Proven or Suspected Gram-negative Bacterial InfectionPhase 1NCT02266706

Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)

A Phase 1 study testing Ceftolozane/Tazobactam 1000/500 mg, Ceftolozane/Tazobactam 30/15 mg/kg and Ceftolozane/Tazobactam 20/10 mg/kg in people with Proven or Suspected Gram-negative Bacterial Infection and Peri-operative Prophylaxis, run by Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA).

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 7 days to 17 years
Conditions the study is for: Proven or Suspected Gram-negative Bacterial Infection, Peri-operative Prophylaxis
What is being tested?: Ceftolozane/Tazobactam 1000/500 mg, Ceftolozane/Tazobactam 30/15 mg/kg and Ceftolozane/Tazobactam 20/10 mg/kg
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 43 participants
Where: No sites listed yet
Study dates: 17 Sep 2014to 15 Jun 2017
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 7 days to 17 years
All sexes
No healthy volunteers
Child

Who may be able to join

Males or non-pregnant females from birth to <18 years of age
Receiving standard of care antibiotic therapy for suspected or diagnosed Gram-negative infection or for peri-operative prophylaxis
Groups 1-4: Calculated creatinine clearance rate (CLCR) ≥ 80 ml/min/1.73m2 at baseline
Group 5: CLCR ≥ 50 ml/min/1.73m2 at baseline
Group 6: CLCR ≥ 20 ml/min/1.73m2 at baseline

Who cannot join

Known allergy/hypersensitivity to any β-lactam antibacterial
History of clinically significant renal, hepatic, or hemodynamic instability
Planned use of cardiopulmonary bypass or dialysis
Planned blood transfusion within 24 hours of study drug administration
Clinically significant abnormal laboratory test results not related to the underlying infection
Receipt of piperacillin/tazobactam within 24 hours of study drug administration
Likely to be at risk of hemodynamic disturbance following collection of the required PK blood samples

About this study

Official title: A Phase 1, Non-comparative, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/Tazobactam in Pediatric Patients Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis

The purpose of this study was to assess the pharmacokinetics, safety, and tolerability of a single intravenous dose of ceftolozane/tazobactam (MK-7625A) in pediatric participants. In each of the 6 age cohorts, an interim analysis of pharmacokinetics (PK) and safety data was conducted after approximately 3 participants had received the initially proposed dose. The interim analysis was to determine whether the initial dose was appropriate based on pre-defined criteria. If data from the interim analysis demonstrated that the initially proposed dose met the above criteria, enrollment was to continue with the same dose administered to approximately 3 additional participants of the same age range. However, if the interim analysis demonstrated that a new optimized dose was required, the new dose was to be administered to approximately 3 additional participants of the same age range.

Conditions: Proven or Suspected Gram-negative Bacterial Infection, Peri-operative Prophylaxis
Being tested: Ceftolozane/Tazobactam 1000/500 mg, Ceftolozane/Tazobactam 30/15 mg/kg, Ceftolozane/Tazobactam 20/10 mg/kg, Ceftolozane/Tazobactam 18/9 mg/kg, Ceftolozane/Tazobactam 12/6 mg/kg

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Ceftolozane/Tazobactam 1000/500 mgDrug
A fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.
Ceftolozane/Tazobactam 30/15 mg/kgDrug
A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.
Ceftolozane/Tazobactam 20/10 mg/kgDrug
A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.
Ceftolozane/Tazobactam 18/9 mg/kgDrug
A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.
Ceftolozane/Tazobactam 12/6 mg/kgDrug
A FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute infusion.

Study groups in NCT02266706
Study group	Role	What they receive
Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC	Experimental	Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1. Receives: Drug: Ceftolozane/Tazobactam 1000/500 mg
Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg	Experimental	Participants ≥7 to <12 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Receives: Drug: Ceftolozane/Tazobactam 18/9 mg/kg
Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg	Experimental	Participants ≥2 to <7 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg. Receives: Drug: Ceftolozane/Tazobactam 30/15 mg/kg; Drug: Ceftolozane/Tazobactam 18/9 mg/kg
Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg	Experimental	Participants ≥3 months to <2 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg. Receives: Drug: Ceftolozane/Tazobactam 30/15 mg/kg; Drug: Ceftolozane/Tazobactam 18/9 mg/kg
Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg	Experimental	Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 mg/kg was changed to TOL/TAZ 20/10. Receives: Drug: Ceftolozane/Tazobactam 20/10 mg/kg
Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg	Experimental	Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance =20 - 49 mL/min/1.73 m^2 received a single dose of TOL/TAZ 12/6 mg/kg as a 60-minute infusion on Day 1; participants with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 was changed to TOL/TAZ 20/10 mg/kg for participants with creatinine clearance ≥50 mL/min/1.73 m^2. Receives: Drug: Ceftolozane/Tazobactam 20/10 mg/kg; Drug: Ceftolozane/Tazobactam 12/6 mg/kg

