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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT03697993
• Collaborator: (none)
• Enrollment: 62
• Locations: 12
• Arms: 2
• Actual Duration (Months): 11.5
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

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 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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 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: Nov 7, 2018
• Actual Primary Completion Date: Oct 24, 2019
• Actual Study Completion Date: Oct 24, 2019

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving Treatment Success at Test of Cure (TOC) [Day 21]

   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.

Secondary Outcome Measures

1. Number of Participants Reporting Solicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin [Day 1 through Day 12]

   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.

2. Number of Participants Reporting Unsolicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin [Day 1 through Day 12]

   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.

3. Number of Participants Reporting Serious Adverse Events (SAEs) Among Those Who Received at Least Two Doses of Fosfomyci [Day 1 through Day 21]

   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.

4. Percentage of Participants Reporting Solicited Adverse Events (AEs) [Day 1 through Day 21]

   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.

5. Percentage of Participants Reporting Solicited Adverse Events (AEs) by Severity [Day 1 through Day 21]

   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.

6. Percentage of Participants Achieving Treatment Success at End of Therapy (EOT) [Day 5 through Day 10]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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.

1. 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.

2. 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.

1. Male or non-pregnant female.

2. Aged 18 years or older.

3. 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.

1. 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.

1. 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.

2. 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.

1. Able to reliably take, tolerate, and absorb oral medications, at the investigator's discretion.

2. 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.

3. Women breastfeeding or donating breast milk.

4. Have intractable UTI infection at baseline that the investigator anticipates would require more than 7 days of study drug therapy.

5. 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.

1. Have confirmed fungal UTI at time of randomization (with greater than or equal to 10^3 fungal CFU/mL).

2. Have suspected or confirmed perinephric or intrarenal abscess.

3. Have suspected or confirmed prostatitis, epididymitis.

4. Have an ileal loop or known vesico-ureteral reflux.

5. 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.

1. 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).

2. Have bacteremia with a uropathogen causing cUTI.

3. 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.

4. 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).

1. Have participated in any interventional trial of an investigational product within 30 days before the proposed first day of study drug administration.

2. Plans to participate or currently enrolled in any interventional study of an investigational agent for the duration of the trial.

3. Previous randomization in this trial.

4. Any recent (less than 4 weeks) history of trauma to the pelvis or urinary tract.

5. Prior fosfomycin use in the past 12 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles - Olive View Medical Center	Sylmar	California	United States	91342-1437
2	Harbor UCLA Medical Center - Medicine - Infectious Diseases	Torrance	California	United States	90502-2006
3	Emory Vaccine Center - The Hope Clinic	Decatur	Georgia	United States	30030-1705
4	Northwestern Medicine - Department of Obstetrics and Gynecology - Division of Female Pelvic Medicine and Reconstructive Surgery	Chicago	Illinois	United States	60611
5	University of Iowa - Vaccine Research and Education Unit	Iowa City	Iowa	United States	52242-2600
6	Infectious Disease Consultants - Wichita	Wichita	Kansas	United States	67214
7	Brigham and Women's Hospital - Infectious Diseases	Boston	Massachusetts	United States	02115-6110
8	Henry Ford Health System - Henry Ford Hospital	Detroit	Michigan	United States	48202-2608
9	Truman Medical Center - Hospital Hill	Kansas City	Missouri	United States	64108-2640
10	U. of New Mexico Health Sciences Center - Dept. of Emergency Medicine	Albuquerque	New Mexico	United States	81731
11	University of Rochester Medical Center - Strong Memorial Hospital - Infectious Diseases	Rochester	New York	United States	14642-0001
12	The Miriam Hospital - Infectious Diseases and Immunology Center	Providence	Rhode Island	United States	02906

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 16, 2020
• Study Protocol - Jul 10, 2019

More Information

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT03697993
• Other Study ID Numbers: 15-0045; HHSN272201300018I
• First Posted: Oct 5, 2018
• Last Update Posted: Dec 19, 2020
• Last Verified: Sep 11, 2018

• 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: Infections; Urinary Tract Infections; Levofloxacin; Ofloxacin; Fosfomycin

