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

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ClinicalTrials.gov Identifier: NCT03697993
Recruitment Status : Recruiting
First Posted : October 5, 2018
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

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 a significant related AE (either grade 3 or at the investigator's discretion) to the initial or step-down oral 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 536 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 approximately 12 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).

Condition or disease Intervention/treatment Phase
Urinary Tract Infection Drug: Fosfomycin tromethamine Drug: Levofloxacin Phase 4

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 a significant related AE (either grade 3 or at the investigator's discretion) to the initial or step-down oral 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 approximately 12 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 634 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Multi-center, Randomized, Open-label Trial to Evaluate the Efficacy of Oral Fosfomycin Versus Oral Levofloxacin Strategies in Complicated Urinary Tract Infections (FOCUS)
Actual Study Start Date : November 7, 2018
Estimated Primary Completion Date : January 30, 2021
Estimated Study Completion Date : January 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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
Drug: Fosfomycin tromethamine
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.

Experimental: 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
Drug: Levofloxacin
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.




Primary Outcome Measures :
  1. The difference in the proportion of subjects achieving treatment success at Test of Cure (TOC) between Strategy 1 arm and Strategy 2 arm [ Time Frame: Day 21 ]
  2. The proportion of subjects achieving treatment success at Test of Cure (TOC) in Strategy 1 arm [ Time Frame: Day 21 ]
  3. The proportion of subjects achieving treatment success at Test of Cure (TOC) in Strategy 2 arm [ Time Frame: Day 21 ]

Secondary Outcome Measures :
  1. The difference in rates of solicited AEs in subjects in Strategy 1 arm and Strategy 2 arm [ Time Frame: Day 1 through Day 21 ]
  2. The difference in severity of solicited AEs in subjects in Strategy 1 arm and Strategy 2 arm [ Time Frame: Day 1 through Day 21 ]
  3. The difference in the proportion of subjects achieving treatment success at End of Therapy (EOT) between Strategy 1 arm and Strategy 2 arm [ Time Frame: Day 5 through Day 10 ]
  4. The number of serious adverse events (SAEs) after receiving at least two doses of Fosfomycin during the trial in Strategy 1 arm [ Time Frame: Day 1 through Day 21 ]
  5. The number of solicited AEs grade 2 and above in Strategy 1 arm [ Time Frame: Day 1 through Day 12 ]
  6. The number of solicited AEs in subjects in Strategy 1 arm [ Time Frame: Day 1 through Day 21 ]
  7. The number of solicited AEs in subjects in Strategy 2 arm [ Time Frame: Day 1 through Day 21 ]
  8. The number of unsolicited AEs grade 2 and above in Strategy 2 arm [ Time Frame: Day 1 through Day 12 ]
  9. The proportion of subjects achieving treatment success at End of Therapy (EOT) in Strategy 1 arm [ Time Frame: Day 5 through Day 10 ]
  10. The proportion of subjects achieving treatment success at End of Therapy (EOT) in Strategy 2 arm [ Time Frame: Day 5 through Day 10 ]
  11. The severity of solicited AEs in subjects in Strategy 1 arm [ Time Frame: Day 1 through Day 21 ]
  12. The severity of solicited AEs in subjects in Strategy 2 arm [ Time Frame: Day 1 through Day 21 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  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 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 38C without any rigors/chills AND the subject must have an improvement in baseline symptoms of cUTI and no new cUTI symptoms.

  4. Male or non-pregnant female.
  5. Aged 18 years or older.
  6. Women of childbearing potentia 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 with spermicide or foam, effective intrauterine devices, NuvaRing, 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.
  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 fosfomycin or a fluoroquinolone.
  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 enrollment.

    *******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 105 CFU/mL
  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.
  7. Have confirmed fungal UTI at time of randomization (with greater than or equal to 103 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 End of Treatment (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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03697993


Contacts
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Contact: Nadine Rouphael 14047121435 nroupha@emory.edu

Locations
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United States, California
University of California Los Angeles - Olive View Medical Center Not yet recruiting
Sylmar, California, United States, 91342-1437
Harbor UCLA Medical Center - Medicine - Infectious Diseases Not yet recruiting
Torrance, California, United States, 90502-2006
United States, Georgia
Emory Vaccine Center - The Hope Clinic Recruiting
Decatur, Georgia, United States, 30030-1705
United States, Illinois
Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery Recruiting
Chicago, Illinois, United States, 60611
United States, Iowa
University of Iowa - Vaccine Research and Education Unit Recruiting
Iowa City, Iowa, United States, 52242-2600
United States, Kansas
Infectious Disease Consultants - Wichita Not yet recruiting
Wichita, Kansas, United States, 67214
United States, Massachusetts
Brigham and Women's Hospital - Infectious Diseases Not yet recruiting
Boston, Massachusetts, United States, 02115-6110
United States, Michigan
Henry Ford Health System - Henry Ford Hospital Not yet recruiting
Detroit, Michigan, United States, 48202-2608
United States, Missouri
Truman Medical Center - Hospital Hill Not yet recruiting
Kansas City, Missouri, United States, 64108-2640
United States, New Mexico
U. of New Mexico Health Sciences Center - Dept. of Emergency Medicine Not yet recruiting
Albuquerque, New Mexico, United States, 81731
United States, New York
University of Rochester Medical Center - Strong Memorial Hospital - Infectious Diseases Recruiting
Rochester, New York, United States, 14642-0001
United States, Rhode Island
The Miriam Hospital - Infectious Diseases and Immunology Center Not yet recruiting
Providence, Rhode Island, United States, 02906
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03697993     History of Changes
Other Study ID Numbers: 15-0045
HHSN272201300018I
First Posted: October 5, 2018    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: September 11, 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Fosfomycin
levofloxacin
Open-label
Phase IV
UTI

Additional relevant MeSH terms:
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Infection
Urinary Tract Infections
Anti-Infective Agents, Urinary
Urologic Diseases
Levofloxacin
Ofloxacin
Fosfomycin
Anti-Infective Agents
Renal Agents
Anti-Bacterial Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Cytochrome P-450 CYP1A2 Inhibitors
Cytochrome P-450 Enzyme Inhibitors