PROOF: PK/PD and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adults

• Sponsor: Vance Fowler, M.D. (Other)
• Overall Status: Completed
• CT.gov ID: NCT02570074
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 19
• Location: 1
• Arms: 2
• Actual Duration (Months): 10
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

Oral dosage regimens for fosfomycin tromethamine (Monurol™) are not established for the treatment of cUTI. The most common and recommended adult dosage regimen in the literature is a single-dose sachet containing the equivalent of 3 grams of fosfomycin administered every other day (QOD) for a total of three doses.

There are a myriad of different oral fosfomycin dosing regimens currently being used in clinical practice, including up to 3 grams orally twice daily for 7-21 days, but these regimens are not based on solid pharmacokinetic, pharmacodynamic or safety rationale. Initial pharmacokinetic studies performed with oral fosfomycin tromethamine primarily examined single dose regimens and did not use modern day bioanalytical or pharmacokinetic techniques. As the use of fosfomycin becomes more pervasive in concordance with the increase in multidrug resistant pathogens, further pharmacokinetic and safety data are needed for more intensive dosing regimens to support its continued use.

The rationale of this study is that oral fosfomycin tromethamine requires a modern pharmacokinetic-pharmacodynamic study to identify alternative oral dosage regimens that are appropriate and safe. This study provided safety/tolerability and clinical pharmacology information regarding two oral dosing regimens that may have application to treat various types of infections involving resistant pathogens or when other oral antibacterial options are not available.

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects	Drug: Fosfomycin	Phase 1

Detailed Description

The study was designed as a randomized, two-way crossover trial involving up to 24 randomized participants with an anticipated drop-out rate no higher than 25% to give a total of 18 evaluable healthy adult participants. The study was fully explained to each participant, informed consent was obtained, and an IRB-approved informed consent form was signed before any study procedures were initiated. All participants underwent screening assessments within 30 days prior to the initial dosing to determine their eligibility for enrollment into the study. All participants met the inclusion and exclusion criteria and underwent screening procedures that included a complete medical history, physical examination, assessment of clinical laboratory parameters (chemistry and hematology), ECG, and pregnancy test (females of child bearing potential only).

Randomization was stratified by gender, using permuted blocks. Within each gender, eligible participants were randomized with equal probability to one of the 2 treatment sequences shown in Table 3. According to the sequence to which the participant was randomized, the participant initially received one of two oral dosage regimens of fosfomycin: 3 g every other day x 3 doses or 3 g once-daily x 7 doses. After completion of the initial dosing regimen each participant was crossed over to receive the other dosing regimen. There was a minimum 5-day, and a recommended maximum 14-day, washout period prior to starting the next dosing regimen. Blood and urine samples were collected throughout the study as well as detailed drug administration and adverse event data for each participant.

Fosfomycin tromethamine sachet (Monurol™) was used in this study. Each participant was instructed how to stir and dissolve the single-dose sachet into 3 to 4 ounces of water, and take each dose immediately after dissolving in water. Compliance was assessed by participant interviews (every 2 days) and counting of empty of sachets.

Participants reported to the outpatient study center on Day -30 to -1 for study criteria review, clinical assessment, and blood collection for screening laboratory tests prior to fosfomycin administration. Each participant participated in the study up to 120 days (i.e., screening visit; day -1 for clinical assessment and blood collection; days 1-7 for fosfomycin administration and sample collection period; and day 8-10 for follow-up assessment; crossed over to receive the other dosing regimen and schedule of events.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Phase I Study to Evaluate Pharmacokinetics, Pharmacodynamics and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants
• Actual Study Start Date: Jan 1, 2016
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fosfomycin - 3 doses QoD/7 doses QD Fosfomycin given as a 3 gm dose, every other day for 3 doses, followed by 3 gm dose, once a day for 7 doses.	Drug: Fosfomycin; Broad spectrum antibiotic
Experimental: Fosfomycin - 7 doses QD/3 doses QoD Fosfomycin given as a 3 gm dose, once a day for 7 doses, followed by 3 gm dose, every other day for 3 doses.	Drug: Fosfomycin; Broad spectrum antibiotic

Outcome Measures

Primary Outcome Measures

1. Number (%) of Grade 2 or Higher AEs Regardless of Relationship to Study Drug [3 months]

2. Day 1: Plasma PK Concentrations [mg/L] [Day 1: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose]

   Day 1 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose

3. Day 5: Plasma PK Concentrations [mg/L] [Day 5: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose]

   Day 5 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose

4. Maximum Plasma Concentration (Cmax) [24 hours]

   To estimate the fosfomycin pharmacokinetic parameter maximum plasma concentration (Cmax) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants

