Safety and Efficacy Study of Oral Fosfomycin Versus Oral Levofloxacin to Treat Complicated Urinary Syndromes (FOCUS)

Multi-center, Randomized, Open-label Trial to Evaluate the Efficacy of Oral Fosfomycin Versus Oral Levofloxacin Strategies in Complicated Urinary Tract Infections (FOCUS)

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).

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).

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.