A Safety and Tolerability Study of Doripenem Compared With Cefepime in Children Hospitalized With Complicated Urinary Tract Infections

• Sponsor: Janssen Research & Development, LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01110408
• Collaborator: (none)
• Enrollment: 41
• Locations: 38
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 1.1
• 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 complicated urinary tract infections.

Condition or Disease	Intervention/Treatment	Phase
Complicated Urinary Tract Infections or Pyelonephritis	Drug: Doripenem; Drug: Doripenem placebo; Drug: Cefepime; Drug: Cefepime 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 are 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 the antibiotic doripenem compared with the antibiotic cefepime 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 a complicated urinary tract infection (cUTI). 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 the 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. Safety and tolerability will be evaluated by examining the incidence, severity, and type of adverse events, changes in clinical laboratory tests, vital sign measurements, and findings from physical examinations that are recorded as adverse events during treatment and at each posttreatment visit. An independent monitoring committee (IDMC) will be established for this study to ensure that the safety of 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. IV study drug therapy (Cefepime [50mg/kg up to 2g/dose] and doripenem placebo or doripenem [20mg/kg up to 500mg/dose] and cefepime placebo will be administered once every 8 hours for up to 14 days. After receiving a minimum of 3 days of IV study drug therapy, patients may be discharged from the hospital and continue PO antibiotic therapy with amoxicillin/clavulanate potassium, ciprofloxacin, or alternative antibiotic therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 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 Complicated Urinary Tract Infections
• Study Start Date: Dec 1, 2010
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

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: 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: 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: 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 dministered 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.	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: 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: 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 in signs and symptoms of complicated urinary tract infection; had no fever; no additional antimicrobial therapy was required for the treatment of the infection; and a clinical response assessment of improvement at End of IV visit.

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)]

   The participants were considered as clinical improved if they had clinical improvement in signs and symptoms from baseline; no fever for at least the 24 hours before discontinuing the IV study drug; and not received nonstudy antibiotics for the treatment of urinary tract infection 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 of complicated urinary tract infection showed no evidence of recurrence after test of cure.

3. The Number of Participants With Favorable Per-participant Microbiological Response [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)]

   The favorable per-pathogen microbiological outcome 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).A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).

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)]

   The favorable per-pathogen microbiological outcome 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). A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).

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)]

   The sustained favorable per-pathogen microbiological outcome 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). A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients who are eligible for the study must have a current episode of cUTI or pyelonephritis

• Have evidence of pyuria that meets criteria specified in the study protocol

• Have a study-qualifying pretreatment "baseline" urine culture specimen obtained by an acceptable method within 48 hours before the start of the administration of the first dose of iv study drug from which a bacterial pathogen is isolated with a growth of >= 100000 colony forming units (CFU)/mL

• Require hospitalization initially and 10 to 14 days of antibacterial therapy [of which at least 72 hours should be iv therapy] for the treatment of the presumed UTI

• Have a signed informed consent form completed by the patient's parent or legal representative (and a signed assent form obtained from patients who are capable of providing assent, typically, children 7 years of age or older)

Exclusion Criteria:

• Have a history of hypersensitivity reactions to carbapenems, cephalosporins, penicillins, or other beta-lactam antibiotics

• concomitant infection including but not limited to suspected or confirmed meningitis or central nervous system infection requiring systemic antibiotic or antifungal therapy in addition to the iv study drug therapy at the time of randomization

• Receipt of any amount of systemic antibiotic within 96 hours before obtaining the study-qualifying pretreatment baseline urine or systemic antibiotic therapy for more than 24 hours after obtaining the study-qualifying pretreatment baseline urine specimen

• Have a diagnosis of intractable UTI/pyelonephritis infection anticipated to require more than 14 days of study drug therapy, a permanent indwelling bladder catheter or instrumentation including nephrostomy or current urinary catheter that will not be removed or anticipation of urinary catheter placement that will not be removed during the course of iv study drug therapy administration, complete and permanent obstruction of the urinary tract, confirmed fungal UTI, suspected or confirmed perinephric or intrarenal abscess, suspected or confirmed prostatitis, known ileal loops, or any of the following clinically significant laboratory abnormalities: absolute neutrophil count (ANC) <500 cells/µL, platelet count <40,000 cells/µL, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin >5x the age-specific upper limit of normal (ULN), acute or chronic renal insufficiency with a baseline creatinine clearance <60 mL per minute or requires dialysis therapy for any reason

