Safety and Efficacy Study of Oral Fosfomycin Versus Oral Levofloxacin to Treat Complicated Urinary Syndromes (FOCUS)
Condition: Urinary Tract Infection
MeSH terms: Infections; Urinary Tract Infections
Intervention: Fosfomycin tromethamine; Levofloxacin
Intervention description: Administered orally as 3-gram single-dose sachet into 3-4 ounces (1 / 2 cup) of cool water; each dose must be taken immediately after dissolving in water. Hot water should not be used to dissolve fosfomycin. It may be taken either with or without food for normal kidney function. If Creatinine Clearance (CrCl) is less than 20 mL/min, fosfomycin should be taken as 3 grams every other day.; 750 mg is administered orally as one tablet once daily with or without food for normal kidney function. If Creatinine Clearance (CrCl) is 20-49 mL/min, 750 mg should be taken every other day. If on subsequent testing post-randomization, the Creatinine Clearance (CrCl) is less than 20 mL/min, followed by the dose is 500 mg every other day.
Intervention MeSH terms: Levofloxacin; Fosfomycin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Fosfomycin; levofloxacin; Open-label; Phase IV; UTI

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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Have documented clinical signs and/or symptoms of complicated urinary tract infection
             (cUTI) at diagnosis*.

             *Clinical signs and symptoms of cUTI include either:

               1. 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

               2. Complicated lower UTI, as indicated by at least 2 of the following new or
                  worsening symptoms of cUTI:

                    -  Dysuria, urinary frequency, or urinary urgency

                    -  Documented fever (temperature greater than 38 degrees Celsius) accompanied
                       by symptoms of rigors, chills, or "warmth"

                    -  Documented hypothermia (temperature less than 35.5 degrees Celsius)

                    -  Suprapubic pain or pelvic pain

                    -  Suprapubic tenderness on physical exam

                    -  New onset of foul smell to urine or increased cloudiness of urine per
                       subject or their caregiver

                    -  Nausea or vomiting

             AND at least 1 of the following complicating factors:

               -  Males with documented history of urinary retention

               -  Indwelling urinary catheter that is planned to be removed or replaced during
                  study therapy and before End of Therapy (EOT)

               -  Current obstructive uropathy that is scheduled to be medically or surgically
                  relieved during study therapy and before End of Therapy (EOT)

               -  Any functional or anatomical abnormality of the urogenital tract (including
                  anatomic malformations or neurogenic bladder) with voiding disturbance resulting
                  in at least 100 mL of residual urine OR with the need for intermittent or ongoing
                  self-catheterization.

          2. Able to understand and provide written informed consent*. *A legally acceptable
             representative may provide consent if the subject is unable to do so, provided this is
             approved by local institution-specific guidelines.

          3. Anticipated to be able to be stepped down or initially started on study oral
             antibiotic therapy within 48 hours of enrollment*,**.

             *The readiness of a subject for initial or step-down oral therapy is determined by the
             primary medical team. In addition, for step down therapy the following conditions have
             to be met: temperature at randomization must be less than 38 degrees Celsius without
             any rigors/chills AND the subject must have an improvement in baseline symptoms of
             cUTI and no new cUTI symptoms.

             **Subject may be enrolled if he/she received a non-study oral antibiotic only if it is
             followed by parenteral antibiotics for less than 48 hours prior to de-escalation with
             study drugs.

          4. Male or non-pregnant female.

          5. Aged 18 years or older.

          6. Women of childbearing potential* must agree to use an effective method of
             contraception** for the duration of the trial.

             *Female is considered of childbearing potential unless postmenopausal, or
             surgically/non surgically sterilized and at least 3 months has passed since
             sterilization procedure. A woman is considered postmenopausal if her last menstrual
             period was greater than or equal to 12 months.

             **Includes, but is not limited to, non-male sexual relationships, abstinence from
             sexual intercourse with a male partner, monogamous relationship with vasectomized
             partner who has been vasectomized for greater than or equal to 180 days before the
             subject receiving the first dose of study drug, barrier methods such as condoms or
             diaphragms, effective intrauterine devices, NuvaRing (R), and licensed hormonal
             methods such as implants, injectables but not oral contraceptives.

          7. If female of childbearing potential*, a negative urine or serum pregnancy test within
             48 hours of randomization.

             *Female is considered of childbearing potential unless postmenopausal, or
             surgically/non surgically sterilized and at least 3 months has passed since
             sterilization procedure. A woman is considered postmenopausal if her last menstrual
             period was greater than or equal to 12 months.

          8. Have pyuria (WBC count greater than or equal to 10/µL in unspun urine or greater than
             or equal to 10 per high power field in spun urine) or dipstick analysis positive
             (excluding "trace") for leukocyte esterase.

          9. Have a pretreatment baseline urine culture specimen obtained within 48 hours before
             the first dose of any antibiotic is administered (including pre-study antibiotics)*.

             *Subjects may be enrolled in the trial and start study drug before the investigator
             knows the results of the baseline urine culture.

         10. Able to reliably take, tolerate, and absorb oral medications, at the investigator's
             discretion.

         11. Ability to understand study procedures and willing and able to comply with all
             required procedures and visits for the duration of the trial.

        Exclusion Criteria:

          1. Have a documented history of any moderate or severe hypersensitivity or allergic
             reaction to all five oral therapy options.

          2. 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.

          3. 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:

               1. The subject has a known baseline urinary pathogen (urine culture positive) and
                  has failed prior therapy clinically (persistence of inclusion criteria) AND

               2. 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.

          4. Women breastfeeding or donating breast milk.

          5. Have intractable UTI infection at baseline that the investigator anticipates would
             require more than 7 days of study drug therapy.

          6. 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.

          7. Have confirmed fungal UTI at time of randomization (with greater than or equal to 10^3
             fungal CFU/mL).

          8. Have suspected or confirmed perinephric or intrarenal abscess.

          9. Have suspected or confirmed prostatitis, epididymitis.

         10. Have an ileal loop or known vesico-ureteral reflux.

         11. Have a current urinary catheter that is not scheduled to be replaced before EOT*.

             *Intermittent straight catheterization or replacement of new nephrostomy catheters is
             acceptable.

         12. Have planned inpatient urological intervention(s) for suspected infected kidney stone
             or any other planned urological procedure with anticipated antibiotic prophylaxis
             between randomization and End of Treatment (EOT).

         13. Have bacteremia with a uropathogen causing cUTI.

         14. Have an estimated or calculated Creatinine Clearance (CrCl) less than or equal to 20
             mL/min or currently receiving hemo- or peritoneal dialysis at screening.

         15. Have any condition or circumstance that, in the opinion of the investigator, would
             compromise the safety of the subject or the quality of study data*.

             *Including any rapidly progressing disease or immediately life-threatening (acute
             hepatic failure, respiratory failure or septic shock).

         16. Have participated in any interventional trial of an investigational product within 30
             days before the proposed first day of study drug administration.

         17. Plans to participate or currently enrolled in any interventional study of an
             investigational agent for the duration of the trial.

         18. Previous randomization in this trial.

         19. Any recent (less than 4 weeks) history of trauma to the pelvis or urinary tract.

         20. Prior fosfomycin use in the past 12 months.