Trial to Evaluate Beta-Lactam Antimicrobial Therapy of Community Acquired Pneumonia in Children

This is a multi-center, randomized, double-blind, placebo-controlled, superiority clinical
trial evaluating short course (5 day) vs. standard course (10 day) of oral beta-lactam
antibiotic therapy (amoxicillin, amoxicillin-clavulanate, cefdinir) for treatment of CAP in
children 6-71 months of age who have clinically improved prior to enrollment. The study will
randomize approximately 400 enrolled subjects to one of the two study arms (approximately 200
children in each arm) in order to reach 360 subjects completing Outcome Assessment Visit 1.
Subjects will be randomized (1:1) to receive either a standard course of the initially
prescribed antibiotic (10 days) or a short course of the initially prescribed antibiotic (5
days) plus 5 days of matching placebo. The study will recruit potential subjects from
children who are diagnosed with CAP and who are initiated on oral beta-lactam therapy by
healthcare providers in EDs, outpatient clinics, and urgent care centers at the study sites.
Day -5 is defined as the date on which oral beta-lactam therapy is initiated for a diagnosis
of CAP. Potential subjects will be identified at any time following clinical diagnosis of
pneumonia. These subjects will be assessed for eligibility and enrolled on Day -3 to -1 of
their initially prescribed oral beta-lactam therapy. Subjects may also be enrolled on Day 1
(the first day of receipt of study agent) provided they have not yet received any doses of
the healthcare provider-prescribed antibiotic therapy for that day. The Primary objective is
to compare the composite overall outcome (Desirability of Outcome Ranking, DOOR) among
children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs
standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visit #1
(Study Day 8 +/- 2 days). The Secondary objectives are: 1) To compare the composite overall
outcome (DOOR) among children 6-71 months of age with CAP assigned to a strategy of short
course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome
Assessment Visit #2 (Study Day 22 +/- 3 days); 2) To compare the resolution of symptoms (a
component of DOOR) among children 6-71 months of age with CAP assigned to a strategy of short
course (5 days) vs standard course (10 days) outpatient beta-lactam therapy at Outcome
Assessment Visits #1 and #2; 3) To compare the clinical response (a component of DOOR) among
children 6-71 months of age with CAP assigned to a strategy of short course (5 days) vs
standard course (10 days) outpatient beta-lactam therapy at Outcome Assessment Visits #1 and
#2; 4) To compare solicited events (a component of DOOR) among children 6-71 months of age
with CAP assigned to a strategy of short course (5 days) vs standard course (10 days)
outpatient beta-lactam therapy at Outcome Assessment Visits #1 and #2; 5) To compare
medically attended visits to Emergency Departments (ED) or outpatient clinics,
hospitalizations, surgical procedures, and receipt of non-study systemic antibiotics
(components of the clinical response) among children 6-71 months of age with CAP assigned to
a strategy of short course (5 days) vs standard course (10 days) outpatient beta-lactam
therapy at Outcome Assessment Visits #1 and #2

Inclusion Criteria:

1. Age 6 - 71 months

2. Provider diagnosis of CAP and prescription of antibiotic therapy with amoxicillin,
amoxicillin-clavulanate, or cefdinir

- amoxicillin or amoxicillin-clavulanate prescribed at a amoxicillin dose of 60
mg/kg/day

-- cefdinir prescribed at a minimum dose of 10 mg/kg/day

3. Parental report of clinical improvement

- based on lack of either subjective or known fever temperature >/= 38.3°C in the
preceding 24 hours; current respiratory rate no greater than 50 breaths/minute (<2
years of age) or breaths/minute (= / > 2 years of age); and current grade of cough < 3

4. Ability of a parent or guardian to understand and comply with the study procedures and
be available for all study visits

5. Signed written informed consent by a parent or guardian

Exclusion Criteria:

1. Treatment with any systemic antibiotic therapy within 7 days before the diagnosis of CAP
2. Initial therapy for CAP with combination antibiotic therapy

- amoxicillin, amoxicillin/clavulanate or cefdinir plus one or more additional oral,
intravenous, or intramuscular antibiotics 3. History of anaphylaxis or severe drug
allergy to amoxicillin, if prescribed amoxicillin or amoxicillin/clavulanic acid; or
oral cephalosporin antibiotics (except cefaclor), if prescribed cefdinir 4. Presence
of concomitant bacterial infection that requires > 5 days of antibiotic therapy 5.
Radiographic findings (where applicable) of complicated pneumonia at presentation or
any subsequent chest radiograph up to the time of enrollment

- clinically significant pleural effusion, lung abscess, or pneumatocele 6.
Hospitalization for pneumonia during Day -5 to -1 of antibiotic therapy for CAP

- subjects who require serial clinical assessments, but are discharged within 24 hours
will not be considered hospitalized and will not satisfy this exclusion criterion 7.
Pneumonia due to S. aureus or group A streptococcus documented by positive blood
culture or PCR, at the time of enrollment 8. History of pneumonia within the previous
6 months 9. History of persistent asthma within the previous 6 months or current acute
asthma exacerbation

- persistent asthma is defined as receiving daily asthma maintenance therapy such as
inhaled corticosteroids, cromolyn, theophylline, or leukotriene receptor antagonists

-- acute asthma exacerbation is defined as receiving concomitant bronchodilator
therapy and systemic corticosteroids 10. Provider-diagnosis of aspiration pneumonia,
bronchiolitis, or bronchitis 11. Surgery or other invasive procedures of the upper or
lower airway (e.g., bronchoscopy, laryngoscopy) with general anesthesia or
hospitalization medical condition

- including chronic heart disease, chronic lung disease (except asthma), congenital
anomalies of the airways or lung, cystic fibrosis, chronic renal disease including
nephrotic syndrome, protein-losing enteropathy of any cause, severe malnutrition,
neurocognitive disorders, metabolic disorders (including phenylketonuria), or genetic
disorders (note: genetic syndromes such as Down syndrome and Edwards Syndrome are
excluded; however, children with genetic disorders (e.g., hemophilia) but who do not
have a genetic syndrome may not satisfy this particular exclusion criterion; it is
important that children with such genetic disorders do not have symptoms and/or
comorbidities that would pose additional risk to them nor jeopardize the adequacy of
study assessments.) 13. History of a condition that compromises the immune system

- HIV infection, primary immunodeficiency, anatomic or functional asplenia; receipt of a
hematopoietic stem cell or solid organ transplant at any time; receipt of
immunosuppressive therapy including chemotherapeutic agents, biologic agents,
antimetabolites or radiation therapy during the past 12 months; or daily use of
systemic corticosteroids for more than 7 consecutive days during the past 14 days 14.
Any other condition that in the judgment of the investigator precludes participation
because it could affect the safety of the subject 15. Current enrollment in another
clinical trial of an investigational agent 16. Previous enrollment in this trial