• Have a history of uncontrolled epilepsy defined as at least 1 seizure within the 6 months before randomization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Little Rock	Arkansas	United States
2		Oakland	California	United States
3		Orange	California	United States
4		San Diego	California	United States
5		Washington	District of Columbia	United States
6		New Brunswick	New Jersey	United States
7		Albany	New York	United States
8		Bronx	New York	United States
9		Cleveland	Ohio	United States
10		Toledo	Ohio	United States
11		Pittsburgh	Pennsylvania	United States
12		Buenos Aires		Argentina
13		Córdoba		Argentina
14		Loma Hermosa N/A		Argentina
15		Santa Fe		Argentina
16		Belo Horizonte		Brazil
17		Caxias Do Sul		Brazil
18		Passo Fundo		Brazil
19		São Paulo		Brazil
20		Santiago		Chile
21		Valdivia X Región		Chile
22		Bogota		Colombia
23		Cali		Colombia
24		Floridablanca		Colombia
25		Medellin		Colombia
26		Hradec Kralove		Czech Republic
27		Praha		Czech Republic
28		Riga		Latvia
29		Kaunas		Lithuania
30		Vilnius		Lithuania
31		Guadajalara		Mexico
32		Monterrey		Mexico
33		Zapopan		Mexico
34		Zona		Panama
35		Lublin		Poland
36		Szczecin		Poland
37		Kharkiv		Ukraine
38		Poltava		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

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT01110408
• Other Study ID Numbers: CR016792; DORIPED3002; 2009-015953-18
• First Posted: Apr 26, 2010
• Last Update Posted: Jul 15, 2014
• Last Verified: Jul 1, 2014

• Keywords provided by Janssen Research & Development, LLC: Antibiotic; Child, Hospitalized; Complicated Urinary Tract Infection; Pyelonephritis; Doripenem; Cefepime
• Additional relevant MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; 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	31	10
COMPLETED	30	10
NOT COMPLETED	1	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	31	10	41
Age (Count of Participants)
<=18 years	31 100%	10 100%	41 100%
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]	4.7 (5.15)	4.3 (4.16)	4.6 (4.88)
Age, Customized (participants) [Number]
3 months to <2 years	12 38.7%	4 40%	16 39%
2 to <6 years	8 25.8%	2 20%	10 24.4%
6 to <12 years	7 22.6%	3 30%	10 24.4%
12 to <18 years	4 12.9%	1 10%	5 12.2%
Sex: Female, Male (Count of Participants)
Female	26 83.9%	5 50%	31 75.6%
Male	5 16.1%	5 50%	10 24.4%

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 in signs and symptoms of complicated urinary tract infection; had no fever; no additional antimicrobial therapy was required for the treatment of the infection; and a clinical response assessment of improvement at End of IV visit.
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 complicated urinary tract infection regardless if a baseline pathogen was isolated from the pretreatment urine 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	30	10
Number [Participants]	20 64.5%	5 50%

2. Secondary Outcome

Title	The Number of Participants With Clinical Improvement Rate at End of IV (EIV) Visit
Description	The participants were considered as clinical improved if they had clinical improvement in signs and symptoms from baseline; no fever for at least the 24 hours before discontinuing the IV study drug; and not received nonstudy antibiotics for the treatment of urinary tract infection 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 (CITT): All randomized participants who met the minimal disease definition of complicated urinary tract infection regardless if a baseline pathogen was isolated from the pretreatment urine 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	30	10
Number [Participants]	28 90.3%	10 100%

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 of complicated urinary tract infection showed no evidence of recurrence after test of cure.
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 complicated urinary tract infection regardless if a baseline pathogen was isolated from the pretreatment urine 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	30	10
Number [Participants]	18 58.1%	5 50%

4. Secondary Outcome

Title	The Number of Participants With Favorable Per-participant Microbiological Response
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 all CITT with at least 1 baseline bacterial pathogen isolated from the pretreatment urine culture, susceptible to both doripenem and cefepime. 6 and 2 participants from doripenem and cefepime, respectively had no susceptible urine 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	24	8
EIV visit	24 77.4%	8 80%
TOC visit	19 61.3%	4 40%
LFU visit	16 51.6%	4 40%

5. Secondary Outcome

Title	Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at End of IV (EIV) Visit
Description	The favorable per-pathogen microbiological outcome 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).A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).
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 all CITT with at least 1 baseline bacterial pathogen isolated from the pretreatment urine culture, susceptible to both doripenem and cefepime. 6 and 2 participants from doripenem and cefepime, respectively had no susceptible urine 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	24	8
Staphylococcus aureus (3, 0)	3 9.7%	NA NaN
Escherichia coli (22, 7)	22 71%	7 70%
Klebsiella oxytoca (1, 0)	1 3.2%	NA NaN
Klebsiella pneumoniae (1, 1)	1 3.2%	1 10%

