Complicated Urinary Tract Infection, Pyelonephritis
Conditions
Brief summary
This study aims to evaluate the safety and tolerability of MK-7625A (ceftolozane/tazobactam) compared with that of meropenem in pediatric participants with cUTI, including pyelonephritis.
Interventions
12 to \<18 years of age: Ceftolozane 1 g/dose; Tazobactam 0.5 g/dose via a 60-minute (±10 minutes) IV infusion every 8 hours for 7-14 days. \<12 years of age: Ceftolozane 20 mg/kg with Tazobactam 10 mg/kg (not to exceed Ceftolozane 1 g and Tazobactam 0.5 g) via a 60-minute (±10 minutes) IV infusion every 8 hours for 7-14 days.
DRUGMeropenem
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for between 7 to 14 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
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. * Ages from birth (defined as \>32 weeks gestational age and ≥7 days postnatal) to \<18 years of age. * Requires IV antibacterial therapy for the treatment of cUTI. * Have a pretreatment baseline urine culture specimen obtained within 48 hours before the start of administration of the first dose of study treatment and preferably prior to administration of any potentially therapeutic antibiotics. * Has pyuria. * Has clinical signs and/or symptoms of cUTI at the Screening Visit. * 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 a history of a cUTI 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 nonstudy 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. * Has any of the following: a) intractable UTI or pyelonephritis infection at baseline that the Investigator anticipates would require more than 14 days of study treatment; b) confirmed fungal urinary tract infection at time of randomization; c) permanent indwelling bladder catheter or instrumentation including nephrostomy; d) current urinary catheter that is not scheduled to be removed before the end of all study treatment; e) complete, permanent obstruction of the urinary tract; f) suspected or confirmed perinephric or intrarenal abscess; g) documented ileal loop reflux; h) suspected or confirmed prostatitis, urethritis, or epididymitis; i) trauma to pelvis/urinary tract. * 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 With ≥1 Adverse Events (AEs) | Up to Day 88 | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
| Number of Participants Discontinuing Study Therapy Due to AE | Up to Day 15 | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Clinical Response of Cure at the Test of Cure Visit | Up to Test of Cure Visit (up to 35 days) | Clinical response of cure is complete resolution or marked improvement in signs and symptoms of the complicated urinary tract infection (cUTI) or return to pre-infection signs and symptoms, such that no further antibiotic therapy (IV or oral) is required for the treatment of the cUTI. The 95% confidence intervals (CIs) of each treatment are unstratified Wilson CIs. |
| Percentage of Participants With a Clinical Response of Cure at the End of Treatment Visit | Up to 48 hours after last oral dose (up to 19 days) | Clinical response of cure is complete resolution or marked improvement in signs and symptoms of the cUTI or return to pre-infection signs and symptoms, such that no further antibiotic therapy (IV or oral) is required for the treatment of the cUTI. The 95% CIs of each treatment are unstratified Wilson CIs. |
| Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the Test of Cure Visit | Up to Test of Cure Visit (up to 35 days) | Microbiological eradication of all baseline pathogens is defined as a postbaseline urine culture shows all uropathogens found at baseline at ≥10\^5 colony-forming units (CFU)/mL are reduced to \<10\^4 CFU/mL. The 95% CIs of each treatment are unstratified Wilson CIs. |
| Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the End of Treatment Visit | Up to 48 hours after last oral dose (up to 19 days) | Microbiological eradication of all baseline pathogens is defined as a postbaseline urine culture shows all uropathogens found at baseline at ≥10\^5 colony-forming units (CFU)/mL are reduced to \<10\^4 CFU/mL. The 95% CIs of each treatment are unstratified Wilson CIs. |
Countries
Greece, Hungary, Mexico, Poland, Romania, Russia, South Africa, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Males and females from birth (\>32 weeks gestational age and ≥7 days postnatal), to \<18 years of age with complicated urinary tract infection (cUTI), including pyelonephritis, were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Ceftolozane/Tazobactam Ceftolozane 20 mg/kg and tazobactam 10 mg/kg (maximum 1 g and 0.5 g/dose) administered intravenously (IV) every 8 hours for 7-14 days | 101 |
| Meropenem Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days | 33 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Temperature excursion | 1 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Meropenem | Total | Ceftolozane/Tazobactam |
|---|---|---|---|
| Age, Continuous | 5.5 Years STANDARD_DEVIATION 5.7 | 5.4 Years STANDARD_DEVIATION 5.4 | 5.3 Years STANDARD_DEVIATION 5.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 14 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 108 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 12 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 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 | 33 Participants | 133 Participants | 100 Participants |
| Sex: Female, Male Female | 20 Participants | 85 Participants | 65 Participants |
| Sex: Female, Male Male | 13 Participants | 49 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 101 | 0 / 33 |
| other Total, other adverse events | 25 / 100 | 10 / 33 |
| serious Total, serious adverse events | 3 / 100 | 2 / 33 |
Outcome results
Primary
Number of Participants Discontinuing Study Therapy Due to AE
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: Up to Day 15
Population: All randomized participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftolozane/Tazobactam | Number of Participants Discontinuing Study Therapy Due to AE | 1 Participants |
| Meropenem | Number of Participants Discontinuing Study Therapy Due to AE | 0 Participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-9.5, 5.5]
Primary
Number of Participants With ≥1 Adverse Events (AEs)
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol specified procedure, whether or not considered related to the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE.
