Trial Outcomes & Findings for Intravenous Fosfomycin Pharmacokinetics Study (NCT NCT03910673)

Last Updated: 2023-10-23

Results Overview

Mean and standard deviation (SD) of the AUC 0-8 (h\*ug/mL) and AUC 0-inf (h\*ug/mL). PK parameters were estimated from the ZTI-01 plasma concentration-time data after Dose 1 (Day 1) and Dose 3 (Day 2) using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study. AUC 0-8 was estimated for the plasma concentration data after Dose 1 and Dose 3. AUC 0-inf was estimated for the plasma concentration data after Dose 3 with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax).

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

39 participants

Primary outcome timeframe

Day 1 to Day 2

Results posted on

2023-10-23

Participant Flow

The study population included healthy male and female adults, aged 18-45 years, inclusive, with body mass index (BMI) 18-30 kg/m2, inclusive, and body weight \>50 kg (110 lbs) who met all eligibility criteria. Participants were enrolled between 27JUN2019 and 08DEC2020, and were recruited from the community at large.

Participant milestones

Participant milestones
Measure	30 Minute BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 30 minutes after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	75 Minute BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 75 minutes after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	2 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 2 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	5 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 5 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	8 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 8 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.
Overall Study STARTED	7	6	7	13	6
Overall Study Enrolled and Randomized	6	6	6	6	6
Overall Study Enrolled as Replacement	1	0	1	7	0
Overall Study Began Infusion of Dose 1	7	6	7	13	6
Overall Study Completed Dose 1	7	6	7	13	6
Overall Study Completed Dose 2	7	6	7	13	6
Overall Study Completed Dose 3	6	6	7	12	6
Overall Study Completed All Scheduled Treatment	6	6	7	12	6
Overall Study Completed All PK Blood Draws	6	6	6	6	6
Overall Study Completed Bronchoscopy With BAL	6	6	6	6	6
Overall Study Completed All Plasma Urea Samples	6	6	6	6	6
Overall Study At Least One PK Blood Draw Concurrent With BAL Timepoint	6	6	6	6	6
Overall Study COMPLETED	7	6	7	11	6
Overall Study NOT COMPLETED	0	0	0	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	30 Minute BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 30 minutes after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	75 Minute BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 75 minutes after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	2 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 2 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	5 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 5 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.	8 Hour BAL ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. Bronchoscopy and bronchoalveolar lavage (BAL) performed 8 hours after start of third infusion dose. Fosfomycin disodium: Fosfomycin (a phosphonic acid derivative) formulated as a disodium salt.
Overall Study Adverse Event	0	0	0	2	0

