Clinical trial NCT03709914: PK Study of Single-Dose ZTI-01 in Children (<12 Years of Age)
Official title: Phase 1, Non-comparative, Open-Label Study of Pharmacokinetics and Safety of a Single-Dose of ZTI-01 (Fosfomycin for Injection) in Pediatric Subjects (<12 Years of Age)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Pediatric ALL
Keywords: Pediatric PK
Lead sponsor: Nabriva Therapeutics AG
Sponsor class: INDUSTRY
First posted: 2018-10-17
Enrollment: 21
Sex: ALL
Maximum age (years): 11
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: multiple-center, non-comparative, open-label, PK study
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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

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

Primary outcomes:
measure: Area under plasma concentration-time curve (AUC) after a single dose of ZTI-01
timeFrame: From time end of 1-hour infusion on Day 1, up to 8-12 hours post infusion on Day 1
Secondary outcomes:
measure: Safety: Treatment Emergent Adverse Events (TEAE)
timeFrame: Baseline (start of dosing) through end of study follow-up (Day 2)
measure: Maximum concentration (Cmax) after a single dose of ZTI-01
timeFrame: From time end of 1-hour infusion on Day 1, up to 8-12 hours post infusion on Day 1
Other outcomes:
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital
state: California
city: Louisville
country: United States
facility: Kosair Charities Pediatric Clinical Research Unit
state: Kentucky
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Albuquerque
country: United States
facility: University of New Mexico Hospital
state: New Mexico
Study officials:
affiliation: Rady Children's Hospital / Department of Pediatrics, University of California, School of Medicine
name: John S Bradley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Nabriva Therapeutics
name: Jennifer Schranz, MD
role: STUDY_CHAIR
References: