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

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01110421
• Collaborator: (none)
• Enrollment: 7
• Locations: 25
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 0.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of doripenem compared to cefepime in children hospitalized with pneumonia.

Condition or Disease	Intervention/Treatment	Phase
Pneumonia, Bacterial; Community-Acquired Infections; Nosocomial Infection; Pneumonia, Ventilator-Associated	Drug: Cefepime placebo; Drug: Cefepime; Drug: Doripenem; Drug: Doripenem placebo; Drug: Amoxicillin/clavulanate potassium	Phase 3

Detailed Description

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 pneumonia (includes nosocomial pneumonia [NP], severe community-acquired pneumonia (CAP), and ventilator-assisted pneumonia [VAP]). 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. 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. Patients will receive IV Doripenem (20 mg/kg up to a maximum of 500 mg/dose) and cefepime placebo OR cefepime (50 mg/kg up to a maximum of 2 grams/dose and doripenem placebo once every 8 hours for up to 14 days. After receiving a minimum of 3 days of IV study drug therapy, patients may be switched to the oral antibiotic (amoxicillin/clavulanate potassium suspension or tablets) or an approved alternative oral agent to complete a total 10-14 days course of antibiotics.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Prospective, Randomized, Double-Blind, Multicenter Study to Establish the Safety and Tolerability of Doripenem Compared With Cefepime in Hospitalized Children With Bacterial Pneumonia
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Doripenem Doripenem 20 mg/kg per dose (up to 500 mg/dose) will be administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Drug: Cefepime placebo; Form=solution for infusion, Route=intravenous use, administered once every 8 hours infused over 30 minutes immediately before each iv infusion of doripenem for up to 14 days; Drug: Doripenem; Type=once every 8 hours infused over 60 minutes, Unit=mg, Number=20mg/kg up to 500mg/dose, Form=solution for infusion, Route=intravenous use. At least 3 days of iv doripenem administered every 8 hours immediately after each iv infusion of cefepime placebo for up to 14 days; Drug: Amoxicillin/clavulanate potassium; Form=suspension or tablets, Route=oral (by mouth), may be administered at the discretion of the investigator once every 12 hours for up to 14 days following IV therapy with doripenem or cefepime.
Experimental: Cefepime Cefepime 50 mg/kg per dose (up to 2 g/dose) will be administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefipime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Drug: Cefepime; Type=once every 8 hours, Unit=mg, Number=50 mg/kg up to 2g/dose, Form=solution for infusion, Route=intravenous use. At least 3 days of iv cefepime administered every 8 hours infused over 30 minutes immediately before each iv infusion of doripenem placebo for up to 14 days; Drug: Doripenem placebo; Form=solution for infusion, Route=intravenous use, administered once every 8 hours infused over 60 minutes immediately following each iv infusion of cefepime for up to 14 days; Drug: Amoxicillin/clavulanate potassium; Form=suspension or tablets, Route=oral (by mouth), may be administered at the discretion of the investigator once every 12 hours for up to 14 days following IV therapy with doripenem or cefepime.

Outcome Measures

Primary Outcome Measures

1. The Number of Participants With Clinical Cure Rate at Test Of Cure (TOC) Visit [TOC (7 to 14 days after the last dose of study medication therapy)]

   The participants were classified as cure if they had resolution or clinical improvement of signs and symptoms of pneumonia, favorable response at End of treatment for IV study (EIV) visit; had no fever; improvement or no progression of radiographic findings of pneumonia on chest X ray; improvement in oxygenation or discontinued mechanical ventilation in intubated participants; and not received nonstudy systemic antibacterial therapy for pneumonia.

Secondary Outcome Measures

1. The Number of Participants With Clinical Improvement Rate at End of IV (EIV) Visit [EIV (within 24 hours after completion of the last dose of IV study medication therapy)]

   Participants were considered as clinical improved if they had no fever, clinical improvement in signs and symptoms of pneumonia from baseline, decrease in WBC, improvement or lack of progression of radiographic findings in comparison with the screening chest X-ray, and not received any nonstudy systemic antibacterial therapy for the treatment of pneumonia after IV study drug therapy had begun.

2. The Number of Participants With Clinical Cure Rate at Late Follow-Up (LFU) Visit [LFU (28 to 42 days after the last dose of study medication therapy)]

   The participants were classified as clinical cure if all pretreatment signs and symptoms showed no evidence of resurgence after administration of the last dose of study medication and no nonstudy systemic antibacterial therapy was given for the treatment of pneumonia.

3. The Number of Participants With Favorable Per-participant Microbiological Response Rate [EIV (within 24 hours after completion of the last dose of IV study medication therapy), TOC (7 to 14 days after the last dose of study medication therapy), and LFU (28 to 42 days after the last dose of study medication therapy)]

   Favorable per-participant microbiological response rate was evaluated at the at End of IV (EIV) visit, Test Of Cure (TOC) visit, and Late Follow-Up (LFU) visit. The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment).

4. Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at End of IV (EIV) Visit [EIV (within 24 hours after completion of the last dose of IV study medication therapy)]

   A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.

5. Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Test Of Cure (TOC) Visit [TOC (7 to 14 days after the last dose of study medication therapy)]

   A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.

6. Number of Participants With Sustained Favorable Per-pathogen Microbiological Outcome Rate at Late Follow-Up (LFU) Visit [LFU (28 to 42 days after the last dose of study medication therapy)]

   A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Require parenteral antibacterial therapy for the treatment of pneumonia

• Have new or progressive radiographic infiltrate(s) (alveolar, lobar, or consolidation) consistent with a bacterial pneumonia that is not related to cardiac or other disease processes

• Must, based on the judgment of the investigator, require hospitalization initially and antibacterial therapy for 10 to 14 days for the treatment of the current pneumonia. (Note that the patient must require at least 3 days of IV antibiotic therapy initially)

• Have a diagnosis of nosocomial pneumonia , severe community-acquired pneumonia, or ventilator-associated pneumonia, defined by the disease-specific criteria as stated in the study protocol

• Have a clinical presentation compatible with bacterial pneumonia( with fever or hypothermia AND leukocytosis OR leucopenia AND at least 2 of the following clinical signs or symptoms in non-intubated patients: cough, new onset of lower respiratory tract secretions (including change in character of secretions or increase in the quantity of secretions or suctioning requirements), auscultatory findings of pneumonia or consolidation (rales, rhonchi bronchial breath sounds, decreased breath sounds, wheezing, and egophony), dyspnea, increased work of breathing expressed as retractions, nasal flaring, or grunting, hypoxemia or oxygen saturation less than 90% on room air, and tachypnea

Exclusion Criteria:

• Received more than 24 hours of systemic antibacterial therapy in the 48 hours before the start of the infusion of the first dose of study drug for the current episode of pneumonia

• Known presence at randomization of pulmonary infection caused only by bacteria that is resistant to cefepime or doripenem (including methicillin resistant Staphylococcus aureus) or presence at baseline of pulmonary infection with Stenotrophomonas species, or Burkholderia cepacia

• Has any of the following conditions at baseline that may interfere with the diagnosis or response to therapy: chest trauma with severe lung contusion, acute respiratory distress syndrome, empyema, flail chest (severe injury to the chest), history of active lung cancer, chronic bronchitis with an exacerbation within the last 30 days, bronchiectasis (an obstructive lung disease), lung abscess(s), anatomical bronchial obstruction, active pulmonary tuberculosis with treatment, suspected pulmonary tuberculosis, suspected or documented atypical viral pneumonia without bacterial superinfection, suspected or documented pertussis, chemical pneumonitis (eg, aspiration of gastric contents, inhalation injury), or cystic fibrosis

• The patient has any of the following clinically significant laboratory abnormalities: hematocrit of less than 20%

• absolute neutrophil count (ANC) <500 cells/microL, platelet count <40,000 cells/microL, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin >5x the age specific upper limit of normal, acute or chronic renal insufficiency with a baseline creatinine clearance of <60 mL/minute or requires dialysis therapy for any reason, or are profoundly immunodeficient and require prophylactic antimicrobial therapy for Pneumocystis jirovicei, Toxoplasma gondii, or herpes viruses, and/or chronic or intermittent immunoglobin replacement therapy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Cleveland	Ohio	United States
3		Toledo	Ohio	United States
4		Pittsburgh	Pennsylvania	United States
5		Buenos Aires		Argentina
6		Córdoba		Argentina
7		Loma Hermosa N/A		Argentina
8		Santa Fe		Argentina
9		Belo Horizonte		Brazil
10		Porto Alegre		Brazil
11		São Paulo		Brazil
12		Bogota		Colombia
13		Cali		Colombia
14		Medellin		Colombia
15		Riga		Latvia
16		Kaunas		Lithuania
17		Taurage		Lithuania
18		Vilnius		Lithuania
19		Guadajalara		Mexico
20		Mexico		Mexico
21		Monterrey		Mexico
22		Zona		Panama
23		Lublin		Poland
24		Szczecin		Poland
25		Kharkiv		Ukraine

Sponsors and Collaborators

• Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC C. Clinical Trial, Janssen Research & Development, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01110421
• Other Study ID Numbers: CR016975; DORIPED3003; 2009-016069-27
• First Posted: Apr 26, 2010
• Last Update Posted: Jul 15, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Janssen Research & Development, LLC: Doripenem; Child, Hospitalized; Cefepime; Infusions, Intravenous; Severe community acquired pneumonia; Nosocomial pneumonia; Ventilator associated pneumonia
• Additional relevant MeSH terms: Infections; Communicable Diseases; Pneumonia; Cross Infection; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Community-Acquired Infections; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Cefepime; Doripenem; Amoxicillin-Potassium Clavulanate Combination