Baseline Characteristics

Intravenous Fosfomycin Pharmacokinetics Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	30 Minute BAL n=7 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. BAL performed 30 minutes after start of third infusion dose.	75 Minute BAL n=6 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. BAL performed 75 minutes after start of third infusion dose.	2 Hour BAL n=7 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. BAL performed 2 hours after start of third infusion dose.	5 Hour BAL n=13 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. BAL performed 5 hours after start of third infusion dose.	8 Hour BAL n=6 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium. BAL performed 8 hours after start of third infusion dose.	Total n=39 Participants Total of all reporting groups
Sex: Female, Male Male	4 Participants n=5 Participants	5 Participants n=7 Participants	3 Participants n=5 Participants	6 Participants n=4 Participants	3 Participants n=21 Participants	21 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	0 Participants n=21 Participants	4 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	6 Participants n=7 Participants	6 Participants n=5 Participants	10 Participants n=4 Participants	6 Participants n=21 Participants	34 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	5 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants	5 Participants n=4 Participants	2 Participants n=21 Participants	15 Participants n=10 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants	4 Participants n=21 Participants	16 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	1 Participants n=10 Participants
Height	170.26 cm STANDARD_DEVIATION 10.52 • n=5 Participants	173 cm STANDARD_DEVIATION 8.67 • n=7 Participants	163.07 cm STANDARD_DEVIATION 4.54 • n=5 Participants	168.22 cm STANDARD_DEVIATION 8.44 • n=4 Participants	173.28 cm STANDARD_DEVIATION 8.17 • n=21 Participants	169.2 cm STANDARD_DEVIATION 8.62 • n=10 Participants
Weight	70.64 kg STANDARD_DEVIATION 11.87 • n=5 Participants	73.98 kg STANDARD_DEVIATION 11.26 • n=7 Participants	67.6 kg STANDARD_DEVIATION 6.14 • n=5 Participants	74.96 kg STANDARD_DEVIATION 12.68 • n=4 Participants	75.78 kg STANDARD_DEVIATION 7.49 • n=21 Participants	72.84 kg STANDARD_DEVIATION 10.59 • n=10 Participants
BMI	24.31 kg/m^2 STANDARD_DEVIATION 3.35 • n=5 Participants	24.6 kg/m^2 STANDARD_DEVIATION 2.11 • n=7 Participants	25.47 kg/m^2 STANDARD_DEVIATION 2.68 • n=5 Participants	26.89 kg/m^2 STANDARD_DEVIATION 2.99 • n=4 Participants	25.27 kg/m^2 STANDARD_DEVIATION 2.4 • n=21 Participants	25.54 kg/m^2 STANDARD_DEVIATION 2.84 • n=10 Participants
Age, Continuous	31.3 years STANDARD_DEVIATION 6.5 • n=5 Participants	31.2 years STANDARD_DEVIATION 4.6 • n=7 Participants	31.4 years STANDARD_DEVIATION 6.8 • n=5 Participants	32.3 years STANDARD_DEVIATION 6.6 • n=4 Participants	30.3 years STANDARD_DEVIATION 9.4 • n=21 Participants	31.4 years STANDARD_DEVIATION 6.5 • n=10 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants	7 Participants n=4 Participants	3 Participants n=21 Participants	18 Participants n=10 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Population: The PK population includes the population of evaluable participants. An evaluable participant is defined as a participant who received all doses of ZTI-01, underwent BAL at the randomized sampling timepoint with BAL return volume adequate for testing, and obtained at least one blood sample that was concurrent with the BAL sampling timepoint, with blood sampling volume that was adequate for testing. All arms are reported jointly as all received the same dose, following the same dosing schedule.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 AUC 0-8, after Dose 1	780.9 h*ug/mL Standard Deviation 112.2
Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 AUC 0-8, after Dose 3	959.4 h*ug/mL Standard Deviation 147.5
Area Under the Concentration-time Curve (AUC 0-8 and AUC 0-inf ) of ZTI-01 AUC 0-inf, after Dose 3	1086.0 h*ug/mL Standard Deviation 183.3

PRIMARY outcome

Timeframe: Day 2

Mean and SD of the clearance (CL) of ZTI-01 (L/h). The clearance PK parameter was estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for plasma samples collected during the study. If the amount extrapolated portion of AUC 0-inf was \>20%, the estimated CL value was excluded from statistical summaries of the parameter estimates.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Clearance (CL) of ZTI-01	5.69 L/h Standard Deviation 1.04

PRIMARY outcome

Timeframe: Day 2

Intrapulmonary pharmacokinetics of ZTI-01 was defined as the percent penetration of lung epithelial lining fluid (ELF) and alveolar macrophages (AMs). The estimate of the percent lung penetration was calculated by dividing the AUC 0-8 of ELF and AM by the AUC 0-8 of plasma fosfomycin. The AUC 0-8 of ELF and AM was calculated using the median result at each BAL sampling timepoint, resulting in a single AUC 0-8 of ELF and AM across all subjects. The AUC 0-8 of plasma fosfomycin was calculated using the median result of the plasma fosfomycin concentrations at the corresponding BAL timepoint.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Intrapulmonary Pharmacokinetics of ZTI-01 ELF	31.8 Plasma percent penetration
Intrapulmonary Pharmacokinetics of ZTI-01 AM	17.5 Plasma percent penetration