Time frame: Up to Day 88
Population: All randomized participants who received any amount of study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ceftolozane/Tazobactam | Number of Participants With ≥1 Adverse Events (AEs) | 59 Participants |
| Meropenem | Number of Participants With ≥1 Adverse Events (AEs) | 20 Participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-19.7, 17.9]
Secondary
Percentage of Participants With a Clinical Response of Cure at the End of Treatment Visit
Clinical response of cure is complete resolution or marked improvement in signs and symptoms of the cUTI or return to pre-infection signs and symptoms, such that no further antibiotic therapy (IV or oral) is required for the treatment of the cUTI. The 95% CIs of each treatment are unstratified Wilson CIs.
Time frame: Up to 48 hours after last oral dose (up to 19 days)
Population: All randomized participants who received any amount of study treatment and have at least 1 acceptable causative uropathogen identified from a study-qualifying baseline urine culture.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam | Percentage of Participants With a Clinical Response of Cure at the End of Treatment Visit | 94.4 Percentage of participants |
| Meropenem | Percentage of Participants With a Clinical Response of Cure at the End of Treatment Visit | 100.0 Percentage of participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-14.09, 8.88]
Secondary
Percentage of Participants With a Clinical Response of Cure at the Test of Cure Visit
Clinical response of cure is complete resolution or marked improvement in signs and symptoms of the complicated urinary tract infection (cUTI) or return to pre-infection signs and symptoms, such that no further antibiotic therapy (IV or oral) is required for the treatment of the cUTI. The 95% confidence intervals (CIs) of each treatment are unstratified Wilson CIs.
Time frame: Up to Test of Cure Visit (up to 35 days)
Population: All randomized participants who received any amount of study treatment and have at least 1 acceptable causative uropathogen identified from a study-qualifying baseline urine culture.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam | Percentage of Participants With a Clinical Response of Cure at the Test of Cure Visit | 88.7 Percentage of participants |
| Meropenem | Percentage of Participants With a Clinical Response of Cure at the Test of Cure Visit | 95.8 Percentage of participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-17.99, 10.05]
Secondary
Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the End of Treatment Visit
Microbiological eradication of all baseline pathogens is defined as a postbaseline urine culture shows all uropathogens found at baseline at ≥10\^5 colony-forming units (CFU)/mL are reduced to \<10\^4 CFU/mL. The 95% CIs of each treatment are unstratified Wilson CIs.
Time frame: Up to 48 hours after last oral dose (up to 19 days)
Population: All randomized participants who received any amount of study treatment and have at least 1 acceptable causative uropathogen identified from a study-qualifying baseline urine culture.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam | Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the End of Treatment Visit | 93.0 Percentage of participants |
| Meropenem | Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the End of Treatment Visit | 95.8 Percentage of participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-12.67, 13.41]
Secondary
Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the Test of Cure Visit
Microbiological eradication of all baseline pathogens is defined as a postbaseline urine culture shows all uropathogens found at baseline at ≥10\^5 colony-forming units (CFU)/mL are reduced to \<10\^4 CFU/mL. The 95% CIs of each treatment are unstratified Wilson CIs.
Time frame: Up to Test of Cure Visit (up to 35 days)
Population: All randomized participants who received any amount of study treatment and have at least 1 acceptable causative uropathogen identified from a study-qualifying baseline urine culture.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam | Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the Test of Cure Visit | 84.5 Percentage of participants |
| Meropenem | Percentage of Participants With Microbiological Eradication of All Baseline Pathogens at the Test of Cure Visit | 87.5 Percentage of participants |
Comparison: Difference in Percentage (C/T minus Mero)95% CI: [-17.13, 17.4]