Single-Dose ZTI-01 for Pediatric Patients

(Pediatric_PK Trial)

Recruiting at 4 trial locations

Overseen By Steve Gelone

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Nabriva Therapeutics AG

Must be taking: Antibiotics

Must not be taking: Anticonvulsants, QT-prolonging drugs

Disqualifiers: HIV, Hepatitis B/C, Seizures, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 1 day

21 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a single dose of ZTI-01, an antibiotic, in children under 12 who need treatment for bacterial infections. The goal is to understand how their bodies process the drug compared to adults, which can help determine the right dose for children. Children already receiving antibiotics for a known or suspected infection or for surgery preparation might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you must be receiving standard antibiotics for a bacterial infection to participate.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that fosfomycin, the main ingredient in ZTI-01, is very safe for children and is well-tolerated even with long-term use. Studies have found that fosfomycin can be safely combined with many other intravenous drugs, allowing it to be administered alongside other treatments. Although data on high doses is limited, existing evidence supports its safety in children. Overall, current studies and its use in other conditions consider fosfomycin safe. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ZTI-01 because it offers a fresh approach to treating bacterial infections in children using the active ingredient fosfomycin. Unlike many standard antibiotics, fosfomycin works by uniquely targeting bacterial cell wall synthesis, which can be effective against resistant strains. Additionally, ZTI-01 is administered as a single intravenous dose, potentially simplifying treatment and improving compliance compared to multi-dose regimens. This combination of a novel action mechanism and simplified delivery makes ZTI-01 a promising candidate in the fight against pediatric bacterial infections.

What evidence suggests that ZTI-01 might be an effective treatment for bacterial infections in pediatric patients?

Research has shown that ZTI-01, also known as fosfomycin for injection, effectively treats serious infections in children, particularly those caused by bacteria resistant to other treatments. It has successfully treated complicated urinary tract infections and pneumonia in both adults and children. Studies have found that fosfomycin works well against tough bacteria often resistant to other antibiotics. Although fosfomycin is mainly used for urinary tract infections, researchers are exploring its use for other serious infections due to its effectiveness. Early findings suggest that fosfomycin could be a valuable option for treating severe infections in children, offering a new way to combat resistant germs. Participants in this trial will receive a single dose of ZTI-01, with different cohorts based on age to evaluate its safety and effectiveness in pediatric patients. ^{1 6 7 8 9}

Who Is on the Research Team?

John S Bradley, MD

Principal Investigator

Rady Children's Hospital / Department of Pediatrics, University of California, School of Medicine

Jennifer Schranz, MD

Principal Investigator

Nabriva Therapeutics

Are You a Good Fit for This Trial?

This trial is for children under 12 years old who are hospitalized and currently receiving antibiotics for a bacterial infection or as prevention around surgery. They must have normal organ function, not be at risk of pregnancy, and have proper intravascular access. Children with seizure disorders, significant lab abnormalities, known drug allergies, impaired kidney function, or certain viral infections cannot participate.

Inclusion Criteria

Has sufficient intravascular access to receive study drug through peripheral or central line

Signed consent/assent

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

Exclusion Criteria

I have not been in this trial or taken ZTI-01 or fosfomycin in the last 30 days.

I have surgery planned during the time my blood will be tested for fosfomycin levels.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive a single, weight-adjusted dose of ZTI-01 via continuous IV infusion or syringe pump over a 1-hour period

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and pharmacokinetics, including blood collection for fosfomycin concentration measurement and assessment of adverse events

1 day

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• ZTI-01

Trial Overview

The study tests how a single dose of ZTI-01 (an antibiotic) behaves in the bodies of children compared to adults. It's an open-label Phase 1 trial across multiple centers aiming to find the right pediatric dosage by scaling from an adult dose using weight-based calculations.

How Is the Trial Designed?

Group I: ZTI-01 Cohort 3c ≥ 6 to < 24 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group II: ZTI-01 Cohort 3b ≥ 3 to < 6 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group III: ZTI-01 Cohort 3a Birth to < 3 mos of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 75 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group IV: ZTI-01 Cohort 2 ≥ 2 to <6 years of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

Group V: ZTI-01 Cohort 1 ≥ 6 to <12 years of age Experimental Treatment 1 Intervention

ZTI-01 (fosfomycin IV) 100 mg/kg (single dose) Subjects weighing within the 3rd to \< 97th percentile for age

ZTI-01 is already approved in United States for the following indications:

Approved in United States as ZTI-01 for:

• Complicated urinary tract infections (cUTI)
• Acute pyelonephritis (AP)

Who Is Running the Clinical Trial?

Nabriva Therapeutics AG

Lead Sponsor

Trials

10

Recruited

2,100+

Published Research Related to This Trial

Invasive fungal infections (IFIs) are a significant health risk for immunocompromised children, highlighting the need for effective prevention and treatment strategies.

Current antifungal treatments for pediatric patients are limited due to a lack of approved agents, established dosages for different age groups, and insufficient postmarketing safety and efficacy data.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of antifungals in pediatric patients. Groll, AH.[2019]

Pediatric patients have different pharmacokinetic parameters compared to adults, which means they need individualized medication dosing rather than just smaller doses of adult medications.

The lack of specific dosing guidelines and appropriate pediatric dosage forms can lead to serious dosing errors and complications, highlighting the need for tailored dosing strategies to ensure safety and efficacy in young patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dosing considerations in the pediatric patient. Skaer, TL.[2013]

In a study involving 465 hospitalized adults with complicated urinary tract infections (cUTI) or acute pyelonephritis (AP), ZTI-01 (fosfomycin) demonstrated noninferiority to piperacillin-tazobactam, achieving a success rate of 64.7% compared to 54.5% for the comparator, indicating its effectiveness against serious Gram-negative infections.