PRIMARY outcome

Timeframe: Day 1 to Day 2

Mean and standard deviation (SD) of the Cmax (ug/mL) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 1 and Dose 3 using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Maximum Measured Plasma Concentration (Cmax) of ZTI-01 Cmax, after Dose 3	335.1 ug/mL Standard Deviation 63.5872
Maximum Measured Plasma Concentration (Cmax) of ZTI-01 Cmax, after Dose 1	297.5 ug/mL Standard Deviation 46.074

PRIMARY outcome

Timeframe: Day 1 to Day 2

Population: The safety population includes all participants who received any amount of ZTI-01 (started the first infusion). All arms are reported jointly as all received the same dose, following the same dosing schedule

Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical chemistry assessments with toxicity grading and associated thresholds include sodium \<135 mEq/L or \>145 mEq/L, potassium \<3.5 mEq/L or \>5.0 mEq/L, random glucose \<=69 mg/dL or \>=141 mg/dL, blood urea nitrogen (BUN) \>=21 mg/dL, creatinine \>1.0 mg/dL (Females) or \>1.3 mg/dL (Males), calcium \<8.7 mg/dL or \>10.2 mg/dL, magnesium \<=1.7 mg/dL, phosphorous \<=2.2 mg/dL, creatine phosphokinase (CPK) \>=221 mg/dL, albumin \>=2.8 g/dL, total protein \<5.8 g/dL, alkaline phosphatase (ALP) \>=111 U/L, aspartate aminotransferase (AST) \>=42 U/L, alanine aminotransferase (ALT) \>54 U/L (Females) or \>63 (Males) U/L, total bilirubin \>=1.6 mg/dL, direct bilirubin \>=0.7 mg/dL, total cholesterol \>=301 mg/dL, triglycerides \>500 mg/dL, and lactate dehydrogenase (LDH) \>200 U/L.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Sodium - Increase	2 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Sodium - Decrease	2 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Potassium - Increase	19 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Potassium - Decrease	19 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Magnesium - Decrease	31 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Calcium - Increase	16 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Calcium - Decrease	16 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Phosphorus - Decrease	5 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Albumin - Decrease	4 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Random Glucose - Increase	8 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Random Glucose - Decrease	8 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Blood Urea Nitrogen - Increase	4 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Total Protein - Decrease	2 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Creatinine - Increase	0 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Triglycerides - Increase	5 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Total Cholesterol - Increase	0 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Creatine Phosphokinase - Increase	3 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Alkaline Phosphatase - Increase	1 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Aspartate Aminotransferase - Increase	0 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Alanine Aminotransferase - Increase	14 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Total Bilirubin - Increase	1 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Direct Bilirubin - Increase	5 Participants
Number of Participants Experiencing Abnormal Clinical Chemistry Laboratory Assessments Lactate Dehydrogenase - Increase	0 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical hematology assessments with toxicity grading and associated threshold include hemoglobin \<=11.9 g/dL (Females) or \<= 13.6 g/dL (Males), white blood cell count \<=3.1 10\^9/L or \>=9.9 10\^9/L, lymphocytes \<0.6 10\^9/L, neutrophils \<2.0 10\^9/L, eosinophils \>0.7 10\^9/L, and platelets \<=149 10\^9/L.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments Hemoglobin - Decrease	7 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments Platelets - Decrease	1 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments WBC - Increase	7 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments WBC - Decrease	7 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments Neutrophils - Decrease	6 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments Lymphocytes - Decrease	0 Participants
Number of Participants Experiencing Abnormal Clinical Hematology Laboratory Assessments Eosinophils - Increase	1 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical coagulation assessments with toxicity grading and associated threshold include prothrombin time (PT) \>13.1 seconds and activated partial thromboplastic time (aPTT) \>37.1 seconds.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments PT - Increase	9 Participants
Number of Participants Experiencing Abnormal Clinical Coagulation Laboratory Assessments aPTT - Increase	6 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Each subject is only counted once per toxicity grade for the worst severity recorded. Clinical urinalysis assessments with toxicity grading and associated threshold include protein \>= 1+, glucose \>= 1+, and red blood cell (RBC) count from microscopy \>= 5 rbc/hpf.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments Protein	2 Participants
Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments Glucose	1 Participants
Number of Participants Experiencing Abnormal Clinical Urinalysis Laboratory Assessments RBC Count	1 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Physical exams included assessment of skin, head and neck, lungs, heart, liver, spleen, extremities, lymph nodes, musculoskeletal system/extremities, abdomen, nervous system, weight, height, and body mass index (BMI).

