Overview

This trial has been completed.

Condition healthy subjects
Treatment fosfomycin
Phase phase 1
Sponsor Vance Fowler, M.D.
Collaborator National Institute of Allergy and Infectious Diseases (NIAID)
Start date December 2015
End date September 2016
Trial size 19 participants
Trial identifier NCT02570074, 1UM1AI104681-01, Pro00066102

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 will provide 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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety study
Intervention model crossover assignment
Masking open label
Primary purpose basic science
Arm
(Experimental)
Fosfomycin given as a 3 gm dose, every other day for 3 doses
fosfomycin
Broad spectrum antibiotic
(Experimental)
Fosfomycin given as a 3 gm dose, once a day for 7 doses
fosfomycin
Broad spectrum antibiotic

Primary Outcomes

Measure
Number (%) of Grade 2 or higher AEs regardless of relationship to study drug
time frame: 3 months
Area-under-the-plasma concentration-time curve (AUC0-infinity)
time frame: 3 months
Maximum plasma concentration (Cmax)
time frame: 3 months
Number of subjects who prematurely discontinue study drug
time frame: 3 months

Secondary Outcomes

Measure
Total body clearance (CL)
time frame: 3 months
Apparent volume of distribution (Vss)
time frame: 3 months
Elimination rate constant (z)
time frame: 3 months
Elimination half-life (t½)
time frame: 3 months
Renal clearance (CLR)
time frame: 3 months
Amount excreted in the urine (Ae)
time frame: 3 months
Urinary inhibitory (UTI) titers
time frame: 3 months
Urinary bactericidal (UBT) titers
time frame: 3 months
Urinary bactericidal kinetics (UBK)
time frame: 3 months
Area under the 24-hour UIT-time curve (AUIT24)
time frame: 3 months
UBT-time curve (AUBT24)
time frame: 3 months

Eligibility Criteria

Male or female participants from 18 years up to 55 years old.

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

Additional Information

Official title Phase I Study to Evaluate Pharmacokinetics, Pharmacodynamics and Safety/Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants
Principal investigator Vance Fowler, MD
Description 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.
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Duke University.