Study Results

Participant Flow

Recruitment Details	Participants were males and non-pregnant females aged >=18 years and diagnosed with complicated urinary tract infections (cUTIs) without bacteremia with a uropathogen. Participants were enrolled between 14NOV2018 and 03OCT2019.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Period Title: Overall Study
STARTED	32	30
Initiated Treatment	30	28
Switched Treatment	0	6
Treated With at Least Two Dose of Fosfomycin	27	4
COMPLETED	22	25
NOT COMPLETED	10	5

Baseline Characteristics

Arm/Group Title	Strategy 1	Strategy 2	Total
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Total of all reporting groups
Overall Participants	32	30	62
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.9 (19.4)	46.3 (20.7)	46.1 (19.9)
Sex: Female, Male (Count of Participants)
Female	25 78.1%	21 70%	46 74.2%
Male	7 21.9%	9 30%	16 25.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 12.5%	4 13.3%	8 12.9%
Not Hispanic or Latino	28 87.5%	26 86.7%	54 87.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	15 46.9%	16 53.3%	31 50%
White	14 43.8%	11 36.7%	25 40.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 9.4%	3 10%	6 9.7%
Region of Enrollment (participants) [Number]
United States	32 100%	30 100%	62 100%
cUTI (Count of Participants)
Pyelonephritis	29 90.6%	25 83.3%	54 87.1%
Other cUTI	3 9.4%	5 16.7%	8 12.9%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.02 (7.52)	29.29 (8.65)	28.12 (8.10)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Treatment Success at Test of Cure (TOC)
Description	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.
Time Frame	Day 21

Outcome Measure Data

Analysis Population Description

The microbiologic Intention-to-Treat population includes all randomized participants who have a positive baseline bacterial culture of urine.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	24	27
Number (95% Confidence Interval) [percentage of participants]	55 171.9%	73 243.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Strategy 1, Strategy 2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Multiple imputation using Wald method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-18
	Confidence Interval	(2-Sided) 95%; -43.4 to 8.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants Reporting Solicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin
Description	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.
Time Frame	Day 1 through Day 12

Outcome Measure Data

Analysis Population Description

The fosfomycin safety population includes all subjects treated with at least two doses of fosfomycin.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	27	4
Count of Participants [Participants]	19 59.4%	4 13.3%

3. Secondary Outcome

Title	Number of Participants Reporting Unsolicited Adverse Events (AEs) Grade 2 and Above Among Those Who Received Fosfomycin
Description	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.
Time Frame	Day 1 through Day 12

Outcome Measure Data

Analysis Population Description

The fosfomycin safety population includes all subjects treated with at least two doses of fosfomycin.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	27	4
Count of Participants [Participants]	2 6.3%	0 0%

4. Secondary Outcome

Title	Number of Participants Reporting Serious Adverse Events (SAEs) Among Those Who Received at Least Two Doses of Fosfomyci
Description	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.
Time Frame	Day 1 through Day 21

Outcome Measure Data

Analysis Population Description

The Fosfomycin safety population includes all subjects treated with at least two doses of Fosfomycin.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	27	4
Count of Participants [Participants]	2 6.3%	0 0%

5. Secondary Outcome

Title	Percentage of Participants Reporting Solicited Adverse Events (AEs)
Description	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.
Time Frame	Day 1 through Day 21

Outcome Measure Data

Analysis Population Description

The safety population includes all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	30	28
Number (95% Confidence Interval) [percentage of participants]	67 209.4%	68 226.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Strategy 1, Strategy 2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1
	Confidence Interval	(2-Sided) 95%; -26.2 to 24.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants Reporting Solicited Adverse Events (AEs) by Severity
Description	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.
Time Frame	Day 1 through Day 21

Outcome Measure Data

Analysis Population Description

The safety population includes all enrolled participants who received at least one dose of study drug.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	30	28
Moderate	53 165.6%	50 166.7%
Severe	13 40.6%	18 60%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Strategy 1, Strategy 2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.894
	Comments
	Method	Proportional odds model using Wald test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.9
	Confidence Interval	(2-Sided) 95%; 0.3 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants Achieving Treatment Success at End of Therapy (EOT)
Description	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.
Time Frame	Day 5 through Day 10

Outcome Measure Data

Analysis Population Description

The microbiologic Intention-to-Treat population includes all randomized participants who have a positive baseline bacterial culture of urine.

