A Safety and Tolerability Study of Doripenem Compared With Cefepime in Hospitalized Children With Bacterial Pneumonia

This is a randomized (study assigned by chance), double-blind (neither physician nor patient
knows the name of the assigned study drugs), double-dummy (all patients will be given both a
placebo [salt solution] and study drug in alternating periods of time during the study),
active comparator-controlled (compare the 'test' treatment to standard-of-care therapy),
multinational, multicenter study to establish the safety and tolerability of doripenem (an
antibiotic) compared with cefepime (an antibiotic) administered by intravenous (iv) infusion
(slow injection of drug solution into the vein over a period of time) in children ages 3
months to less than 18 years hospitalized with confirmed or suspected pneumonia. A minimum
of 120 patients will be enrolled in this study and randomly assigned to 1 of 2 treatment
groups in a 3:1 ratio: a minimum of 90 patients will be assigned to the doripenem group and
30 patients will be assigned to the cefepime group. The study includes 3 periods: a
pretreatment (screening) period that will occur within 2 days prior to randomization
(assignment of study drug); a treatment period of 10 to 14 days where patients will receive
study drug treatment, and a posttreatment period consisting of 2 study visits. The maximum
duration of study drug therapy is 14 days. The total duration of the study is approximately
7 to 8 weeks for each patient. During the pretreatment period, the patient's eligibility for
the study will be determined by review of specific entry criteria. After a signed informed
consent form explaining the details about the study has been obtained from the patient's
parent or legal representative (and a signed assent form has been obtained from patients who
are capable of providing assent, typically, children 7 years of age and older), screening
procedures will be performed. Screening procedures will include the collection of
information about the patient's medical history, demographics (age and race), therapies
(including medications) taken within the last 30 days, and any preplanned surgeries or
procedures. If a patient is receiving treatment for any chronic pre-existing diseases at the
time of study entry, the type and dosage of medications taken should not be changed during
the study, if medically appropriate. During screening, a physical examination will be
performed, vital signs (heart rate, respiratory rate, and blood pressure) and body
temperature obtained, height/length and body weight measured, and signs and symptoms of
pneumonia assessed. Within 48 hours before treatment assignment, blood samples (about 3 mL
[less than a teaspoon]) will be obtained from patients for laboratory testing (urinalysis,
serum chemistry, hematology) and for culture to test for the presence of bacteria in the
blood. A chest X-ray (picture of the lung) will be taken to see if the patient has
pneumonia. A computerized tomography (CT) Scan, which is a specialized X-ray may also be
required if the necessary details are not visible on the chest X-ray. The chest X-ray will
be repeated before the end of iv study drug therapy and may be repeated again only if needed
at follow-up visits. The study doctor will use a device called a pulse-oximeter (placed on
the patient's finger) to measure the amount of oxygen in patient's blood. A sputum (mucus
coughed-up from the lung) sample will be collected to test for the bacteria that may be
causing the infection in the lung. Fluid that is between the outside of the lungs (called
the pleura) and the chest wall that may be infected and cause discomfort and difficulty
breathing may be removed with a needle or tube and cultured for the presence of bacteria. In
addition, a urine (or serum) pregnancy test will be performed on all girls who have had
their first menstrual period. After all screening procedures have been completed, the
patient will be assigned to receive iv study drug (doripenem or cefepime) which will be
considered Day 1 of the study. Patients will begin treatment with doripenem or cefepime iv
infusion within the following 24 hours. Because doripenem will be administered over a
60-minute period and cefepime will be administered over a shorter 30-minute period there is
the potential for the patient and study staff to know which study drug is being
administered. To prevent this, patients will be administered study drug along with (or
paired with) a placebo as follows: patients randomized to receive a 60-minute iv infusion of
doripenem will first receive a 30-minute iv infusion of a placebo identical in appearance to
cefepime, and patients who are randomized to receive cefepime will receive a 60-minute iv
infusion of placebo identical in appearance to doripenem. The 30-minute iv infusions of
cefepime/cefepime placebo will be always administered first. During the study, patients will
receive a 10 to 14-day course of study drug therapy, which may consist of iv study drug only
or at least 3 days of iv study drug followed by other iv or PO antibiotic therapies.
Patients will remain hospitalized for the duration of their treatment with iv study drug
therapy. During the treatment period, patients who develop renal impairment with a
calculated creatinine clearance (measure of the level of the waste product creatinine in the
blood and urine) of less than 60 mL per minute or require dialysis for any reason will
discontinue treatment with iv study drug but continue to be monitored in the study for
safety. Patients with specific types of pneumonia that were contracted in the hospital will
be required to complete their treatment course with iv study drug only. After receiving a
minimum of 9 paired doses (approximately 72 hours) of iv study drug therapy, patients who
contracted pneumonia in the community, do not have other complications and meet specific
criteria demonstrating improvement; may, at the discretion of the investigator, be switched
to an oral antibiotic (amoxicillin/clavulanate potassium suspension or tablets 3 times a
day) to complete a 10- to 14-day antibiotic course of therapy. An alternative oral
antibiotic may be considered in cases of intolerance or resistance to
amoxicillin/clavulanate potassium. Other therapy for pneumonia will be permitted as follows:
azithromycin, vancomycin or aminoglycoside therapy may be administered at any time for other
suspected or confirmed infections not covered by the study drug. This therapy may be
continued at the discretion of the investigator. If after 72 hours of treatment with iv
study drug, no improvement in the signs or symptoms of the patient's pneumonia is observed,
or the patient continues to have a fever that is not resolving without an alternative
explanation, or continues to has clinical evidence of pneumonia and requires treatment with
alternative antibiotic therapy, the patient will be considered a treatment failure and
discontinue iv study drug therapy but will continue to be monitored for safety in the study.
Throughout the study, all patients will be monitored daily for safety, signs and symptoms of
pneumonia, and occurrence of adverse events. In addition, blood samples for serum chemistry
and hematology laboratory assessments, and pharmacokinetic (determination of doripenem
plasma concentrations), and calculated creatinine clearance will be performed on selected
days. Values that are outside of normal limits and more severe will be repeated until they
are normal or stable. Within 24 hours of the last dose of study drug (and before discharge
from the hospital), patients will have end of treatment (EIV) clinical outcome assessment
performed. Patients will be rated with a clinical outcome of "clinical improvement",
"clinical failure", or "indeterminate" on the basis of their response to treatment. After
the EIV, patients will return for 2 posttreatment study visits conducted 7 to 14 days and 28
to 42 days, respectively, after the last dose of study drug and follow up safety procedures
performed. Any patients withdrawn from the study at any time will return to have
posttreatment visit procedures performed. The primary outcome measure in the study is safety
and tolerability. Safety and tolerability will be evaluated by examining the incidence,
severity, and type of adverse events, changes in clinical laboratory tests, vital signs
measurements, and findings from physical examinations observed during treatment and at each
posttreatment visit. An independent monitoring committee (IDMC) will be established for this
study to ensure that the safety of the patients is not compromised. The IDMC will consist of
individuals who are not associated with the conduct of the study, and will include but will
not be limited to individuals with expertise relevant to the care of pediatric patients, and
including at least one infectious disease physician and at least one statistician. Doripenem
OR cefepime will be administered to children by iv infusion. Doripenem will be administered
at a dose of 20 mg/kg to 500 mg per dose every 8 hours over 60 minutes or cefepime will be
administered at a dose of 50 mg/kg to 2 grams per dose every 8 hours over 30 minutes).
Matching placebo will be given for alternate study drug (ie, doripenem with cefepime placebo
OR cefepime with doripenem placebo)