5. Day 1: Area Under the Concentration Time Curve (AUC 0-infinity) [24 hours]

   To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-infinity) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants

6. Day 5: Area Under the Concentration Time Curve (AUC Tau-infinity) [24 hours]

   To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-tau) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants

7. Number of Subjects Who Prematurely Discontinue Study Drug [Dosing period: 7 days]

Secondary Outcome Measures

1. Total Body Clearance (CL) [Pooled over 24 hours: Day 1]

2. Apparent Volume of Distribution (Vss) [Pooled over 24 hours at Day 1 and Day 5]

3. Elimination Rate Constant (z) [Pooled over 24 hours at Day 1 and Day 5]

4. Elimination Half-life (t½) [Pooled over 24 hours at Day 1 and Day 5]

5. Renal Clearance (CLR) [Pooled over 24 hours at Day 1 and Day 5]

6. Amount Excreted in the Urine (Ae) [Pooled over 24 hours at Day 1 and Day 5]

7. Urinary Bactericidal (UBT) Titers for E. Coli ATCC 25922 [3 months]

   UBT for E.coli ATCC 25922

8. Urinary Bactericidal Kinetics (UBK) [3 months]

9. Urine Fosfomycin Concentrations [mg/L] [Day 1: 24 hours]

   Urine Fosfomycin concentrations [mg/L]

10. UBT-time Curve (AUBT24) [24 hours at Day 1 and Day 5]

    For pathogens E. coli ATCC 25922, E. coli ATCC BAA-2323, K. pneumoniae ATCC 33495, K. pneumoniae ATCC 700603 and P. mirabilis ATCC 35659

11. Urine Fosfomycin Concentrations [mg/L] [Day 5: 24 hours]

    Urine Fosfomycin concentrations [mg/L]

12. Urinary Bactericidal (UBT) Titers for E. Coli ATCC BAA-2323 [24 hours on Day 1 and Day 5]

    UBT for E. Coli ATCC BAA-2323

13. Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 33495 [24 hours on Day 1 and Day 5]

    UBT for E.coli K. Pneumoniae ATCC 33495

14. Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 700603 [24 hours on Day 1 and Day 5]

    UBT for K. Pneumoniae ATCC 700603

15. Urinary Bactericidal (UBT) Titers for P. Mirabilis ATCC 35659 [24 hours on Day 1 and Day 5]

    UBT for P. Mirabilis ATCC 35659

16. Urinary Inhibitory (UIT) Titers for E. Coli ATCC 25922 [24 hours on Day 1 and Day 5]

    UIT for E.coli ATCC 25922

17. Urinary Inhibitory (UIT) Titers for E. Coli ATCC BAA-2323 [24 hours on Day 1 and Day 5]

    UIT for E. Coli ATCC BAA-2323

18. Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 33495 [24 hours on Day 1 and Day 5]

    UIT for E.coli K. Pneumoniae ATCC 33495

19. Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 700603 [24 hours on Day 1 and Day 5]

    UIT for K. Pneumoniae ATCC 700603

20. Urinary Inhibitory (UIT) Titers for P. Mirabilis ATCC 35659 [24 hours on Day 1 and Day 5]

    UIT for P. Mirabilis ATCC 35659

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. The participant is healthy as judged by the site investigator with no clinically significant abnormality identified on a medical evaluation including history, physical examination, laboratory tests, blood pressure, and heart rate.

2. Male and female participants between 18 to 55 years old.

3. Female participants of childbearing potential (not surgically sterilized and between menarche and one-year post-menopause) must have a negative pregnancy test at the time of enrollment and must agree to use appropriate contraception for as long as they are taking the study drug and for 1 month afterwards. During the screening visit, participants will be instructed to use a second reliable method of birth control in accordance with the protocol during the study and for one month following. Medically acceptable contraceptives include:

• Surgical sterilization (such as a tubal ligation or hysterectomy)

• Approved hormonal contraceptives (such as birth control pills, patches, implants or injections)

• Barrier methods (such as a condom or diaphragm) used with a spermicide, or

• An intrauterine device (IUD). i. NOTE: Contraceptive measures such as Plan B™, sold for emergency use after unprotected sex, are not acceptable methods for routine use.

1. Nonsmokers defined as abstinence from cigarette smoking for the previous 6 months before enrollment into the study.

2. Provide a signed and dated written informed consent prior to any study-specific procedures (including screening procedures).

3. Body weight ≥50 kg

4. Body mass index (BMI) 18.5-29.9 kg/m2

Exclusion Criteria:

1. History of significant hypersensitivity reaction or intolerance to fosfomycin tromethamine that in the opinion of the site investigator, contraindicates participation in the study. In addition, if heparin is used during pharmacokinetic sampling, participants with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.

2. History of significant cardiac, neurological, thyroid, muscular, or immune disorder.

3. Any laboratory abnormality grade 2 or higher as defined according to the U.S. Department of Health and Human Services common terminology criteria for AEs (CTCAE).26

4. Estimated creatinine clearance (CLCR) <60 ml/minute as determined by Cockcroft-Gault equation

5. Positive serum pregnancy test.

6. Currently breast feeding.

7. History of alcohol or substance abuse or dependence within 6 months of the screening: History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. 1 drink is equivalent to 12g alcohol = 5 oz (150 mL) of wine or 12 oz (360 mL) of beer or 1.5 oz (45 mL) of 80 proof distilled spirits.

8. The use of prescription (except birth control pills or hormone replacement in females) or non-prescription drugs, including herbal and dietary supplements (including St. John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of site investigator the medication will not interfere with the study procedures or compromise participant safety.

9. The participant has participated in a clinical trial and has received a drug or a new chemical entity within 30 days prior to the first dose of study medication.

10. Participants who have donated blood to the extent where participation in the study would result in excess of 500 mL blood donated within a 56 day period.

11. Those who, in the opinion of the site investigator, have a risk of non-compliance with study procedures.

12. QTc interval with Fredericia correction >450ms or any other clinically relevant ECG abnormalities

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois at Chicago	Chicago	Illinois	United States	60612

Sponsors and Collaborators

• Vance Fowler, M.D.
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Vance Fowler, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vance Fowler, M.D., Professor, Duke University
• ClinicalTrials.gov Identifier: NCT02570074
• Other Study ID Numbers: Pro00066102; 1UM1AI104681-01
• First Posted: Oct 7, 2015
• Last Update Posted: Jul 30, 2019
• Last Verified: Jul 1, 2019

• Additional relevant MeSH terms: Fosfomycin

Study Results

Participant Flow

Arm/Group Title	Fosfomycin - 3 Doses QoD/7 Doses QD	Fosfomycin - 7 Doses QD/3 Doses QoD
Arm/Group Description	Fosfomycin given as a 3 gm dose, every other day for 3 doses, followed by 3 gm dose, once a day for 7 doses. Fosfomycin: Broad spectrum antibiotic	Fosfomycin given as a 3 gm dose, once a day for 7 doses, followed by 3 gm dose, every other day for 3 doses. Fosfomycin: Broad spectrum antibiotic
Period Title: Period 1 (First Dosing Regimen)
STARTED	9	10
COMPLETED	9	10
NOT COMPLETED	0	0
Period Title: Period 1 (First Dosing Regimen)
STARTED	9	10
COMPLETED	8	10
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Fosfomycin - 3 Doses QoD/7 Doses QD	Fosfomycin - 7 Doses QD/3 Doses QoD	Total
Arm/Group Description	Fosfomycin given as a 3 gm dose, every other day for 3 doses, followed by 3 gm dose, once a day for 7 doses. Fosfomycin: Broad spectrum antibiotic	Fosfomycin given as a 3 gm dose, once a day for 7 doses, followed by 3 gm dose, every other day for 3 doses. Fosfomycin: Broad spectrum antibiotic	Total of all reporting groups
Overall Participants	9	10	19
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	27	27	27
Sex: Female, Male (Count of Participants)
Female	4 44.4%	6 60%	10 52.6%
Male	5 55.6%	4 40%	9 47.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 22.2%	3 30%	5 26.3%
Not Hispanic or Latino	7 77.8%	7 70%	14 73.7%
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%	1 10%	1 5.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 11.1%	1 10%	2 10.5%
White	5 55.6%	7 70%	12 63.2%
More than one race	0 0%	1 10%	1 5.3%
Unknown or Not Reported	3 33.3%	0 0%	3 15.8%
Region of Enrollment (participants) [Number]
United States	9 100%	10 100%	19 100%
Weight (kilogram) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram]	75.3 (12.3)	76.0 (10.9)	75.7 (11.3)
Entry site - University of Illinois Chicago (participants) [Number]
Number [participants]	9 100%	10 100%	19 100%
Height (centimeter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter]	173.2 (12.0)	173.8 (7.9)	173.6 (9.7)
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.0 (2.5)	24.9 (2.4)	24.9 (2.4)
Estimated creatinine clearance (mL/min) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min]	105.0 (14.6)	113.7 (23.0)	109.6 (19.4)
QTC Interval (milliseconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milliseconds]	402.8 (19.7)	405.2 (17.2)	404.1 (17.9)

