MK-7625A Plus Metronidazole Versus Meropenem in Pediatric Participants With Complicated Intra-Abdominal Infection (cIAI) (MK-7625A-035)

Study Overview
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Brief Summary
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This study aims to evaluate the safety and tolerability of MK-7625A (ceftolozane/tazobactam) plus metronidazole, compared with that of meropenem in pediatric participants with cIAI.

Official Title
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A Phase 2, Randomized, Active Comparator-Controlled, Multicenter, Double-Blind Clinical Trial to Study the Safety and Efficacy of Ceftolozane/Tazobactam (MK-7625A) Plus Metronidazole Versus Meropenem in Pediatric Subjects With Complicated Intra-Abdominal Infection

Conditions
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Complicated Intra-Abdominal Infection

Intervention / Treatment
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* Drug: Ceftolozane/Tazobactam
* Drug: Metronidazole
* Drug: Meropenem
* Drug: Placebo for Metronidazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a legally acceptable representative who provides documented informed consent/assent for the trial. Aged from birth (defined as >32 weeks gestational age and ≥7 days postnatal) to <18 years of age. Require IV antibacterial therapy for the treatment of presumed or documented cIAI. Has an operative procedure for the current diagnosis and management of cIAI planned or completed within 24 hours of the first dose of an antibacterial drug. Note: Participants with a diagnosis of necrotizing enterocolitis are exempt and not required to have surgery planned or completed in order to be eligible. Has in compliance baseline intra-abdominal specimen collection. Is not of reproductive potential; but if of reproductive potential agrees to avoid becoming pregnant or impregnating a partner during screening, while receiving study treatment and for at least 30 days after the last dose of study treatment. Female of reproductive potential is not pregnant, and not planning to become pregnant within 30 days of the last day of treatment administration; and is nonlactating. Exclusion Criteria: Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to the first dose of study treatment in this current trial. Has previously participated in any trial of ceftolozane or ceftolozane/tazobactam or has enrolled previously in the current trial and been discontinued. Has a history of any moderate or severe hypersensitivity (e.g, anaphylaxis), allergic reaction, or other contraindication to any of the following: β-lactam antibiotics (e.g, penicillins, cephalosporins, and carbapenems), β-lactamase inhibitors (e.g, tazobactam, sulbactam, clavulanic acid, avibactam), or metronidazole. Has an IAI within the past 1 year prior to randomization known to be caused by a pathogen resistant to either IV study treatment. Has a concomitant infection at the time of randomization that requires non-study systemic antibacterial therapy in addition to IV study treatment or oral step-down therapy. Has received potentially therapeutic antibacterial therapy for a duration more than 24 hours during the 48 hours preceding the first dose of study treatment, unless is considered to be failing antibiotic therapy for cIAI. Has any of the following: a) intractable cIAI that the investigator anticipates would require more than 14 days of study treatment; b) abdominal wall abscess; c) small bowel obstruction; d) ischemic bowel disease without perforation; e) traumatic bowel perforation with surgery within 12 hours of perforation; f) perforation of gastroduodenal ulcers requiring surgery within 24 hours of perforation; g) suspected uncomplicated intra-abdominal infection (e.g, cholecystitis without rupture or extension beyond the gallbladder wall); h) acute suppurative cholangitis; i) infected necrotizing pancreatitis; j) pancreatic abscess. Has moderate or severe impairment of renal function. Has a seizure disorder or is anticipated to be treated with divalproex sodium or valproic acid during the course of study treatment. Is receiving, or is expected to receive, any prohibited medications. Has any rapidly progressing disease or immediately life-threatening illness, including acute hepatic failure, respiratory failure, or septic shock. Has an immunocompromising condition. Has a history of malignancy ≤5 years prior to signing informed consent. Is planning to receive suppressive/prophylactic antibiotics with gram-negative activity after completion of study treatment.

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftolozane/Tazobactam + Metronidazole<br>Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose), plus metronidazole 10 mg/kg (maximum 1.5 g/day) administered intravenously (IV) every 8 to 12 hours for 5 to 14 days. | Drug: Ceftolozane/Tazobactam<br>* Ceftolozane 20 mg/kg (maximum 1 g) and tazobactam 10 mg/kg (maximum 0.5 g/dose) administered IV every 8 hours for between 5 to 14 days.<br>* Other names: MK-7625A;Drug: Metronidazole<br>* Metronidazole 10 mg/kg (maximum 1.5 g/day) administered IV every 8 hours for between 5 to 14 days. Participants ≤ 28 days old, start with a loading dose of 15 mg/kg; then if ≤ 2 kg are dosed 7.5 mg/kg/ every 12 hours; or if > 2 kg are dosed 10 mg/kg every 8 hours.<br>|
| Active Comparator: Meropenem + Placebo for Metronidazole<br>Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for Metronidazole administered IV every 8 hours for 5 to 14 days. | Drug: Meropenem<br>* Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for between 5 to 14 days.<br>* Other names: MERREM;Drug: Placebo for Metronidazole<br>* Placebo for metronidazole administered IV every 8 hours for between 5 to 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing ≥1 Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced an AE is presented. | Up to approximately 75 days | 
| Number of Participants Who Discontinued Study Therapy Due to AE(s) | An AE was defined as any untoward medical occurrence in a participant administered study treatment and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 18 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Clinical Response of Cure at the End of Treatment (EOT) Visit | The percentage of participants who had a clinical outcome of cure at the time of the EOT visit is presented. The cure clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to pre-infection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures. | Up to approximately 27 days | 
| Percentage of Participants With a Clinical Response of Cure at the Test of Cure (TOC) Visit | The percentage of participants who had a clinical outcome of cure at the time of the TOC visit is presented. The cure clinical outcome was defined as complete resolution or marked improvement in signs and symptoms of the complicated intra-abdominal infection (cIAI) or return to pre-infection signs and symptoms such that no further antibiotic therapy (intravenous or oral) or surgical or drainage procedure is required for treatment of the cIAI. Participants who were missing clinical response data were considered treatment failures. | Up to approximately 39 days | 
| Percentage of Participants With Microbiological Eradication at the EOT Visit | The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the EOT visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used. | Up to approximately 27 days | 
| Percentage of Participants With Microbiological Eradication at the TOC Visit | The percentage of participants who achieved either eradication or presumed eradication of each baseline infecting pathogen by the time of the TOC visit is presented. Eradication was defined as absence of the baseline pathogen(s) in a postbaseline specimen appropriately obtained from the original site of infection. Presumed eradication was defined as absence of material to culture in a participant who is assessed as having partial improvement, or clinical cure. In the event of multiple baseline pathogens, the least favorable microbiological response from all possible baseline pathogens was used. | Up to approximately 39 days |