Safety and pharmacokinetics of ceftolozane/tazobactam in pediatric participants with nosocomial pneumonia

Phase 1

Conditions: osocomial pneumonia
MedDRA version: 21.1Level: LLTClassification code 10052596Term: Nosocomial pneumoniaSystem Organ Class: 100000004862
Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Registration Number: EUCTR2018-004704-19-GR

Lead Sponsor: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co.,Inc

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 40

Inclusion Criteria

1. Has a diagnosis of proven or suspected NP (including HABP or VABP), as determined by the investigator.
Note: The diagnosis of NP does not require a pathogen to be isolated from a diagnostic test.
2. Is hospitalized and anticipated to receive a minimum of 8 days of concomitant standard-of-care antibiotic therapy for proven or suspected NP. The concomitant standard-of-care antibiotic therapy can have coverage for either gram positive and/or gram-negative respiratory pathogen(s).
Note: Concomitant SOC antibiotics may be stopped before the 8-day minimum at the discretion of the investigator. Participants who discontinue or complete concomitant SOC antibiotic therapy in less than 8 days may also discontinue ceftolozane/tazobactam prior to the minimum duration of 8 days at the investigator’s discretion. However, participants are strongly encouraged to receive a minimum of 8 days of ceftolozane/tazobactam.
Demographics:
3. Is male or female (not pregnant or nursing) from birth (defined as >32 weeks gestational age and =7 days postnatal) to <18 years of age inclusive, at the time of signing the informed consent/assent.
Male Participants:
Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Male participants are eligible to participate if they agree to the following during the intervention period and for at least 30 days after the last dose of study intervention:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause ) as detailed below:
- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration.
Female Participants:
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least [30 days] after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within [48 hours] before the first dose of study intervention.
• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent/Assent:
4. The participant (or legally acceptable representative if applicable) provides written informed consent/as

Exclusion Criteria

Medical Conditions:
1. Has a documented history of any moderate or severe hypersensitivity (or allergic) reaction to any ß-lactam antibacterial.
Note: A history of a rash while on a ß-lactam antibiotic does not automatically exclude a participant (eg, a participant with history of a mild rash followed by uneventful re-exposure may be considered for enrollment).
2. For Groups 1-4, has moderate to severe impairment of renal function, defined as an estimated (CrCL) <50 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
For Group 5, has CrCL <20 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration.
Prior/Concomitant Therapy
3. Is receiving or is anticipated to receive piperacillin/tazobactam while receiving ceftolozane/tazobactam or has received piperacillin/tazobactam within 24 hours prior to the first dose of ceftolozane/tazobactam.
Prior/Concurrent Clinical Study Experience
4. Participation in any clinical study of a therapeutic investigational product within 30 days prior to the first dose of ceftolozane/tazobactam.
5.Previous participation in any study of ceftolozane or ceftolozane/tazobactam.
Diagnostic Assessments:
Not applicable.
Other Exclusions:
6. Has one or more of the following laboratory abnormalities in a specimen obtained at screening:
• Absolute neutrophil count (ANC) <1000/mm3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =3 × the upper limit of normal (ULN)
• Total bilirubin =2 × the ULN (if 7 to =28 days of age and breastfeeding, total bilirubin >10 mg/dL OR =2 × ULN).
7. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the participant or the quality of study data.
8. Has any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure or septic shock.
9. Has active immunosuppression, including any of the following:
•human immunodeficiency virus (HIV) infection, with a known CD4 percentage of <15% in pediatric participants =5 years of age, or CD4 count of <200 cells/mm3 in pediatric participants >5 years of age
•active hematological malignancy
•recipient of solid organ or bone marrow transplants
•currently on immunosuppressive therapy, including cancer chemotherapy currently on medications for prevention of transplant rejection
•chronic administration of systemic corticosteroids (defined as the systemic equivalent of =2 mg/kg total daily dose of prednisone for participants =20 kg, or >40 mg of prednisone per day for participants >20 kg, administered continuously for more than 14 days in the 30 days prior to the first dose of
ceftolozane/tazobactam)
10. Is or has an immediate family member (eg, parent/legal guardian or sibling) who is investigational site or Sponsor staff directly involved with this study.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the safety and tolerability of ceftolozane/tazobactam for all participants;Secondary Objective: To evaluate the pharmacokinetics (PK) of multiple doses of ceftolozane/tazobactam for each age group and/or dose level<br><br>;Primary end point(s): 1.Percentage of participants with any adverse events (AEs)<br>2.Percentage of participants with any serious AEs (SAEs)<br>3.Percentage of participants with any drug-related AEs<br>4.Percentage of participants with any drug-related SAEs<br>5.Percentage of participants with AEs leading to discontinuation of study intervention<br>;Timepoint(s) of evaluation of this end point: 1.Up to Day 31<br>2.Up to Day 31<br>3.Up to Day 31<br>4.Up to Day 31<br>5.Up to Day 14<br>

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1.Plasma concentrations of ceftolozane<br>2.Plasma concentrations of tazobactam<br>3.Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma ceftolozane<br>4.Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma tazobactam<br>5.Maximum observed concentration during a dosage interval (Cmax) of plasma ceftolozane<br>6.Maximum observed concentration during a dosage interval (Cmax) of plasma tazobactam<br>7.Elimination half-life (t1/2) of plasma ceftolozane<br>8.Elimination half-life (t1/2) of plasma tazobactam<br>9.Volume of distribution (Vd) of plasma ceftolozane<br>10.Volume of distribution (Vd) of plasma tazobactam<br>11.Clearance (CL) of plasma ceftolozane<br>12.Clearance (CL) of plasma tazobactam<br>;Timepoint(s) of evaluation of this end point: Day 3: 1, between 4-5, and between 7-8 hours after start of infusion<br>

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