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

NCT03697993 | Terminated Phase 4 Results FDA Drug

• 2 other identifiers: 15-0045HHSN272201300018I
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 12

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).

Conditions

Urinary Tract Infection

Keywords

Fosfomycin; levofloxacin; Open-label; Phase IV; UTI

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants Achieving Treatment Success at Test of Cure (TOC)

  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.

  Day 21

Secondary Outcomes (6)

• Number of Participants Reporting Solicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin

  Day 1 through Day 12

• 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)

  Day 1 through Day 21

• Percentage of Participants Reporting Solicited Adverse Events (AEs) by Severity

  Day 1 through Day 21

Study Arms (2)

Strategy 1

EXPERIMENTAL

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

Strategy 2

EXPERIMENTAL

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

Interventions

Fosfomycin tromethamine DRUG

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.

Strategy 1

Levofloxacin DRUG

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.

Strategy 2

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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 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.
• Have confirmed fungal UTI at time of randomization (with greater than or equal to 10\^3 fungal CFU/mL).
• Have suspected or confirmed perinephric or intrarenal abscess.
• Have suspected or confirmed prostatitis, epididymitis.
• Have an ileal loop or known vesico-ureteral reflux.
• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (12)

University of California Los Angeles - Olive View Medical Center

Sylmar, California, 91342-1437, United States

Location

Harbor UCLA Medical Center - Medicine - Infectious Diseases

Torrance, California, 90502-2006, United States

Location

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, 30030-1705, United States

Location

Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery

Chicago, Illinois, 60611, United States

Location

University of Iowa - Vaccine Research and Education Unit

Iowa City, Iowa, 52242-2600, United States

Location

Infectious Disease Consultants - Wichita

Wichita, Kansas, 67214, United States

Location

Brigham and Women's Hospital - Infectious Diseases

Boston, Massachusetts, 02115-6110, United States

Location

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, 48202-2608, United States

Location

Truman Medical Center - Hospital Hill

Kansas City, Missouri, 64108-2640, United States

Location

U. of New Mexico Health Sciences Center - Dept. of Emergency Medicine

Albuquerque, New Mexico, 81731, United States

Location

University of Rochester Medical Center - Strong Memorial Hospital - Infectious Diseases

Rochester, New York, 14642-0001, United States

Location

The Miriam Hospital - Infectious Diseases and Immunology Center

Providence, Rhode Island, 02906, United States

Location

MeSH Terms

Conditions

Urinary Tract Infections

Interventions

Fosfomycin; Levofloxacin

Condition Hierarchy (Ancestors)

Infections; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Ofloxacin; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Nadine Rouphael, MD, MSc
• Organization: Vaccine Treatment Evaluation Unit (VTEU)

nroupha@emory.edu

(404) 822-1411

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 4, 2018
• First Posted: October 5, 2018
• Study Start: November 7, 2018
• Primary Completion: October 24, 2019
• Study Completion: October 24, 2019
• Last Updated: December 19, 2020
• Results First Posted: December 19, 2020

Record last verified: 2018-09-11

Locations

US (12)