Outcome Measures

1. Primary Outcome

Title	Number (%) of Grade 2 or Higher AEs Regardless of Relationship to Study Drug
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The number of all AE is summarized by treatment but not sequence. The total number of subjects analyzed is 19.	The number of all AE is summarized by treatment but not sequence. The total number of subjects analyzed is 19.
Measure Participants	19	18
Count of Participants [Participants]	1 11.1%	3 30%

2. Primary Outcome

Title	Day 1: Plasma PK Concentrations [mg/L]
Description	Day 1 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose
Time Frame	Day 1: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose

Outcome Measure Data

Analysis Population Description

Please note that one person did not complete the Fosfomycin 3 doses QoD regimen.

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	The analysis is by Dosing Regimen	The analysis is by by dosing regimen
Measure Participants	18	18
0 hours	0.08 (0.36)	0 (0)
1 hour	16.61 (5.44)	15.90 (6.70)
1.5 hours	22.20 (7.98)	21.35 (7.17)
2 hours	23.36 (7.04)	22.12 (6.34)
3 hours	18.72 (5.13)	17.86 (4.67)
4 hours	14.08 (4.00)	13.53 (3.87)
6 hours	9.11 (2.38)	8.43 (2.38)
8 hours	6.08 (1.48)	5.69 (1.57)
12 hours	3.43 (1.01)	3.19 (1.28)
24 hours	0.88 (0.59)	1.33 (2.70)

3. Primary Outcome

Title	Day 5: Plasma PK Concentrations [mg/L]
Description	Day 5 mean and standard deviation plasma concentrations [mg/L] at 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose
Time Frame	Day 5: 0, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours from dose

Outcome Measure Data

Analysis Population Description

Please note that one person did not complete the Fosfomycin 3 doses QoD regimen.

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	The analysis is by Dosing Regimen	The analysis is by by dosing regimen
Measure Participants	18	18
0 hours	0.23 (0.37)	1.33 (1.12)
1 hour	16.29 (6.23)	16.81 (4.27)
1.5 hours	21.21 (6.91)	22.07 (5.02)
2 hours	22.48 (6.44)	23.37 (5.71)
3 hours	19.38 (5.34)	19.45 (5.10)
4 hours	14.98 (4.82)	15.12 (4.27)
6 hours	9.78 (3.08)	9.91 (2.74)
8 hours	6.47 (1.95)	6.93 (1.96)
12 hours	3.71 (1.31)	4.02 (1.61)
24 hours	0.82 (0.40)	1.12 (1.07)

4. Primary Outcome

Title	Maximum Plasma Concentration (Cmax)
Description	To estimate the fosfomycin pharmacokinetic parameter maximum plasma concentration (Cmax) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Please note that one person did not complete the Fosfomycin 3 doses QoD regimen.

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	18	18
Day 1	23.79 (7.48)	23.47 (6.62)
Day 5	24.41 (6.23)	23.75 (5.61)

5. Primary Outcome

Title	Day 1: Area Under the Concentration Time Curve (AUC 0-infinity)
Description	To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-infinity) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	18	18
Mean (Standard Deviation) [mg*hour/L]	148.57 (35.57)	176.44 (176.96)

6. Primary Outcome

Title	Day 5: Area Under the Concentration Time Curve (AUC Tau-infinity)
Description	To estimate the fosfomycin pharmacokinetic parameter area-under-the-plasma concentration-time curve (AUC 0-tau) at steady-state for orally-dosed fosfomycin tromethamine in healthy adult participants
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	18	18
Mean (Standard Deviation) [mg*hours/L]	151.60 (35.61)	156.62 (42.52)