6. Secondary Outcome

Title	Number of Participants With Favorable Per-pathogen Microbiological Outcome Rate at Test Of Cure (TOC) Visit
Description	The favorable per-pathogen microbiological outcome 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). A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).
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 all CITT with at least 1 baseline bacterial pathogen isolated from the pretreatment urine culture, susceptible to both doripenem and cefepime. 6 and 2 participants from doripenem and cefepime, respectively had no susceptible urine 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	24	8
Staphylococcus aureus (3, 0)	3 9.7%	NA NaN
Escherichia coli (22, 7)	17 54.8%	4 40%
Klebsiella oxytoca (1, 0)	1 3.2%	NA NaN
Klebsiella pneumoniae (1, 1)	1 3.2%	0 0%

7. Secondary Outcome

Title	Number of Participants With Sustained Favorable Per-pathogen Microbiological Outcome Rate at Late Follow-Up (LFU) Visit
Description	The sustained favorable per-pathogen microbiological outcome 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). A total of 4 pathogens in the doripenem group and 2 pathogens in the cefepime group were isolated at baseline from urine culture and were susceptible to the study drug received (see listed in the table below; the numbers in parenthesis next to each pathogen represent the number of participants with the pathogen isolated at baseline in the doripenem and cefepime treatment groups, respectively).
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 all CITT with at least 1 baseline bacterial pathogen isolated from the pretreatment urine culture, susceptible to both doripenem and cefepime. 6 and 2 participants from doripenem and cefepime, respectively had no susceptible urine 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	24	8
Staphylococcus aureus (3, 0)	2 6.5%	NA NaN
Escherichia coli (22, 7)	14 45.2%	4 40%
Klebsiella oxytoca (1, 0)	1 3.2%	NA NaN
Klebsiella pneumoniae (1, 1)	1 3.2%	0 0%

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	1/30 (3.3%)		3/10 (30%)
Infections and infestations
Pseudomembranous Colitis	0/30 (0%)		1/10 (10%)
Pyelonephritis Acute	0/30 (0%)		1/10 (10%)
Urinary Tract Infection	0/30 (0%)		2/10 (20%)
Renal and urinary disorders
Pyuria	1/30 (3.3%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Doripenem		Cefepime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/30 (36.7%)		6/10 (60%)
Blood and lymphatic system disorders
Eosinophilia	1/30 (3.3%)		1/10 (10%)
Hypochromic Anaemia	0/30 (0%)		1/10 (10%)
Neutrophilia	0/30 (0%)		1/10 (10%)
Congenital, familial and genetic disorders
Congenital Thrombocyte Disorder	0/30 (0%)		1/10 (10%)
Gastrointestinal disorders
Vomiting	3/30 (10%)		0/10 (0%)
Diarrhoea	2/30 (6.7%)		0/10 (0%)
General disorders
Pyrexia	3/30 (10%)		1/10 (10%)
Infusion Site Pain	0/30 (0%)		1/10 (10%)
Vessel Puncture Site Pain	0/30 (0%)		1/10 (10%)
Infections and infestations
Nasopharyngitis	3/30 (10%)		0/10 (0%)
Bacteriuria	0/30 (0%)		1/10 (10%)
Candidiasis	0/30 (0%)		1/10 (10%)
Pharyngitis	0/30 (0%)		1/10 (10%)
Injury, poisoning and procedural complications
Overdose	0/30 (0%)		1/10 (10%)
Investigations
Basophil Count Increased	0/30 (0%)		1/10 (10%)
Urine Leukocyte Esterase	0/30 (0%)		1/10 (10%)
Metabolism and nutrition disorders
Hypoalbuminaemia	0/30 (0%)		1/10 (10%)
Musculoskeletal and connective tissue disorders
Myalgia	0/30 (0%)		1/10 (10%)
Renal and urinary disorders
Crystalluria	0/30 (0%)		1/10 (10%)
Haematuria	0/30 (0%)		1/10 (10%)
Leukocyturia	0/30 (0%)		1/10 (10%)
Proteinuria	0/30 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Rhinorrhoea	2/30 (6.7%)		0/10 (0%)
Productive Cough	0/30 (0%)		1/10 (10%)
Skin and subcutaneous tissue disorders
Papule	1/30 (3.3%)		1/10 (10%)
Rash	0/30 (0%)		1/10 (10%)
Skin Haemorrhage	0/30 (0%)		1/10 (10%)
Vascular disorders
Phlebitis	0/30 (0%)		1/10 (10%)

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.