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

The study is 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 will be fully explained to each participant,
informed consent will be obtained, and an IRB-approved informed consent form will be signed
before any study procedures are initiated. All participants will undergo screening
assessments within 30 days prior to the initial dosing to determine their eligibility for
enrollment into the study. All participants must meet the inclusion and exclusion criteria
and undergo screening procedures that include 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 will be stratified by gender, using permuted blocks. Within each gender,
eligible participants will be 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 will initially receive 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 will be crossed over to receive the other dosing
regimen. There will be a minimum 5-day, and a recommended maximum 14-day, washout period
prior to starting the next dosing regimen. Blood and urine samples will be collected
throughout the study as well as detailed drug administration and adverse event data for each
participant.

Fosfomycin tromethamine sachet (Monurol™) will be used in this study. Each participant will
be 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 will be assessed by
participant interviews (every 2 days) and counting of empty of sachets.

Participants will report 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 will participate 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.

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.

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

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

6. Body weight ≥50 kg

7. 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