PK Study of Single-Dose ZTI-01 in Children (<12 Years of Age)

Phase 1

Recruiting

• Conditions: Pediatric ALL
• Interventions: Drug: ZTI-01 100 mg/kg; Drug: ZTI-01 75 mg/kg

• Registration Number: NCT03709914
• Lead Sponsor: Nabriva Therapeutics AG

Brief Summary

Phase 1 study, a single dose of ZTI-01 given to pediatric subjects (under 12 years of age) who require antibiotic therapy to see what the body does to the drug (pharmacokinetics) and to compare if these effects are similar to those observed in adults at a 6g ZTI-01 dose. Study will help establish pediatric dosing in younger children by age cohort. This is a multiple-center, open-label, PK study of ZTI-01 (fosfomycin for injection) single dose scaled by allometric weight-modeling from an adult ZTI-01 dose of 6 grams. Eligible subjects must be receiving standard of care antibiotics for proven or suspected bacterial infection or for peri-operative prophylaxis surgery (in or out of hospital).

Detailed Description

Based on pre-dose weight on Day -1, subjects weighing within the 3rd to \< 97th percentile based on age - will receive a single, weight adjusted dose of ZTI-01 via continuous IV infusion or syringe pump over a 1- hour (+10 min) period. Pediatric subjects participating in this study will be assigned to one of three cohorts based on age:

Cohort 1: ≥ 6 years to \<12 years (n=6 PK evaluable subjects) Cohort 2: ≥ 2 years to \<6 years (n=6 PK evaluable subjects)

Cohort 3: Birth to \< 2 years (n=9 PK evaluable subjects), split into 3 subgroups:

(3a) Birth (defined as full term: 37 weeks of gestations or greater) to \< 3 mos, (3b) ≥ 3 mos to \< 6 mos, (3c) ≥ 6 mos to \< 24 months

Cohorts 1 and 2 will be enrolled first with safety and PK data evaluated before enrolling the youngest Cohort 3. Blood for fosfomycin concentration measurement will be collected throughout the study. Safety will be assessed by monitoring adverse and serious adverse events based on medical history, vital signs, ECG, laboratory assessment and physical examination.

Study Timeline

• Study Start: 2018-05-24
• Study First Submitted: 2018-10-10
• Study First Submitted QC: 2018-10-15
• Study First Posted: 2018-10-17
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-14
• Last Update Posted: 2023-09-15
• Primary Completion: 2025-12-31
• Study Completion: 2026-01-10

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 21

Inclusion Criteria

• Signed consent/assent
• Male or female subjects aged from Birth (defined as full term: 37 weeks of gestation or greater) but less than 12 years old
• Hospitalized, currently receiving antibacterial treatment for confirmed or suspected bacterial infection
• If of reproductive potential, agrees to avoid becoming pregnant or impregnating a partner from the time of consent through 24 hours after completion of study drug administration
• Has sufficient intravascular access to receive study drug through peripheral or central line

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Exclusion Criteria

• Has history of known allergy, hypersensitivity, or intolerance to oral or intravenous fosfomycin
• Screening serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN or total bilirubin >2x ULN
• Female is post onset of menarche and currently pregnant, or breast feeding, or has a positive serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test
• Impaired renal function at screening based on the Revised Schwartz Formula using actual body height
• Known infection with immunodeficiency virus (HIV), hepatitis C virus, or hepatitis B virus
• Other laboratory tests, obtained as standard of care, that are outside the normal limits, considered by the Investigator, to be clinically significant
• Have surgery scheduled during collection period of plasma for fosfomycin concentrations
• Weighs outside of the 3rd to less than <97th percentile based on age
• History of a seizure disorder requiring ongoing treatment with anticonvulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years
• Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days or 5 half-lives, or twice the duration of the biological effect of any drug (whichever is longer) of administration of the study drug
• Has enrolled previously in the current trial or has received ZTI-01 or fosfomycin (IV or oral) for any other reason within the last 30 days
• Is expected to survive less than 72 hours after completion of study drug administration
• Plans to use cardiopulmonary bypass, extracorporeal membrane oxygenation, hemodialysis, or peritoneal dialysis during the study
• Clinically significant abnormalities on the ECG; or have or be at risk for major cardiac events or dysfunction including QTc prolongation, clinically unstable cardiac disease, receipt within 24 hours before the start of study drug of a medication that is labelled to prolong the QT interval, and for breastfed infant subjects only - receipt by the subject's mother within 24 hours before the start of study drug of a medication that is labelled to prolong the QT interval
• Planned blood transfusion within 24 hours of study drug administration or expected before the end of the PK sampling, or has had significant blood loss (≥5% of total blood volume) within 4 weeks before the screening visit
• Any condition that, in the opinion of the PI, would compromise the safety of the subject or the quality of the data
• Subject or caregiver/parent is unable or unwilling to adhere to the study-specified procedures and restrictions

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
ZTI-01 Cohort 3b ≥ 3 to < 6 mos of age	ZTI-01 100 mg/kg	ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age
ZTI-01 Cohort 3c ≥ 6 to < 24 mos of age	ZTI-01 100 mg/kg	ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age
ZTI-01 Cohort 1 ≥ 6 to <12 years of age	ZTI-01 100 mg/kg	ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age
ZTI-01 Cohort 2 ≥ 2 to <6 years of age	ZTI-01 100 mg/kg	ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age
ZTI-01 Cohort 3a Birth to < 3 mos of age	ZTI-01 75 mg/kg	ZTI-01 (fosfomycin IV) 75 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Primary Outcome Measures

Name	Time	Method
Area under plasma concentration-time curve (AUC) after a single dose of ZTI-01	From time end of 1-hour infusion on Day 1, up to 8-12 hours post infusion on Day 1	By age cohort, determine the ZTI-01 pharmacokinetic area under the plasma concentration-time curve

Secondary Outcome Measures

Name	Time	Method
Safety: Treatment Emergent Adverse Events (TEAE)	Baseline (start of dosing) through end of study follow-up (Day 2)	Number and Incidence of TEAEs by age cohort
Maximum concentration (Cmax) after a single dose of ZTI-01	From time end of 1-hour infusion on Day 1, up to 8-12 hours post infusion on Day 1	By age cohort, determine the ZTI-01 pharmacokinetic maximum concentration (Cmax)

Trial Locations

Locations (5)

Rady Children's Hospital; 🇺🇸 San Diego, California, United States

University of New Mexico Hospital; 🇺🇸 Albuquerque, New Mexico, United States

Children's Hospital of Orange County; 🇺🇸 Orange, California, United States

Children's Hospital of Michigan; 🇺🇸 Detroit, Michigan, United States

Kosair Charities Pediatric Clinical Research Unit; 🇺🇸 Louisville, Kentucky, United States