ZTI-01 was well tolerated, with most side effects being mild and temporary, suggesting it is a safe treatment option for patients with cUTI and AP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fosfomycin for Injection (ZTI-01) Versus Piperacillin-tazobactam for the Treatment of Complicated Urinary Tract Infection Including Acute Pyelonephritis: ZEUS, A Phase 2/3 Randomized Trial. Kaye, KS., Rice, LB., Dane, AL., et al.[2020]

There has been limited progress in treating invasive fungal infections over the past 40 years, but recent advancements have improved our understanding of the safety and pharmacokinetics of antifungal agents, particularly in children.

Most pediatric antifungal treatment strategies are currently based on adult data due to a lack of studies in children, but ongoing research aims to develop specific dosing strategies that will better serve pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mycoses in pediatric patients. Steinbach, WJ., Walsh, TJ.[2006]

There is limited information on the pharmacokinetics and pharmacodynamics of antifungal drugs in children, leading to a reliance on adult studies for dosing and efficacy, despite the increasing reports of safety and potential effectiveness in pediatric patients.

Future research is essential to determine the optimal dosing of antifungal agents for children to ensure effective prevention of invasive fungal disease while minimizing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antifungal prophylaxis in pediatric patients undergoing therapy for cancer: drugs and dosing. Lehrnbecher, T.[2015]

Fosfomycin for injection demonstrated physical compatibility with 77% of the 95 intravenous drugs tested, indicating it can be safely co-administered with many other medications in clinical settings.

However, 22 drugs were found to be incompatible with fosfomycin in at least one of the two diluents tested (0.9% sodium chloride and 5% dextrose), highlighting the need for careful consideration when combining treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Physical compatibility of fosfomycin for injection with select i.v. drugs during simulated Y-site administration. Monogue, ML., Almarzoky Abuhussain, SS., Kuti, JL., et al.[2019]

Fosfomycin, particularly in its intravenous form ZTI-01, shows promise for treating infections caused by multidrug-resistant bacteria, with a focus on understanding its pharmacokinetic-pharmacodynamic (PK-PD) properties for effective dosing.

The study identified a critical PK-PD index that correlates with fosfomycin's efficacy against resistant E. coli, suggesting specific dosing regimens are necessary to achieve desired bacterial stasis and reductions in bacterial counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploration of the Pharmacokinetic-Pharmacodynamic Relationships for Fosfomycin Efficacy Using an In Vitro Infection Model. VanScoy, BD., McCauley, J., Ellis-Grosse, EJ., et al.[2018]

Fosfomycin, a bactericidal antibiotic that has been used since the 1970s, is being developed for intravenous use in the USA to combat drug-resistant bacteria, particularly for complicated urinary tract infections and acute pyelonephritis.

The review highlights the importance of introducing intravenous fosfomycin (ZTI-01) in the US market as a necessary option to address the growing challenge of antibiotic resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ZTI-01 (fosfomycin for injection) in the treatment of hospitalized patients with complicated urinary tract infections. Burgos, RM., Rodvold, KA.[2019]

Fosfomycin (ZTI-01) shows effective activity against drug-resistant bacteria, including ESBL-producing and carbapenem-resistant strains, in a murine thigh infection model, indicating its potential for treating serious infections.

The study identified that the pharmacokinetic/pharmacodynamic (PK/PD) index, specifically the AUC/MIC ratio, is crucial for determining the efficacy of fosfomycin, with optimal ratios linked to both bacterial stasis and survival in infected mice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In Vivo Pharmacokinetics and Pharmacodynamics of ZTI-01 (Fosfomycin for Injection) in the Neutropenic Murine Thigh Infection Model against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Lepak, AJ., Zhao, M., VanScoy, B., et al.[2020]

Isavuconazole, given as isavuconazonium sulfate, was found to be safe and well-tolerated in a phase 1 study involving 46 immunocompromised pediatric patients, with no significant safety concerns related to age, sex, race, or body mass index.

The pharmacokinetics of isavuconazole in pediatric patients showed that over 80% of those receiving intravenous and over 76% receiving oral doses achieved plasma drug levels within the target range established for adults, indicating effective dosing for treating invasive fungal infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients. Arrieta, AC., Neely, M., Day, JC., et al.[2022]

Citations

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Determining an appropriate fosfomycin (ZTI-01) dosing ...

For P. aeruginosa pneumonia, a dose of 6 g q8h is recommended, with an even higher dose of 8 g q8h necessary for pneumonia patients.

5.

pubmed.ncbi.nlm.nih.gov

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IV fosfomycin is an effective agent in treating severe pediatric infections caused by resistant microorganisms. Fosfomycin can be used in various indications.

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pdf.hres.ca

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Fosfomycin for injection

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Single-Dose ZTI-01 for Pediatric Patients (Pediatric_PK Trial)

Fosfomycin for injection demonstrated physical compatibility with 77% of the 95 intravenous drugs tested, indicating it can be safely co-administered with many ...

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The pharmacokinetics, safety, and tolerability of intravenous (i.v.) fosfomycin disodium (ZTI-01) and oral fosfomycin tromethamine were ...

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Summary of Product Characteristics

There are limited safety data in particular for doses in excess of 16 g/day. ... Paediatric population. The pharmacokinetics of fosfomycin in ...