7. Primary Outcome

Title	Number of Subjects Who Prematurely Discontinue Study Drug
Time Frame	Dosing period: 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	Fosfomycin given as a 3 gm dose, every other day for 3 doses. Fosfomycin: Broad spectrum antibiotic	Fosfomycin given as a 3 gm dose, once a day for 7 doses Fosfomycin: Broad spectrum antibiotic
Measure Participants	19	18
Count of Participants [Participants]	1 11.1%	0 0%

8. Secondary Outcome

Title	Total Body Clearance (CL)
Time Frame	Pooled over 24 hours: Day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.
Measure Participants	18	18
Mean (Standard Deviation) [L/h]	21.62 (6.79)	21.96 (6.51)

9. Secondary Outcome

Title	Apparent Volume of Distribution (Vss)
Time Frame	Pooled over 24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Day 1	172.25 (70.41)	143.97 (55.31)
Day 5	140.57 (67.94)	146.68 (67.64)

10. Secondary Outcome

Title	Elimination Rate Constant (z)
Time Frame	Pooled over 24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Day 1	0.13 (0.04)	0.17 (0.06)
Day 5	0.16 (0.04)	0.16 (0.05)

11. Secondary Outcome

Title	Elimination Half-life (t½)
Time Frame	Pooled over 24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Day 1	5.56 (1.54)	5.90 (7.16)
Day 5	7.53 (4.09)	7.31 (3.46)

12. Secondary Outcome

Title	Renal Clearance (CLR)
Time Frame	Pooled over 24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Day 1	7.10 (3.64)	8.09 (5.60)
Day 5	7.53 (4.09)	7.31 (3.46)

13. Secondary Outcome

Title	Amount Excreted in the Urine (Ae)
Time Frame	Pooled over 24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.
Measure Participants	18	18
Day 1	1047.05 (710.53)	1102.34 (772.67)
Day 5	1177.24 (790.76)	1161.57 (718.09)

14. Secondary Outcome

Title	Urinary Bactericidal (UBT) Titers for E. Coli ATCC 25922
Description	UBT for E.coli ATCC 25922
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	8
Day 1, 4 to 8 hr	8	4.5
Day 1, 8 to 12 hr	4	3
Day 1, 12 to 24 hr	4	6
Day 5, >0 to 4 hr	4	4
Day 5, 4 to 8 hr	12	12
Day 5, 8 to 12 hr	6	6
Day 5, 12 to 24 hr	4	4

15. Secondary Outcome

Title	Urinary Bactericidal Kinetics (UBK)
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

Data not collected.

Arm/Group Title	Fosfomycin - 3 Doses QoD/7 Doses QD	Fosfomycin - 7 Doses QD/3 Doses QoD
Arm/Group Description	Fosfomycin given as a 3 gm dose, every other day for 3 doses, followed by 3 gm dose, once a day for 7 doses. Fosfomycin: Broad spectrum antibiotic	Fosfomycin given as a 3 gm dose, once a day for 7 doses, followed by 3 gm dose, every other day for 3 doses. Fosfomycin: Broad spectrum antibiotic
Measure Participants	0	0

16. Secondary Outcome

Title	Urine Fosfomycin Concentrations [mg/L]
Description	Urine Fosfomycin concentrations [mg/L]
Time Frame	Day 1: 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Pre-dose	0 (0)	0 (0)
0-4 hours post-Dose	471.71 (423.10)	563.55 (665.94)
4-8 hours post-dose	584.23 (348.46)	402.90 (367.31)
8-12 hours post dose	201.99 (119.22)	228.13 (163.30)
12-24 hours post dose	202.73 (149.08)	175.13 (102.21)

17. Secondary Outcome

Title	UBT-time Curve (AUBT24)
Description	For pathogens E. coli ATCC 25922, E. coli ATCC BAA-2323, K. pneumoniae ATCC 33495, K. pneumoniae ATCC 700603 and P. mirabilis ATCC 35659
Time Frame	24 hours at Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.	The number of all AE is summarized by regimen but not sequence. The total number of subjects analyzed is 18.
Measure Participants	19	18
E. coli ATCC 25922, Day 1	175.37 (174.30)	158.67 (199.12)
E. coli ATCC 25922, Day 5	202.53 (218.71)	196.67 (214.84)
E. coli ATCC BAA-2323, Day 1	139.47 (140.45)	121.56 (145.88)
E. coli ATCC BAA-2323, Day 5	198.84 (219.90)	156.33 (172.96)
K. pneumoniae ATCC 33495, Day 1	15.68 (17.75)	11.67 (11.95)
K. pneumoniae ATCC 33495, Day 5	20.63 (19.11)	17.44 (16.13)
K. pneumoniae ATCC 700603, Day 1	10.32 (8.23)	4.56 (7.02)
K. pneumoniae ATCC 700603, Day 5	12.42 (8.83)	9.89 (6.74)
P. Mirabilis ATCC 35659, Day 1	96.53 (135.80)	53.78 (70.75)
P. Mirabilis ATCC 35659, Day 5	96.95 (148.42)	90.33 (146.85)