What is being measured

The primary outcome is the main question the study is designed to answer.

Maximum Plasma Concentration (Cmax) of Ceftolozane
Blood was collected for the determination of Cmax of ceftolozane. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Maximum Plasma Concentration (Cmax) of Tazobactam
Blood was collected for the determination of Cmax of tazobactam. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Time to Maximum Plasma Concentration (Tmax) of Ceftolozane
Blood was collected for the determination of Tmax of ceftolozane.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Time to Maximum Plasma Concentration (Tmax) of Tazobactam
Blood was collected for the determination of Tmax of tazobactam.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane
Blood was collected for the determination of Clast of ceftolozane. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam
Blood was collected for the determination of Clast of tazobactam. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Time of Last Sampling Point (Tlast) of Ceftolozane
Blood was collected for the determination of Tlast of ceftolozane.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Time of Last Sampling Point (Tlast) of Tazobactam
Blood was collected for the determination of Tlast of tazobactam.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane
Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of ceftolozane. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam
Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of tazobactam. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane
Blood was collected for the determination of AUC from time zero extrapolated to infinity of ceftolozane. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam
Blood was collected for the determination of AUC from time zero extrapolated to infinity of tazobactam. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Elimination Half-life (t1/2) of Ceftolozane
Blood was collected for the determination of t1/2 of ceftolozane. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Elimination Half-life (t1/2) of Tazobactam
Blood was collected for the determination of t1/2 of tazobactam. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Volume of Distribution at Steady State (Vss) of Ceftolozane
Blood was collected for the determination of Vss of ceftolozane. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Volume of Distribution at Steady State (Vss) of Tazobactam
Blood was collected for the determination of Vss of tazobactam. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Plasma Clearance (CL) of Ceftolozane
Blood was collected for the determination of CL of ceftolozane. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Plasma Clearance (CL) of Tazobactam
Blood was collected for the determination of CL of tazobactam. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Measured: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.

Secondary outcomes (2)

Number of Participants With One or More Adverse Events
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Measured: Up to Day 10
Number of Participants Who Discontinued the Study Due to an Adverse Event
An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
Measured: Up to Day 10

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

17 Sep 201415 Jun 2017

First posted17 Oct 2014 (estimated)
Study start17 Sep 2014
Primary completion8 Jun 2017
Study completion15 Jun 2017

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Proven or Suspected Gram-negative Bacterial InfectionStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Enrolment: 43 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02266706
Sponsor's protocol ID: 7625A-010
Other IDs: CXA-PEDS-13-08, 2014-003485-24, MK-7625A-010, 2014
Status last verified: Aug 2019
First submitted: 22 Sep 2014
Last updated: 11 Sep 2019
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Publications

Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, Yang S, Yu B, Johnson MG, Rhee EG. Pharmacokinetics and Safety of Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected Gram-Negative Infection. Pediatr Infect Dis J. 2018 Nov;37(11):1130-1136. doi: 10.1097/INF.0000000000002170.
PubMed 30153232

Study at a glance

From the registry record, last updated by the sponsor on 11 Sep 2019. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1, Non-comparative, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/Tazobactam in Pediatric Patients Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis
ClinicalTrials.gov ID: NCT02266706
Acronym / sponsor ID: 7625A-010
Conditions: Proven or Suspected Gram-negative Bacterial Infection, Peri-operative Prophylaxis
Phase: Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 43 participants (actual)
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)Industry (pharma, biotech, devices)
Study start: 17 Sep 2014 (actual)
Primary completion: 8 Jun 2017 (actual)
Study completion: 15 Jun 2017 (actual)
First posted: 17 Oct 2014 (estimated)
Results: Posted 15 Feb 2019