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Physical Examination Findings Abdomen	2 Participants
Number of Participants Experiencing Abnormal Physical Examination Findings Extremities	3 Participants
Number of Participants Experiencing Abnormal Physical Examination Findings General Appearance	4 Participants
Number of Participants Experiencing Abnormal Physical Examination Findings Musculoskeletal	1 Participants
Number of Participants Experiencing Abnormal Physical Examination Findings Skin	2 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Each subject is only counted once per toxicity grade for the worst severity recorded. Vital sign measurements with toxicity grading and associated threshold include systolic blood pressure (BP) \>=141 mmHg or \<=89 mmHg; diastolic BP \>=91 mmHg; heart rate \>=101 beats per minute (bpm) and \>25% change from baseline or \<=54 bpm (if baseline \>=60 bpm) or \<=49 bpm (if baseline \<60 bpm); respiratory rate \>=23 breaths per minute; and temperature \>=38.0 degrees Celsius.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Abnormal Vital Sign Measurements Heart Rate - Decrease	13 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Systolic Blood Pressure - Decrease	2 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Systolic Blood Pressure - Increase	3 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Diastolic Blood Pressure - Increase	2 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Heart Rate - Increase	6 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Respiratory Rate - Increase	9 Participants
Number of Participants Experiencing Abnormal Vital Sign Measurements Temperature - Increase	0 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 3

The number of participants who experienced at least one unsolicited treatment emergent AE (TEAE) of any severity and relatedness by MedDRA System Organ Class (SOC). AEs included local and systemic reactions. Any medical condition that was present at screening was considered as a baseline finding and not reported as an AE. However, if its Grade increased at any time during the trial such that it met the AE definition, it was recorded as an AE.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants Experiencing Adverse Events (AEs) Cardiac disorders	15 Participants
Number of Participants Experiencing Adverse Events (AEs) Gastrointestinal disorders	9 Participants
Number of Participants Experiencing Adverse Events (AEs) General disorders and administration site conditions	10 Participants
Number of Participants Experiencing Adverse Events (AEs) Investigations	37 Participants
Number of Participants Experiencing Adverse Events (AEs) Musculoskeletal and connective tissue disorders	1 Participants
Number of Participants Experiencing Adverse Events (AEs) Nervous system disorders	5 Participants
Number of Participants Experiencing Adverse Events (AEs) Renal and urinary disorders	1 Participants
Number of Participants Experiencing Adverse Events (AEs) Respiratory, thoracic and mediastinal disorders	14 Participants
Number of Participants Experiencing Adverse Events (AEs) Skin and subcutaneous tissue disorders	2 Participants
Number of Participants Experiencing Adverse Events (AEs) Vascular disorders	7 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 2

Each subject is only counted once per toxicity grade for the worst severity recorded. ECG assessments with toxicity grading and associated threshold include QTc Interval \>=450 msec, PR Interval \>=200 msec and \>25% change from baseline, and QRS Interval \>=120 msec and \>25% change from baseline.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=39 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings QTc Interval	1 Participants
Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings PR Interval	0 Participants
Number of Participants With Prolonged QTc, PR, or QRS Intervals in Electrocardiogram (ECG) Readings QRS Duration	0 Participants

PRIMARY outcome

Timeframe: Day 2

Mean and standard deviation (SD) of the t1/2 (h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Terminal Elimination Half-life (t1/2) of ZTI-01	2.62 h Standard Deviation 0.36