18. Secondary Outcome

Title	Urine Fosfomycin Concentrations [mg/L]
Description	Urine Fosfomycin concentrations [mg/L]
Time Frame	Day 5: 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD	Fosfomycin - 7 Doses QD
Arm/Group Description	the analysis is by Dosing Regimen	the analysis is by by dosing regimen
Measure Participants	18	18
Pre-dose	66.24 (102.59)	314.34 (257.97)
0-4 hours post-Dose	642.83 (521.45)	465.74 (266.24)
4-8 hours post-dose	643.93 (496.86)	608.99 (344.54)
8-12 hours post dose	295.01 (272.97)	254.75 (120.71)
12-24 hours post dose	169.51 (112.14)	222.20 (167.87)

19. Secondary Outcome

Title	Urinary Bactericidal (UBT) Titers for E. Coli ATCC BAA-2323
Description	UBT for E. Coli ATCC BAA-2323
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	8
Day 1, 4 to 8 hr	8	2.5
Day 1, 8 to 12 hr	4	3
Day 1, 12 to 24 hr	2	4
Day 5, >0 to 4 hr	16	4
Day 5, 4 to 8 hr	8	16
Day 5, 8 to 12 hr	4	4
Day 5, 12 to 24 hr	4	4

20. Secondary Outcome

Title	Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 33495
Description	UBT for E.coli K. Pneumoniae ATCC 33495
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	1	0
Day 1, 4 to 8 hr	2	0
Day 1, 8 to 12 hr	0	0
Day 1, 12 to 24 hr	0	1
Day 5, >0 to 4 hr	2	1.5
Day 5, 4 to 8 hr	1	2
Day 5, 8 to 12 hr	0	0
Day 5, 12 to 24 hr	0	1.0

21. Secondary Outcome

Title	Urinary Bactericidal (UBT) Titers for K. Pneumoniae ATCC 700603
Description	UBT for K. Pneumoniae ATCC 700603
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	1	0
Day 1, 4 to 8 hr	1	0
Day 1, 8 to 12 hr	0	0
Day 1, 12 to 24 hr	0	0
Day 5, >0 to 4 hr	1	1
Day 5, 4 to 8 hr	1	1
Day 5, 8 to 12 hr	0	0
Day 5, 12 to 24 hr	0	0

22. Secondary Outcome

Title	Urinary Bactericidal (UBT) Titers for P. Mirabilis ATCC 35659
Description	UBT for P. Mirabilis ATCC 35659
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	2.5
Day 1, 4 to 8 hr	4	0.5
Day 1, 8 to 12 hr	1	1
Day 1, 12 to 24 hr	1	2
Day 5, >0 to 4 hr	4	4
Day 5, 4 to 8 hr	2	4
Day 5, 8 to 12 hr	2	1
Day 5, 12 to 24 hr	1	2

23. Secondary Outcome

Title	Urinary Inhibitory (UIT) Titers for E. Coli ATCC 25922
Description	UIT for E.coli ATCC 25922
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	8
Day 1, 4 to 8 hr	8	4.5
Day 1, 8 to 12 hr	4	3
Day 1, 12 to 24 hr	4	6
Day 5, >0 to 4 hr	8	4
Day 5, 4 to 8 hr	16	12
Day 5, 8 to 12 hr	4	6
Day 5, 12 to 24 hr	4	4

24. Secondary Outcome

Title	Urinary Inhibitory (UIT) Titers for E. Coli ATCC BAA-2323
Description	UIT for E. Coli ATCC BAA-2323
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	8
Day 1, 4 to 8 hr	8	2.5
Day 1, 8 to 12 hr	4	3
Day 1, 12 to 24 hr	2	4
Day 5, >0 to 4 hr	16	4
Day 5, 4 to 8 hr	8	16
Day 5, 8 to 12 hr	4	4
Day 5, 12 to 24 hr	4	4