Arm/Group Title	Strategy 1	Strategy 2
Arm/Group Description	Fosfomycin 3 grams oral powder 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion, OR the subject has an underlying condition posing increased 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Levofloxacin 750 mg oral tablet once daily (Strategy 1 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily	Levofloxacin 750 mg oral tablet 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 therapy, and if indicated a subsequent investigator-directed adjustment to another adequate oral therapy. Investigator-directed adjustment to another adequate oral therapy is allowed 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 if the subject develops an intolerance or allergy to the initial step-down oral therapy and at the investigator's discretion. 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). Another adequate oral therapy is defined as an oral therapy to which the pathogen shows in-vitro susceptibility AND to which the subject is tolerant based on history AND which is listed below: Fosfomycin 3 grams oral powder once daily (Strategy 2 only) Amoxicillin-clavulanate 875/125 mg oral tablet twice daily Cefixime 400 mg oral tablet once daily Trimethoprim-sulfamethoxazole (TMP-SMX 160/800 mg) double-strength oral tablet twice daily
Measure Participants	24	27
Number (95% Confidence Interval) [percentage of participants]	67 209.4%	67 223.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Strategy 1, Strategy 2
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.973
	Comments
	Method	Multiple imputation using Wald method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -26.3 to 25.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	The solicited events were collected after first dose of study product was given and until the end of therapy (EOT). If subject was on fosfomycin, solicited AEs were collected for 2 days after last dose of fosfomycin or until EOT, whichever occurred last. 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 occurred last.
Adverse Event Reporting Description	Serious Adverse Events (SAEs) were only recorded in participants receiving at least two doses of fosfomycin and were not collected for other interventions. Therefore the at risk population for SAE is a subset of the safety population who received any study drug.
Arm/Group Title	Fosfomycin		Levofloxacin		Cefixime
Arm/Group Description	Fosfomycin was administered orally as a single 3 gram dose sachet once daily for normal kidney function or every other day for CrCl less than or equal to 20 mL/min.		Levofloxacin was administered orally as 750 mg tablet once daily for normal kidney function, 750 mg tablet every other day for CrCl 20-49 mL/min; 500 mg tablet every other day for CrCl <20 mL/min.		Cefixime was administered orally as 400mg tablet or capsule once daily for normal kidney function; 260 mg of oral suspension once daily for subjects with CrCl between 21-59 mL/min; 200 mg chewable table once daily for subjects with CrCl less than or equal to 20 mL/min.
All Cause Mortality
	Fosfomycin		Levofloxacin		Cefixime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/22 (0%)		0/1 (0%)
Serious Adverse Events
	Fosfomycin		Levofloxacin		Cefixime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/35 (5.7%)		0/0 (NaN)		0/0 (NaN)
Nervous system disorders
Seizure	1/35 (2.9%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Renal and urinary disorders
Hydronephrosis	1/35 (2.9%)	1	0/0 (NaN)	0	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Fosfomycin		Levofloxacin		Cefixime
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/35 (68.6%)		15/22 (68.2%)		0/1 (0%)
Gastrointestinal disorders
Diarrhoea	19/35 (54.3%)	57	2/22 (9.1%)	2	0/1 (0%)	0
Nausea	3/35 (8.6%)	8	7/22 (31.8%)	15	0/1 (0%)	0
Vomiting	2/35 (5.7%)	7	2/22 (9.1%)	2	0/1 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	8/35 (22.9%)	16	6/22 (27.3%)	14	0/1 (0%)	0
Nervous system disorders
Dizziness	0/35 (0%)	0	2/22 (9.1%)	10	0/1 (0%)	0
Headache	3/35 (8.6%)	4	2/22 (9.1%)	4	0/1 (0%)	0
Psychiatric disorders
Insomnia	3/35 (8.6%)	4	7/22 (31.8%)	16	0/1 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.