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Urinary Tract InfectionPhase 4NCT03697993

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

A Phase 4 study testing Fosfomycin tromethamine and Levofloxacin in people with Urinary Tract Infection, run by National Institute of Allergy and Infectious Diseases (NIAID) at 12 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 99 years
Conditions the study is for
Urinary Tract Infection
What is being tested?
Fosfomycin tromethamine and Levofloxacin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
12 sitesUnited States
Study dates
7 Nov 2018to 24 Oct 2019
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • 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.
  • 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.
  • 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.
  • Male or non-pregnant female.
  • Aged 18 years or older.
  • 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.
  • 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.
  • 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.
  • 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.
  • Able to reliably take, tolerate, and absorb oral medications, at the investigator's discretion.
  • Ability to understand study procedures and willing and able to comply with all required procedures and visits for the duration of the trial.

Who cannot join

  • 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.
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  • 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.
  • 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).
  • Have bacteremia with a uropathogen causing cUTI.
  • 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.
  • 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).
  • Have participated in any interventional trial of an investigational product within 30 days before the proposed first day of study drug administration.
  • Plans to participate or currently enrolled in any interventional study of an investigational agent for the duration of the trial.
  • Previous randomization in this trial.
  • Any recent (less than 4 weeks) history of trauma to the pelvis or urinary tract.
  • Prior fosfomycin use in the past 12 months.

Trial locations and contacts

12 sites in 1 country.

12 sites in 1 country

United States12 sites

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

    Albuquerque, New Mexico, 81731

  • Brigham and Women's Hospital - Infectious Diseases

    Boston, Massachusetts, 02115-6110

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

    Chicago, Illinois, 60611

  • Emory Vaccine Center - The Hope Clinic

    Decatur, Georgia, 30030-1705

  • Henry Ford Health System - Henry Ford Hospital

    Detroit, Michigan, 48202-2608

  • University of Iowa - Vaccine Research and Education Unit

    Iowa City, Iowa, 52242-2600

  • Truman Medical Center - Hospital Hill

    Kansas City, Missouri, 64108-2640

  • The Miriam Hospital - Infectious Diseases and Immunology Center

    Providence, Rhode Island, 02906

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

    Rochester, New York, 14642-0001

  • University of California Los Angeles - Olive View Medical Center

    Sylmar, California, 91342-1437

  • Harbor UCLA Medical Center - Medicine - Infectious Diseases

    Torrance, California, 90502-2006

  • Infectious Disease Consultants - Wichita

    Wichita, Kansas, 67214

Other trials in United States

About this study

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)

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).

Read the 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).

Being tested
Fosfomycin tromethamine, Levofloxacin
Keywords
Fosfomycin, levofloxacin, Open-label, Phase IV, UTI
Medical subject headings
Urinary Tract Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Fosfomycin tromethamineDrug

    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.

  • LevofloxacinDrug

    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.

Study groups in NCT03697993
Study groupRoleWhat they receive
Strategy 1ExperimentalFosfomycin 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
Receives: Drug: Fosfomycin tromethamine
Strategy 2ExperimentalLevofloxacin 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
Receives: Drug: Levofloxacin

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Day 21

Secondary outcomes (6)

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

    Solicited AEs are AEs that are common following administration of these types of antibiotics. The solicited AEs were collected after first dose of study product was given and until the end of therapy (EOT). If subject is on fosfomycin, solicited AEs were collected for 2 days after last dose of fosfomycin or until EOT, whichever occurs last. The solicited AEs includes insomnia, headache, dizziness, nausea, vomiting, constipation, diarrhea, back pain, rhinitis, pharyngitis, allergic reaction, and candidiasis.

    Measured: Day 1 through Day 12

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

    The unsolicited AEs were collected in participants who received at least two doses of Fosfomycin from the time of second dose of Fosfomycin until the end of therapy (EOT) or 2 days after last dose of Fosfomycin, whichever occurs last.

    Measured: Day 1 through Day 12

  3. Number of Participants Reporting Serious Adverse Events (SAEs) Among Those Who Received at Least Two Doses of Fosfomyci

    SAEs included any untoward medical occurrence that resulted in death; was life threatening; was a persistent/significant disability/incapacity; required inpatient hospitalization or prolongation or a congenital anomaly/birth defect. Events are included if deemed by the investigator to be related to the study product. SAEs were only recorded in participants receiving at least two doses of fosfomyci.

    Measured: Day 1 through Day 21

  4. Percentage of Participants Reporting Solicited Adverse Events (AEs)

    Solicited AEs are AEs that are common following administration of these types of antibiotics. The solicited AEs were collected after first dose of study product was given and until the end of therapy (EOT). If subject is on fosfomycin, solicited AEs were collected for 2 days after last dose of fosfomycin or until EOT, whichever occurs last. The solicited AEs includes insomnia, headache, dizziness, nausea, vomiting, constipation, diarrhea, back pain, rhinitis, pharyngitis, allergic reaction, and candidiasis.

    Measured: Day 1 through Day 21

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

    Solicited AEs are AEs that are common following administration of these types of antibiotics. The solicited AEs were collected after first dose of study product was given and until the end of therapy (EOT). If subject is on fosfomycin, solicited AEs were collected for 2 days after last dose of fosfomycin or until EOT, whichever occurs last. The solicited AEs includes insomnia, headache, dizziness, nausea, vomiting, constipation, diarrhea, back pain, rhinitis, pharyngitis, allergic reaction, and candidiasis.

    Measured: Day 1 through Day 21

  6. Percentage of Participants Achieving Treatment Success at End of Therapy (EOT)

    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.

    The EOT visit occured within 2 days of the completion of oral therapy.

    Measured: Day 5 through Day 10

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Oct 2018
  2. Study start7 Nov 2018
  3. Primary completion24 Oct 2019
  4. Study completion24 Oct 2019

Why it stopped: inadequate enrollment.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03697993
Sponsor's protocol ID
15-0045
Other IDs
HHSN272201300018I
Status last verified
11 Sep 2018
First submitted
4 Oct 2018
Last updated
19 Dec 2020
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Fosfomycin tromethamine and Levofloxacin in people with Urinary Tract Infection, run by National Institute of Allergy and Infectious Diseases (NIAID) at 12 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 37 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 19 Dec 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Dec 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants Achieving Treatment Success at Test of Cure (TOC) (time frame: Day 21). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03697993.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Dec 2020.

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