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: None (open label)
Number of arms: 6

Arm	Type	Receives
Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC	Experimental	Drug: Ceftolozane/Tazobactam 1000/500 mgParticipants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.
Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg	Experimental	Drug: Ceftolozane/Tazobactam 18/9 mg/kgParticipants ≥7 to <12 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1.
Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg	Experimental	Drug: Ceftolozane/Tazobactam 30/15 mg/kg, Drug: Ceftolozane/Tazobactam 18/9 mg/kgParticipants ≥2 to <7 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg.
Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg	Experimental	Drug: Ceftolozane/Tazobactam 30/15 mg/kg, Drug: Ceftolozane/Tazobactam 18/9 mg/kgParticipants ≥3 months to <2 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg.
Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg	Experimental	Drug: Ceftolozane/Tazobactam 20/10 mg/kgParticipants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 mg/kg was changed to TOL/TAZ 20/10.
Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg	Experimental	Drug: Ceftolozane/Tazobactam 20/10 mg/kg, Drug: Ceftolozane/Tazobactam 12/6 mg/kgParticipants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance =20 - 49 mL/min/1.73 m^2 received a single dose of TOL/TAZ 12/6 mg/kg as a 60-minute infusion on Day 1; participants with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 was changed to TOL/TAZ 20/10 mg/kg for participants with creatinine clearance ≥50 mL/min/1.73 m^2.

Who may qualify

Ages: 7 days to 17 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (5 listed)

Males or non-pregnant females from birth to <18 years of age
Receiving standard of care antibiotic therapy for suspected or diagnosed Gram-negative infection or for peri-operative prophylaxis
Groups 1-4: Calculated creatinine clearance rate (CLCR) ≥ 80 ml/min/1.73m2 at baseline
Group 5: CLCR ≥ 50 ml/min/1.73m2 at baseline
Group 6: CLCR ≥ 20 ml/min/1.73m2 at baseline

Key exclusion criteria (7 listed)

Known allergy/hypersensitivity to any β-lactam antibacterial
History of clinically significant renal, hepatic, or hemodynamic instability
Planned use of cardiopulmonary bypass or dialysis
Planned blood transfusion within 24 hours of study drug administration
Clinically significant abnormal laboratory test results not related to the underlying infection

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Ceftolozane/Tazobactam 1000/500 mgA fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.	Drug	Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
Ceftolozane/Tazobactam 30/15 mg/kgA FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.	Drug	Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg, Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg
Ceftolozane/Tazobactam 20/10 mg/kgA FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.	Drug	Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg, Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg
Ceftolozane/Tazobactam 18/9 mg/kgA FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.	Drug	Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg, Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg, Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg
Ceftolozane/Tazobactam 12/6 mg/kgA FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute infusion.	Drug	Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg

Primary outcome

Maximum Plasma Concentration (Cmax) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Cmax of ceftolozane. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Maximum Plasma Concentration (Cmax) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Cmax of tazobactam. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Time to Maximum Plasma Concentration (Tmax) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Tmax of ceftolozane.
Time to Maximum Plasma Concentration (Tmax) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Tmax of tazobactam.
Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Clast of ceftolozane. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Clast of tazobactam. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Time of Last Sampling Point (Tlast) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Tlast of ceftolozane.
Time of Last Sampling Point (Tlast) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Tlast of tazobactam.
Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of ceftolozane. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of tazobactam. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of AUC from time zero extrapolated to infinity of ceftolozane. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of AUC from time zero extrapolated to infinity of tazobactam. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
Elimination Half-life (t1/2) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of t1/2 of ceftolozane. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Elimination Half-life (t1/2) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of t1/2 of tazobactam. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Volume of Distribution at Steady State (Vss) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Vss of ceftolozane. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Volume of Distribution at Steady State (Vss) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of Vss of tazobactam. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Plasma Clearance (CL) of Ceftolozane
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of CL of ceftolozane. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
Plasma Clearance (CL) of Tazobactam
Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Blood was collected for the determination of CL of tazobactam. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.