Study Results

Participant Flow

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Period Title: Overall Study
STARTED	5	2
COMPLETED	5	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Doripenem	Cefepime	Total
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Total of all reporting groups
Overall Participants	5	2	7
Age (Count of Participants)
<=18 years	5 100%	2 100%	7 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.2 (2.49)	4.5 (0.71)	5 (2.08)
Age, Customized (participants) [Number]
3 months to <2 years	0 0%	0 0%	0 0%
2 to <6 years	3 60%	2 100%	5 71.4%
6 to <12 years	2 40%	0 0%	2 28.6%
12 to <18 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	1 50%	1 14.3%
Male	5 100%	1 50%	6 85.7%

Outcome Measures

1. Primary Outcome

Title	The Number of Participants With Clinical Cure Rate at Test Of Cure (TOC) Visit
Description	The participants were classified as cure if they had resolution or clinical improvement of signs and symptoms of pneumonia, favorable response at End of treatment for IV study (EIV) visit; had no fever; improvement or no progression of radiographic findings of pneumonia on chest X ray; improvement in oxygenation or discontinued mechanical ventilation in intubated participants; and not received nonstudy systemic antibacterial therapy for pneumonia.
Time Frame	TOC (7 to 14 days after the last dose of study medication therapy)

Outcome Measure Data

Analysis Population Description

Clinical Intent-To-Treat (CITT): All randomized participants who met the minimal disease definition of pneumonia regardless if a baseline pathogen was isolated from the baseline lower respiratory tract culture, pleural fluid or blood culture.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	5	2
Number [Participants]	3 60%	2 100%

2. Secondary Outcome

Title	The Number of Participants With Clinical Improvement Rate at End of IV (EIV) Visit
Description	Participants were considered as clinical improved if they had no fever, clinical improvement in signs and symptoms of pneumonia from baseline, decrease in WBC, improvement or lack of progression of radiographic findings in comparison with the screening chest X-ray, and not received any nonstudy systemic antibacterial therapy for the treatment of pneumonia after IV study drug therapy had begun.
Time Frame	EIV (within 24 hours after completion of the last dose of IV study medication therapy)

Outcome Measure Data

Analysis Population Description

Clinical intent-to-treat: All randomized participants who met the minimal disease definition of pneumonia regardless if a baseline pathogen was isolated from the baseline lower respiratory tract culture, pleural fluid or blood culture.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	5	2
Number [Participants]	4 80%	2 100%

3. Secondary Outcome

Title	The Number of Participants With Clinical Cure Rate at Late Follow-Up (LFU) Visit
Description	The participants were classified as clinical cure if all pretreatment signs and symptoms showed no evidence of resurgence after administration of the last dose of study medication and no nonstudy systemic antibacterial therapy was given for the treatment of pneumonia.
Time Frame	LFU (28 to 42 days after the last dose of study medication therapy)

Outcome Measure Data

Analysis Population Description

Clinical Intent-to-Treat (CITT): All randomized participants who met the minimal disease definition of pneumonia regardless if a baseline pathogen was isolated from the baseline lower respiratory tract (LRT) culture, pleural fluid or blood culture.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	5	2
Number [Participants]	3 60%	2 100%

4. Secondary Outcome

Title	The Number of Participants With Favorable Per-participant Microbiological Response Rate
Description	Favorable per-participant microbiological response rate was evaluated at the at End of IV (EIV) visit, Test Of Cure (TOC) visit, and Late Follow-Up (LFU) visit. The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment).
Time Frame	EIV (within 24 hours after completion of the last dose of IV study medication therapy), TOC (7 to 14 days after the last dose of study medication therapy), and LFU (28 to 42 days after the last dose of study medication therapy)

Outcome Measure Data

Analysis Population Description

Microbiological intent-to-treat - Participants of CITT with at least one baseline pneumonia pathogen from pleural fluid, LRT, or blood culture susceptible to doripenem and cefepime. 3 and 2 participants from doripenem and cefepime, respectively had no susceptible pneumonia pathogens at baseline and were excluded from this set.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	2	0
TOC visit	2 40%
EIV visit	2 40%
LFU visit	2 40%

5. Secondary Outcome

Title	Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at End of IV (EIV) Visit
Description	A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
Time Frame	EIV (within 24 hours after completion of the last dose of IV study medication therapy)

