An Efficacy and Safety of Flomoxef Versus Cefepime in the Treatment of Participants With Urinary Tract Infections (FLORUS)

A Phase 3, Randomized, Double-blind, Multicenter Study Comparing the Efficacy and Safety of Intravenous Infusions of Flomoxef Versus Intravenous Infusions of Cefepime in the Treatment of Subjects With Complicated Urinary Tract Infections Including Pyelonephritis

The purpose of this study is to compare the effectiveness of antibiotic flomoxef with cefepime for the treatment of complicated urinary tract infections (cUTIs) in Russian adults.

Study Overview

• Status: Terminated
• Conditions: Urinary Tract Infection
• Intervention / Treatment: Drug: Flomoxef; Drug: Cefepime

Detailed Description

The drug being tested in this study is called Flomoxef. Flomoxef is being tested in people with a complicated urinary tract infection (cUTI) including a kidney infection. This study compares Flomoxef to Cefepime, another antibiotic.

The study enrolled 13 patients.

Participants are randomly assigned by a computer generated number to one of two treatment groups:

• Flomoxef - intravenous infusion 2g twice daily (every 12 hours); or
• Cefepime - intravenous infusion 1g twice daily (every 12 hours).

This multi-center trial is conducted at 4 sites in the Russian Federation. The overall time to participate in this study is 30+/-3 days. Participants make six visits to the clinic.

Study was prematurely terminated due to administrative and strategic reasons.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation
  • Rostov-on-Don, Russian Federation
  • Saint Petersburg, Russian Federation
  • Volgograd, Russian Federation
  • Yaroslavl, Russian Federation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is a man or woman aged 18 to 70 years, inclusive.
2. Has pyuria (a white blood cell [WBC] count greater than 10/μL in unspun urine or greater than or equal to 10 per high power field in spun urine).
3. Has clinical signs and/or symptoms of a complicated lower urinary tract infection (UTI) and/or acute pyelonephritis that include one or more of the following: fever (i.e, axillary temperature greater than 37.7°C), chills, malaise, flank pain, back pain, and/or costo-vertebral angle pain or tenderness and/or any symptoms of dysuria (dysuria, urinary urgency, urinary frequency, suprapubic discomfort, new urinary incontinence or worsening of pre-existing incontinence) that occur in the presence of a functional or anatomical abnormality of the urinary tract or in the presence of catheterization.
4. Has a pretreatment baseline urine culture specimen obtained within 24 hours before the administration of the first dose of study drug (NOTE: Participants may be enrolled in this study and start intravenous (IV) study drug therapy before the Investigator knows the results of the baseline urine culture).
5. Requires IV antibacterial therapy for the treatment of the presumed complicated UTI (cUTI).
6. In the opinion of the investigator, is capable of understanding and complying with protocol requirements.
7. Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures, or has a legally acceptable representative sign the forms.
8. Meets protocol-specified criteria regarding the use of contraception; and 9-Is willing and able to comply with study procedures.

Exclusion Criteria:

1. Has received any investigational compound within 30 days of screening.
2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, spouse, parent, child, or sibling) or may consent under duress.
3. Is a female participant who is pregnant or lactating or intending to become pregnant before, during, or within one month after participating in this study, or intends to donate ova during such time period.
4. Is a male participant who intends to donate sperm during the course of this study or for 12 weeks thereafter.
5. Has participated in another clinical study within the past 30 days.
6. Has a history of allergy to or intolerance of beta-lactams (penicillins, cephalosporins or carbopenems).
7. Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: 1) the safety or well-being of the participant or study staff, 2) the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding), or 3) the analysis of results.
8. Has received any amount of potentially therapeutic antibacterial therapy after collection of the pretreatment baseline urine culture and before administration of the first dose of study drug.
9. Has received any dose of a potentially therapeutic antibacterial agent for the treatment of the current UTI within 48 hours before providing the pretreatment baseline urine culture specimen.
10. Has a current urinary catheter that is not scheduled to be removed before the End-of-Therapy (EOT) visit (intermittent straight catheterization during the IV study drug administration period is acceptable).
11. Has any history of trauma to the pelvis or urinary tract within one year before the screening visit.
12. Has any other contraindications to the medicines that are to be used in the study (according to the manufacturer's instructions).
13. Is considered unlikely to survive the four-week study period or has any rapidly progressing disease or immediately life-threatening illness (including acute hepatic failure, respiratory failure or septic shock).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Flomoxef; Flomoxef, 2g, injection, intravenously, twice daily (every 12 hours), for up to 12 days.	Drug: Flomoxef; Flomoxef intravenous infusion
Active Comparator: Cefepime; Cefepime, 1g, injection, intravenously, twice daily (every 12 hours) for up to 14 days.	Drug: Cefepime; Cefepime intravenous infusion; Other Names: Maxipime