2 secondary outcomes

Number of Participants With One or More Adverse Events
Time frame: Up to Day 10
Number of Participants Who Discontinued the Study Due to an Adverse Event
Time frame: Up to Day 10

Results and safety

Results posted to the registry on 15 Feb 2019, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC	6	6
Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg	7	6
Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg	4	3
Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg	4	3
Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg	1	1
Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg	7	5
Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg	8	7
Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg	2	2
Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg	4	4

Primary outcome: Maximum Plasma Concentration (Cmax) of Ceftolozane

Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.. Geometric least squares mean (95% Confidence Interval). Unit: μg/mL

Measure	Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC n = 5	Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg n = 6	Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg n = 3	Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg n = 3	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg n = 1	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg n = 5	Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 6	Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg n = 2	Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 3
Value	63.5 (50.2 to 80.4)	56.2 (45.3 to 69.7)	51.4 (37.9 to 69.7)	96.6 (71.2 to 131)	50.5 (29.8 to 85.6)	91.3 (72.1 to 116)	45.0 (36.3 to 55.9)	34.9 (24.1 to 50.7)	45.2 (33.3 to 61.2)

Population analysed: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.

Primary outcome: Maximum Plasma Concentration (Cmax) of Tazobactam

Measure	Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC n = 5	Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg n = 6	Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg n = 3	Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg n = 3	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg n = 1	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg n = 5	Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 6	Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg n = 2	Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 3
Value	14.0 (8.59 to 22.9)	9.25 (5.92 to 14.5)	15.7 (8.36 to 29.6)	24.8 (13.2 to 46.6)	11.6 (3.88 to 34.7)	22.4 (13.8 to 36.6)	11.7 (7.48 to 18.3)	6.87 (3.17 to 14.9)	12.1 (6.43 to 22.7)

Primary outcome: Time to Maximum Plasma Concentration (Tmax) of Ceftolozane

Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.. Median (Full Range). Unit: Hours

Measure	Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC n = 5	Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg n = 6	Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg n = 3	Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg n = 3	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg n = 1	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg n = 5	Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 6	Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg n = 2	Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 3
Value	1.02 (1.00 to 1.10)	1.07 (0.58 to 1.13)	1.02 (1.02 to 1.03)	1.03 (1.03 to 1.12)	1.00 (1.00 to 1.00)	1.05 (0.58 to 1.95)	1.08 (0.95 to 1.90)	1.80 (1.03 to 2.57)	1.07 (1.07 to 1.18)

Primary outcome: Time to Maximum Plasma Concentration (Tmax) of Tazobactam

Time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.. Median (Full Range). Unit: Hours

Measure	Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC n = 5	Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg n = 6	Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg n = 3	Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg n = 3	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg n = 1	Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg n = 5	Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 6	Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg n = 2	Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg n = 3
Value	1.00 (0.50 to 1.10)	1.07 (0.58 to 1.13)	1.02 (1.02 to 1.03)	1.03 (1.03 to 1.12)	1.00 (1.00 to 1.00)	1.05 (0.58 to 1.95)	1.08 (0.95 to 1.33)	3.89 (1.03 to 6.75)	1.07 (1.07 to 1.18)

2 secondary outcomes are reported in the full results.

Adverse events

Time frame: Up to Day 10. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC	1 of 6 (16.7%)	2 of 6 (33.3%)	0 of 6
Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg	1 of 6 (16.7%)	0 of 6 (0%)	0 of 6
Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg	0 of 3 (0%)	1 of 3 (33.3%)	0 of 3
Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg	0 of 3 (0%)	1 of 3 (33.3%)	0 of 3
Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg	0 of 1 (0%)	1 of 1 (100%)	0 of 1
Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg	1 of 5 (20%)	1 of 5 (20%)	0 of 5
Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg	0 of 7 (0%)	1 of 7 (14.3%)	0 of 7
Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg	0 of 2 (0%)	2 of 2 (100%)	0 of 2
Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg	0 of 4 (0%)	0 of 4 (0%)	0 of 4

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 11 Sep 2019.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 30153232Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, Yang S, Yu B, Johnson MG, Rhee EG. Pharmacokinetics and Safety of Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected Gram-Negative Infection. Pediatr Infect Dis J. 2018 Nov;37(11):1130-1136. doi: 10.1097/INF.0000000000002170.
Individual participant dataSharing planned: Yes. http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Medical Director study director

Merck Sharp & Dohme LLC

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Sep 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Feb 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Plasma Concentration (Cmax) of Ceftolozane (time frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.). The study lists 18 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02266706, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Sep 2019.