Multi-center, Randomized, Open-label Trial to Evaluate the Efficacy of Oral Fosfomycin Versus Oral Levofloxacin Strategies in Complicated Urinary Tract Infections (FOCUS)
Overview
- Phase
- Phase 4
- Intervention
- Fosfomycin tromethamine
- Conditions
- Urinary Tract Infection
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 62
- Locations
- 12
- Primary Endpoint
- Percentage of Participants Achieving Treatment Success at Test of Cure (TOC)
- Status
- Terminated
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a Phase 4, multi-center, open-label, randomized pragmatic superiority clinical trial comparing two strategies for initial or step-down oral therapy for complicated urinary tract infections (cUTI) after 0-48 hours of parenteral antibiotic therapy. The trial will evaluate the success and safety of a strategy of initial or step-down fosfomycin, administered at a dose of 3 g once daily, vs. a strategy of initial or step-down levofloxacin administered at a dose of 750 mg once daily. Investigator-directed adjustment to another adequate oral therapy is allowed 1) if the causative pathogen is not susceptible in vitro to quinolone initial or step-down therapy in a subject randomized to the levofloxacin strategy, OR 2) if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR 3) the subject has an underlying condition posing increasing risk for adverse events from quinolone therapy. The duration of oral therapy (initial + investigator-directed adjustment if indicated) in each strategy is 5-7 days of any per protocol antibiotic to which the pathogen is susceptible. The dosing of oral therapy depends on creatinine clearance (CrCl). The trial will enroll approximately 634 patients that are either male or female aged 18 or older with cUTI from outpatient and inpatient settings. The study will take place over 25 months in up to 15 US sites. The primary objective is to compare Strategy 1 and Strategy 2 in terms of treatment success rates at Test of Cure (TOC).
Detailed Description
This is a Phase 4, multi-center, open-label, randomized pragmatic superiority clinical trial comparing two strategies for initial or step-down oral therapy for complicated urinary tract infections (cUTI) without bacteremia with a uropathogen after 0-48 hours of parenteral antibiotic therapy. The trial will evaluate the success and safety of a strategy of initial or step-down fosfomycin, administered at a dose of 3 g once daily, vs. a strategy of initial or step-down levofloxacin administered at a dose of 750 mg once daily. Investigator-directed adjustment to another adequate oral therapy is allowed 1) if the causative pathogen is not susceptible in vitro to quinolone initial or step-down therapy in a subject randomized to the levofloxacin strategy, OR 2) if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR 3) the subject has an underlying condition posing increasing risk for adverse events from quinolone therapy. The duration of oral therapy (initial + subsequent if indicated) in each strategy is 5-7 days of any per protocol antibiotic to which the pathogen is susceptible. The dosing of oral therapy depends on creatinine clearance (CrCl). The trial will enroll approximately 634 patients that are either male or female aged 18 or older with cUTI from outpatient and inpatient settings. The study will take place over 25 months in up to 15 US sites. The primary objective is to compare Strategy 1 and Strategy 2 in terms of treatment success rates at Test of Cure (TOC). The secondary objectives are: 1) to assess the safety of Fosfomycin; 2) to compare Strategy 1 and Strategy 2 in terms of solicited adverse events; 3) to compare Strategy 1 and Strategy 2 in terms of treatment success rates at End of Therapy (EOT).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have documented clinical signs and/or symptoms of complicated urinary tract infection (cUTI) at diagnosis\*.
- •\*Clinical signs and symptoms of cUTI include either:
- •Pyelonephritis, as indicated by at least 2 of the following:
- •Documented fever (temperature greater than 38 degrees Celsius) accompanied by symptoms of rigors, chills, or "warmth"
- •Flank pain
- •Costovertebral angle tenderness on physical exam
- •Nausea or vomiting
- •Dysuria, urinary frequency, or urinary urgency OR
- •Complicated lower UTI, as indicated by at least 2 of the following new or worsening symptoms of cUTI:
- •Dysuria, urinary frequency, or urinary urgency
Exclusion Criteria
- •Have a documented history of any moderate or severe hypersensitivity or allergic reaction to all five oral therapy options.
- •Have a concomitant infection at the time of randomization, which requires non-study systemic antibacterial therapy effective against complicated Urinary Tract Infection (cUTI) in addition to study drug.
- •Have received more than 48 hours of a potentially therapeutic antibiotic for treatment of the current cUTI within 72 hours before randomization\*.
- •\*Except if the following apply:
- •The subject has a known baseline urinary pathogen (urine culture positive) and has failed prior therapy clinically (persistence of inclusion criteria) AND
- •The pathogen is known to be non-susceptible to the previous therapeutic regimen used or the urine culture remains positive with a density of greater than or equal to 50,000 CFU/mL or greater than or equal to 10,000 for catheterized patients.
- •Women breastfeeding or donating breast milk.
- •Have intractable UTI infection at baseline that the investigator anticipates would require more than 7 days of study drug therapy.
- •Have complete, permanent obstruction of the urinary tract\*.
- •\*Patients with complete permanent obstruction expected to be medically or surgically treated prior to End of Treatment (EOT) are eligible.
Arms & Interventions
Strategy 1
Fosfomycin 3 g orally once daily for 5-7 days as initial or step-down oral therapy for complicated urinary tract infections (cUTI) without bacteremia with a uropathogen after 0-48 hours of parenteral antibiotic therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. N=317
Intervention: Fosfomycin tromethamine
Strategy 2
Levofloxacin 750 mg orally once daily for 5-7 days as initial or step-down oral therapy for cUTI without bacteremia with a uropathogen after 0-48 hours of parenteral antibiotic therap, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy.y. N=317
Intervention: Levofloxacin
Outcomes
Primary Outcomes
Percentage of Participants Achieving Treatment Success at Test of Cure (TOC)
Time Frame: Day 21
Treatment success is defined as a combination of clinical cure and microbiological success. Clinical cure is defined as: 1) Resolution of UTI symptoms from presentation and 2) No new UTI symptoms and 3) Avoidance of parenteral antibiotic therapy, in or out of hospital, at any time after randomization OR oral antibiotic therapy different from per protocol. Microbiological success is defined as a reduction of the pathogen found at presentation to \<10\^4 CFU/mL for non-catheter specimens or \<10\^3 for catheter specimens on urine culture. A TOC visit was scheduled at 21 days (+7 days) after randomization.
Secondary Outcomes
- Number of Participants Reporting Solicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin(Day 1 through Day 12)
- Percentage of Participants Reporting Solicited Adverse Events (AEs)(Day 1 through Day 21)
- Number of Participants Reporting Unsolicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin(Day 1 through Day 12)
- Number of Participants Reporting Serious Adverse Events (SAEs) Among Those Who Received at Least Two Doses of Fosfomyci(Day 1 through Day 21)
- Percentage of Participants Reporting Solicited Adverse Events (AEs) by Severity(Day 1 through Day 21)
- Percentage of Participants Achieving Treatment Success at End of Therapy (EOT)(Day 5 through Day 10)