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieved Resolution of All Clinical Symptoms of a Complicated Urinary Tract Infection (cUTI) at the End of Treatment (EOT) Visit	At the EOT visit (Days 7 to 14), the Investigator collected information about each symptom and performed a judgement about the participant's status. Clinical symptoms present at trial entry were considered to be resolved if the participant has no pyuria; no fever; no malaise, flank pain, back pain, and/or costo-vertebral angle pain or tenderness; and no symptoms of dysuria, urinary urgency, urinary frequency, suprapubic discomfort, new urinary incontinence, or worsening of pre-existing incontinence. Resolution of all clinical symptoms of cUTI were assessed relative to baseline.	Baseline and Days 7 to 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Microbiological Success at the EOT and Test-of-Cure (TOC) Visits	A urine sample was collected at EOT (Days 7 to 14) and TOC (Days 14 to 21) visits to determine level of uropathogen. Cultures of urine sample were processed by calibrated loop to identify a quantitative count of bacteria, with a lower limit of 10^4 colony forming units per milliliter (CFU/mL). Microbiological success was defined as bacterial uropathogen level of <10^4 CFU/mL. Microbiological response was categorized as:microbiological eradication/persistence/new infection/superinfection. An infection was eradicated if all uropathogens isolated at study entry at a level ≥10^4 CFU/mL have decreased to <10^4 CFU/mL, persistent if level of uropathogen has increased by ≥10^4 CFU/Ml. A new infection, if there is isolation and growth of a uropathogen other than original pathogen and superinfection if there is growth of a uropathogen other than original pathogen at a level ≥10^4 CFU/mL. Microbiological success was assessed relative to baseline.	Baseline, Days 7 to 14 and 14 to 21
Percentage of Participants Who Achieved Clinical Resolution of Symptoms of a cUTI at Visit 3, TOC and Late Follow-up (LFU) Visits	At Visit 3 (Day 3) and at the TOC (Days 14 to 21) and LFU visits (Day 30), the Investigator collected information about each symptom and performed a judgement about the participant's status. Clinical symptoms present at trial entry were considered to be resolved if the participant has no pyuria; no fever; no malaise, flank pain, back pain, and/or costo-vertebral angle pain or tenderness; and no symptoms of dysuria, urinary urgency, urinary frequency, suprapubic discomfort, new urinary incontinence, or worsening of pre-existing incontinence. Resolution of all clinical symptoms of cUTI were assessed relative to baseline.	Baseline, Days 3, 14 to 21 and 30
Percentage of Participants With Microbiologic Eradication of the Unique Pathogen at the EOT and TOC Visits	A urine sample was collected from the participants at the EOT (Days 7 to 14) and TOC (Day 14 to 21) visits to determine the level of uropathogen. Cultures of the urine sample were processed by using a calibrated loop to identify a quantitative count of bacteria, with a lower limit of 10^4 CFU/mL. Microbiological response at the TOC visit was based on the same grades as for the EOT visit. The infection was considered to be eradicated if all uropathogens isolated at study entry at a level equal to or greater than 10^4 CFU/mL have decreased to less than 10^4 CFU/mL.	Baseline, Days 7 to 14 and 14 to 21
Percentage of Participants With Microbiologic Persistence of the Unique Pathogen at the EOT and TOC Visits	A urine sample was collected from the participants at the EOT (Days 7 to 14) and TOC (Days 14 to 21) visits to determine the level of uropathogen. Cultures of the urine sample was processed by using a calibrated loop to identify a quantitative count of bacteria, with a lower limit of 10^4 CFU/mL. Microbiological response at the TOC visit was be based on the same grades as for the EOT visit. The infection was considered to be persistent if the level of the uropathogen has increased by greater than or equal to 10^4 CFU/mL from the time of study entry to that of the EOT and TOC visits.	Baseline, Days 7 to 14 and 14 to 21
Percentage of Participants With a New Infection at the EOT and TOC Visits	A urine sample was collected from the participants at the EOT (Days 7 to 14) and TOC (Days 14 to 21) visits to determine the level of uropathogen. Cultures of the urine sample were processed by using a calibrated loop to identify a quantitative count of bacteria, with a lower limit of 10^4 CFU/mL. A new infection was defined as the isolation and growth of a uropathogen other than the original pathogen.	Baseline, Days 7 to 14 and 14 to 21
Percentage of Participants With a Superinfection at the EOT and TOC Visits	A urine sample was collected from the participants at the EOT (Days 7 to 14) and TOC (Days 14 to 21) visits to determine the level of uropathogen. Cultures of the urine sample were processed by using a calibrated loop to identify a quantitative count of bacteria, with a lower limit of 10^4 CFU/mL. A superinfection was defined as growth of a uropathogen other than the original pathogen at a level greater than or equal to 10^4 CFU/mL at any time during the course of active therapy.	Baseline, Day 7 to 14 and 14 to 21
Number of Participants With Serious Adverse Events (SAEs) and Treatment-Emergent-Adverse Events (TEAEs)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.	Baseline up to Day 30
Number of Participants With Clinically Significant Abnormal Laboratory Values	The number of participants with any markedly abnormal (above or below normal ranges) standard safety laboratory values was collected throughout study.	Day 21
Number of Participants With Clinically Significant Change in Vital Signs	Vital signs included body temperature (axillary measurement), diastolic and systolic blood pressure (5 minutes), respiratory rate, and pulse (bpm).	Day 1 up to Day 21
Number of Participants With Clinically Significant Change in Physical Examination Findings	Physical examination consists of examinations of the following body systems: (1) cardiovascular system; (2) dermatologic system (3) ears, nose, throat; (4) extremities; (5) eyes; (6) gastrointestinal system; (7) genitourinary system; (8) lymph nodes; (9) musculoskeletal system; (10) nervous system; (11) respiratory system.	Day 1 up to Day 21

Collaborators and Investigators

• Sponsor: Takeda

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2015
• Primary Completion (Actual): February 2, 2016
• Study Completion (Actual): December 15, 2016

Study Registration Dates

• First Submitted: November 24, 2014
• First Submitted That Met QC Criteria: November 24, 2014
• First Posted (Estimate): November 26, 2014

Study Record Updates

• Last Update Posted (Actual): October 27, 2017
• Last Update Submitted That Met QC Criteria: June 8, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Drug Therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Anti-Infective Agents; Anti-Bacterial Agents; Cefepime
• Other Study ID Numbers: FLOMOXEF_301; U1111-1154-2448 (Registry Identifier: WHO)