PRIMARY outcome

Timeframe: Day 2

Mean and standard deviation (SD) of the lambdaz (/h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Terminal-phase Elimination Rate Constant (Lambdaz) of ZTI-01	0.2703 /h Standard Deviation 0.0391

PRIMARY outcome

Timeframe: Day 1 to Day 2

Mean and standard deviation (SD) of the Tmax (h) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 1 and Dose 3 using Phoenix WinNonlin Non-compartmental analysis. Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for the plasma samples collected during the study.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Time to Peak Concentration (Tmax) of ZTI-01 Tmax, after Dose 1	1.07 h Standard Deviation 0.06
Time to Peak Concentration (Tmax) of ZTI-01 Tmax, after Dose 3	1.06 h Standard Deviation 0.05

PRIMARY outcome

Timeframe: Day 2

Mean and standard deviation (SD) of the Vss (L) PK parameter were estimated from the ZTI-01 plasma concentration-time data after Dose 3 using Phoenix WinNonlin Non-compartmental analysis with the following Lambda Z Acceptance Criteria: rsq\_adjusted (adjusted r squared) \>= 0.90, span \>= 1.5 half-lives, and includes at least 3 timepoints after time to maximum concentration (tmax). Plasma concentrations were measured by a validated LC-MS/MS bioanalytical assay for plasma samples collected during the study. If the amount extrapolated portion of AUC 0-inf was \>20%, the estimated Vss value was excluded from statistical summaries of the parameter estimates.

Outcome measures

Outcome measures
Measure	ZTI-01 All Participants n=30 Participants ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Volume of Distribution at Steady State (Vss) of ZTI-01	18.08 L Standard Deviation 2.80

Adverse Events

ZTI-01 All Participants

Serious events: 0 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	ZTI-01 All Participants n=39 participants at risk ZTI-01 administered as 1-hour IV infusions (+10 minute window) given every 8 hours for three doses. Each dose comprised of 200 mL (6 g) of fosfomycin disodium.
Cardiac disorders Bradycardia	17.9% 7/39 • Number of events 8 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Cardiac disorders Sinus tachycardia	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Cardiac disorders Tachycardia	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Gastrointestinal disorders Abdominal pain	7.7% 3/39 • Number of events 3 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Gastrointestinal disorders Nausea	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Gastrointestinal disorders Vomiting	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
General disorders Infusion site pain	7.7% 3/39 • Number of events 3 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
General disorders Vessel puncture site pain	5.1% 2/39 • Number of events 2 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood albumin decreased	7.7% 3/39 • Number of events 3 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood calcium decreased	41.0% 16/39 • Number of events 16 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood glucose increased	17.9% 7/39 • Number of events 7 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood magnesium decreased	74.4% 29/39 • Number of events 29 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood phosphorus decreased	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Blood potassium decreased	48.7% 19/39 • Number of events 19 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Haemoglobin decreased	10.3% 4/39 • Number of events 4 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Neutrophil count decreased	7.7% 3/39 • Number of events 3 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Protein urine present	5.1% 2/39 • Number of events 2 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations Prothrombin time prolonged	15.4% 6/39 • Number of events 6 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations White blood cell count decreased	5.1% 2/39 • Number of events 2 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Investigations White blood cell count increased	12.8% 5/39 • Number of events 5 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Nervous system disorders Headache	12.8% 5/39 • Number of events 5 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	12.8% 5/39 • Number of events 5 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Respiratory, thoracic and mediastinal disorders Tachypnoea	20.5% 8/39 • Number of events 8 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Vascular disorders Diastolic hypertension	5.1% 2/39 • Number of events 2 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Vascular disorders Hypotension	5.1% 2/39 • Number of events 2 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.
Vascular disorders Systolic hypertension	7.7% 3/39 • Number of events 3 • The period of observation for AE reporting began on Day 1 at the time of first dosing and continued through the final visit, a follow-up call on Day 3.

Additional Information

Emmanuel Walter, MD, MPH

Duke Vaccine and Trials Unit

Phone: 919-620-5346

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60