25. Secondary Outcome

Title	Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 33495
Description	UIT for E.coli K. Pneumoniae ATCC 33495
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	1	0
Day 1, 4 to 8 hr	2	0
Day 1, 8 to 12 hr	0	0
Day 1, 12 to 24 hr	0	1
Day 5, >0 to 4 hr	2	1.5
Day 5, 4 to 8 hr	1	2
Day 5, 8 to 12 hr	0	0
Day 5, 12 to 24 hr	0	1

26. Secondary Outcome

Title	Urinary Inhibitory (UIT) Titers for K. Pneumoniae ATCC 700603
Description	UIT for K. Pneumoniae ATCC 700603
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	1	0
Day 1, 4 to 8 hr	1	0
Day 1, 8 to 12 hr	0	0
Day 1, 12 to 24 hr	0	0
Day 5, >0 to 4 hr	1	1
Day 5, 4 to 8 hr	1	1
Day 5, 8 to 12 hr	0	0
Day 5, 12 to 24 hr	0	0

27. Secondary Outcome

Title	Urinary Inhibitory (UIT) Titers for P. Mirabilis ATCC 35659
Description	UIT for P. Mirabilis ATCC 35659
Time Frame	24 hours on Day 1 and Day 5

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fosfomycin - 3 Doses QoD Regimen	Fosfomycin - 7 Doses QD Regimen
Arm/Group Description	The analysis is by dosing regimen.	The analysis is by dosing regimen.
Measure Participants	19	18
Day 1, >0 to 4 hr	4	2.5
Day 1, 4 to 8 hr	4	0.5
Day 1, 8 to 12 hr	1	1
Day 1, 12 to 24 hr	1	2
Day 5, >0 to 4 hr	4	4
Day 5, 4 to 8 hr	2	4
Day 5, 8 to 12 hr	2	1
Day 5, 12 to 24 hr	1	2

Adverse Events

Time Frame	Adverse event data were collected though 60 days following the final study visit
Arm/Group Title	Fosfomycin - 3 Doses QoD		Fosfomycin - 7 Doses QD
Arm/Group Description	Fosfomycin given as a 3 gm dose, every other day for 3 doses Fosfomycin: Broad spectrum antibiotic		Fosfomycin given as a 3 gm dose, once a day for 7 doses Fosfomycin: Broad spectrum antibiotic
All Cause Mortality
	Fosfomycin - 3 Doses QoD		Fosfomycin - 7 Doses QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/18 (0%)
Serious Adverse Events
	Fosfomycin - 3 Doses QoD		Fosfomycin - 7 Doses QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		1/18 (5.6%)
Gastrointestinal disorders
Clostridium difficile colitis	0/19 (0%)	0	1/18 (5.6%)	1
Investigations
Transaminases increased	1/19 (5.3%)	1	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	Fosfomycin - 3 Doses QoD		Fosfomycin - 7 Doses QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/19 (84.2%)		16/18 (88.9%)
Ear and labyrinth disorders
Tinnitus	0/19 (0%)	0	1/18 (5.6%)	1
Gastrointestinal disorders
Abdominal Pain	2/19 (10.5%)	2	3/18 (16.7%)	3
Abdominal distension	1/19 (5.3%)	1	0/18 (0%)	0
Diarrhoea	15/19 (78.9%)	15	16/18 (88.9%)	16
Nausea	1/19 (5.3%)	1	1/18 (5.6%)	1
Vomiting	1/19 (5.3%)	1	0/18 (0%)	0
General disorders
Fatigue	1/19 (5.3%)	1	1/18 (5.6%)	1
Infections and infestations
Sinusitis	0/19 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Headache	1/19 (5.3%)	1	3/18 (16.7%)	3
Tremor	0/19 (0%)	0	1/18 (5.6%)	1
Psychiatric disorders
Anxiety	0/19 (0%)	0	1/18 (5.6%)	1
Renal and urinary disorders
Dysuria	1/19 (5.3%)	1	0/18 (0%)	0
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/19 (5.3%)	1	0/18 (0%)	0
Sinus Congestion	1/19 (5.3%)	1	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis contact	2/19 (10.5%)	2	0/18 (0%)	0
Madarosis	1/19 (5.3%)	1	0/18 (0%)	0
Dry skin	0/19 (0%)	0	1/18 (5.6%)	1
Rash	0/19 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.