What are valid, reproducible, and quantifiable clinical end
points (outcomes)?
It would help greatly if the etiology of the pneumonia could
be determined for the majority of the enrolled patients. What
are the current diagnostic tools that can be applied and thereby
“enrich” the patient population?
S122 • CID 2008:47 (Suppl 3) • Gilbert
Multiple precautions are necessary to avoid bias in the in-
terpretation of the results of clinical trials. For example, what
are acceptable methods in the “blinding” of treatment arms?
How can investigators reliably and with reasonable sensitivity
detect adverse drug effects?
The articles that follow address these questions and more.
Participants in this workshop uniformly agreed that the inter-
action of US Food and Drug Administration regulations, in-
dustry sponsors, and Infectious Diseases Society of America
academics represents an opportunity to modernize future clin-
ical trials for CAP.
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Acknowledgments
Supplement sponsorship. This article was published as part of a sup-
plement entitled “Workshop on Issues in the Design and Conduct of Clin-
ical Trials of Antibacterial Drugs for the Treatment of Community-Acquired
Pneumonia,” sponsored by the US Food and Drug Administration and the
Infectious Diseases Society of America.
Potential conflicts of interest. D.N.G. serves on the speakers’ bureau
of Abbott Laboratories, Bayer, GlaxoSmithKline, Lilly, Merck, Pfizer, Roche,
Schering-Plough, and Wyeth; and has received consulting fees from Ad-
vanced Life Sciences and Pacific Beach Bioscience.
References
1. Mandell LA. Epidemiology and etiology of community-acquired pneu-
monia. Infect Dis Clin North Am 2004; 18:761–76.
2. Lamping DL, Schroter S, Marquis P, et al. The community-acquired
pneumonia questionnaire. Chest 2002; 122:920–9.
3. Fine MJ, Auble TE, Yearly DM, et al. A prediction rule to identify low-
risk patients with community-acquired pneumonia. N Engl J Med
1997; 336:243–50.