Outcome Measure Data

Analysis Population Description

Microbiological intent-to-treat - Participants of CITT with at least one baseline pneumonia pathogen from pleural fluid, LRT, or blood culture susceptible to doripenem and cefepime. 3 and 2 participants from doripenem and cefepime, respectively had no susceptible pneumonia pathogens at baseline and were excluded from this set.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	2	0
Staphylococcus aureus (1)	1 20%
Streptococcus pneumoniae (1)	1 20%
Klebsiella pneumoniae (1)	1 20%

6. Secondary Outcome

Title	Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Test Of Cure (TOC) Visit
Description	A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
Time Frame	TOC (7 to 14 days after the last dose of study medication therapy)

Outcome Measure Data

Analysis Population Description

Microbiological intent-to-treat - Participants of CITT with at least one baseline pneumonia pathogen from pleural fluid, LRT, or blood culture susceptible to doripenem and cefepime. 3 and 2 participants from doripenem and cefepime, respectively had no susceptible pneumonia pathogens at baseline and were excluded from this set.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	2	0
Staphylococcus aureus (1)	1 20%
Streptococcus pneumoniae (1)	1 20%
Klebsiella pneumoniae (1)	1 20%

7. Secondary Outcome

Title	Number of Participants With Sustained Favorable Per-pathogen Microbiological Outcome Rate at Late Follow-Up (LFU) Visit
Description	A total of 3 pathogens were isolated at baseline from lower respiratory tract (LRT) culture in 2 participants in the doripenem treatment group and were susceptible to the study drug received: 2 pathogens (Staphylococcus aureus Klebsiella pneumoniae) were isolated at baseline from 1 participant and a 3rd pathogen (Streptococcus pneumoniae) was isolated at baseline from the other participant (see listed in the table below; the number in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem treatment group). The favorable per-participant microbiological response was considered when all baseline pathogens were eradicated (absence) or presumed eradicated (absence of material to culture in a participant who has a positive clinical response to treatment). NOTE: No participants in the cefepime treatment group met criteria for inclusion in the Microbiological intent-to-treat analysis.
Time Frame	LFU (28 to 42 days after the last dose of study medication therapy)

Outcome Measure Data

Analysis Population Description

Microbiological intent-to-treat - Participants of CITT with at least one baseline pneumonia pathogen from pleural fluid, LRT, or blood culture susceptible to doripenem and cefepime. 3 and 2 participants from doripenem and cefepime, respectively had no susceptible pneumonia pathogens at baseline and were excluded from this set.

Arm/Group Title	Doripenem	Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.	Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
Measure Participants	2	0
Staphylococcus aureus (1)	1 20%
Streptococcus pneumoniae (1)	1 20%
Klebsiella pneumoniae (1)	1 20%

Adverse Events

Time Frame	Approximately 8 weeks
Arm/Group Title	Doripenem		Cefepime
Arm/Group Description	Doripenem 20 mg/kg per dose (up to 500 mg/dose) was administered every 8 hours as 60-minutes IV (at least 3 days of IV doripenem only or IV doripenem followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.		Cefepime 50 mg/kg per dose (up to 2 g/dose) was administered every 8 hours as 30-minutes IV (at least 3 days of IV cefepime only or IV cefepime followed by oral amoxicillin/clavulanate potassium or ciprofloxacin). Total duration of treatment 10 to 14 days.
All Cause Mortality
	Doripenem		Cefepime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Doripenem		Cefepime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		0/2 (0%)
Infections and infestations
Empyema	1/5 (20%)		0/2 (0%)
Pneumonia	1/5 (20%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Doripenem		Cefepime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/5 (60%)		1/2 (50%)
Gastrointestinal disorders
Abdominal Pain	1/5 (20%)		0/2 (0%)
Abdominal Pain Upper	1/5 (20%)		0/2 (0%)
Diarrhoea	1/5 (20%)		0/2 (0%)
General disorders
Chest Pain	1/5 (20%)		0/2 (0%)
Immune system disorders
Hypersensitivity	1/5 (20%)		0/2 (0%)
Infections and infestations
Gastroenteritis	1/5 (20%)		0/2 (0%)
Nasopharyngitis	0/5 (0%)		1/2 (50%)
Injury, poisoning and procedural complications
Stab Wound	1/5 (20%)		0/2 (0%)
Investigations
Oxygen Saturation Decreased	1/5 (20%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Flank Pain	1/5 (20%)		0/2 (0%)
Renal and urinary disorders
Dysuria	1/5 (20%)		0/2 (0%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Distress Syndrome	1/5 (20%)		0/2 (0%)
Nasal Congestion	1/5 (20%)		0/2 (0%)
Skin and subcutaneous tissue disorders
Ecchymosis	1/5 (20%)		0/2 (0%)

Limitations/Caveats

This study was terminated early due to business reasons and not related to safety concerns or issues. As such, the limited enrollment precludes a meaningful conclusion about the efficacy and safety of doripenem compared with cefepime.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.