Complicated Intra-Abdominal Infection
Conditions
Brief summary
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.
Interventions
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.
DRUGMetronidazole
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.
DRUGMeropenem
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for between 5 to 14 days.
DRUGPlacebo for Metronidazole
Placebo for metronidazole administered IV every 8 hours for between 5 to 14 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Days to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing ≥1 Adverse Events (AEs) | Up to approximately 75 days | 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. |
| Number of Participants Who Discontinued Study Therapy Due to AE(s) | Up to approximately 18 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Clinical Response of Cure at the End of Treatment (EOT) Visit | Up to approximately 27 days | 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. |
| Percentage of Participants With a Clinical Response of Cure at the Test of Cure (TOC) Visit | Up to approximately 39 days | 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. |
| Percentage of Participants With Microbiological Eradication at the EOT Visit | Up to approximately 27 days | 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. |
| Percentage of Participants With Microbiological Eradication at the TOC Visit | Up to approximately 39 days | 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. |
Countries
Brazil, Hungary, Lithuania, Malaysia, Mexico, Romania, Russia, South Africa, Spain, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Paediatric participants were enrolled from 27 sites in 11 countries.
Participants by arm
| Arm | Count |
|---|---|
| Ceftolozane/Tazobactam + Metronidazole 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. | 71 |
| Meropenem Meropenem 20 mg/kg (maximum 1 g/dose) plus placebo for metronidazole administered IV every 8 hours for 5 to 14 days. | 23 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did Not Meet Criteria after Randomization | 0 | 1 |
| Overall Study | Dispensing Error | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Site Randomized Participant in Error | 0 | 1 |
| Overall Study | Withdrawal by Parent/Guardian | 1 | 0 |
Baseline characteristics
| Characteristic | Meropenem | Total | Ceftolozane/Tazobactam + Metronidazole |
|---|---|---|---|
| Age, Continuous | 8.6 Years STANDARD_DEVIATION 3.6 | 8.7 Years STANDARD_DEVIATION 4.2 | 8.7 Years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 25 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 66 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 81 Participants | 61 Participants |
| Sex: Female, Male Female | 15 Participants | 38 Participants | 23 Participants |
| Sex: Female, Male Male | 8 Participants | 56 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 23 |
| other Total, other adverse events | 46 / 70 | 10 / 21 |
| serious Total, serious adverse events | 8 / 70 | 0 / 21 |
Outcome results
Primary
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.
Time frame: Up to approximately 75 days
Population: All randomized participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Number of Participants Experiencing ≥1 Adverse Events (AEs) | 56 Participants |
| Meropenem | Number of Participants Experiencing ≥1 Adverse Events (AEs) | 13 Participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-2.6, 41.1]
Primary
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.
Time frame: Up to approximately 18 days
Population: All randomized participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Number of Participants Who Discontinued Study Therapy Due to AE(s) | 2 Participants |
| Meropenem | Number of Participants Who Discontinued Study Therapy Due to AE(s) | 0 Participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-12.9, 9.9]
Secondary
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.
Time frame: Up to approximately 27 days
Population: All randomized participants who received any amount of study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Percentage of Participants With a Clinical Response of Cure at the End of Treatment (EOT) Visit | 80.0 Percentage of participants |
| Meropenem | Percentage of Participants With a Clinical Response of Cure at the End of Treatment (EOT) Visit | 95.2 Percentage of participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-26.67, 4.93]
Secondary
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.
Time frame: Up to approximately 39 days
Population: All randomized participants who received any amount of study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Percentage of Participants With a Clinical Response of Cure at the Test of Cure (TOC) Visit | 80.0 Percentage of participants |
| Meropenem | Percentage of Participants With a Clinical Response of Cure at the Test of Cure (TOC) Visit | 100.0 Percentage of participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-30.18, -2.89]
Secondary
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.
Time frame: Up to approximately 27 days
Population: All randomized participants who received any amount of study treatment and had at least 1 pathogen identified from the baseline intra-abdominal culture, regardless of susceptibility to study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Percentage of Participants With Microbiological Eradication at the EOT Visit | 84.1 Percentage of participants |
| Meropenem | Percentage of Participants With Microbiological Eradication at the EOT Visit | 94.7 Percentage of participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-23.66, 9.61]
Secondary
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.
Time frame: Up to approximately 39 days
Population: All randomized participants who received any amount of study treatment and had at least 1 pathogen identified from the baseline intra-abdominal culture, regardless of susceptibility to study treatment. Participants were included in the IV study treatment group to which they were randomized, irrespective of what treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam + Metronidazole | Percentage of Participants With Microbiological Eradication at the TOC Visit | 84.1 Percentage of participants |
| Meropenem | Percentage of Participants With Microbiological Eradication at the TOC Visit | 100 Percentage of participants |
Comparison: Difference in Percentage (C/T+MTZ minus MERO)95% CI: [-27.59, 1.39]