Clinical Trial Results:
A Phase 2, Randomized, Active Comparator-Controlled, Multicenter, Double-Blind Clinical Trial to Study the Safety and Efficacy of Ceftolozane/Tazobactam (MK-7625A) Versus Meropenem in Pediatric Subjects with Complicated Urinary Tract Infection, Including Pyelonephritis
Summary
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EudraCT number |
2016-004153-32 |
Trial protocol |
HU PL GR Outside EU/EEA RO |
Global end of trial date |
20 Jan 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Jul 2021
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First version publication date |
14 Jul 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
7625A-034
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03230838 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Merck Sharp & Dohme Corp.
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Sponsor organisation address |
2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
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Public contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Scientific contact |
Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001142-PIP01-11 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Dec 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Dec 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
20 Jan 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This study aims to evaluate the safety and tolerability of MK-7625A (ceftolozane/tazobactam) compared with that of meropenem in pediatric participants with complicated urinary tract infection (cUTI), including pyelonephritis.
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Protection of trial subjects |
This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Apr 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Greece: 36
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Country: Number of subjects enrolled |
Hungary: 22
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Country: Number of subjects enrolled |
Mexico: 9
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Country: Number of subjects enrolled |
Poland: 17
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Country: Number of subjects enrolled |
Russian Federation: 8
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Country: Number of subjects enrolled |
Turkey: 14
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Country: Number of subjects enrolled |
Ukraine: 22
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Country: Number of subjects enrolled |
United States: 6
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Worldwide total number of subjects |
134
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EEA total number of subjects |
75
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
3
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Infants and toddlers (28 days-23 months) |
50
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Children (2-11 years) |
61
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Adolescents (12-17 years) |
20
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
Pre-assignment
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Screening 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. | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Investigator, Carer, Subject | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Ceftolozane/Tazobactam | |||||||||||||||||||||
Arm description |
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 | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Ceftolozane/Tazobactam
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
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.
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Arm title
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Meropenem | |||||||||||||||||||||
Arm description |
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days | |||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||
Investigational medicinal product name |
Meropenem
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Meropenem 20 mg/kg to maximum 1 g/ dose every 8 hours for 7-14 days
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Baseline characteristics reporting groups
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Reporting group title |
Ceftolozane/Tazobactam
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Reporting group description |
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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Meropenem
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Reporting group description |
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Ceftolozane/Tazobactam
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Reporting group description |
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 | ||
Reporting group title |
Meropenem
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Reporting group description |
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days |
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End point title |
Number of participants with ≥1 adverse events (AEs) | |||||||||
End point description |
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. The population analyzed was all randomized participants who received any amount of study treatment.
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End point type |
Primary
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End point timeframe |
Up to Day 88
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | |||||||||
Statistical analysis description |
The Miettinen & Nurminen method was used.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Percentage Difference | |||||||||
Point estimate |
-1.6
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-19.7 | |||||||||
upper limit |
17.9 |
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End point title |
Number of participants discontinuing study therapy due to an AE | |||||||||
End point description |
An 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. The population analyzed was all randomized participants who received any amount of study treatment.
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End point type |
Primary
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End point timeframe |
Up to Day 15
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | |||||||||
Statistical analysis description |
The Miettinen & Nurminen method was used.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
Method |
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Parameter type |
Percentage Difference | |||||||||
Point estimate |
1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-9.5 | |||||||||
upper limit |
5.5 |
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End point title |
Percentage of participants with a clinical response of cure at the Test of Cure Visit | ||||||||||||
End point description |
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% CIs of each treatment are unstratified Wilson CIs. The population analyzed was 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.
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End point type |
Secondary
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End point timeframe |
Up to Test of Cure Visit (up to 35 days)
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | ||||||||||||
Statistical analysis description |
The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
95
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Percentage Difference | ||||||||||||
Point estimate |
-7.3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-17.99 | ||||||||||||
upper limit |
10.05 |
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End point title |
Percentage of participants with a clinical response of cure at the End of Treatment Visit | ||||||||||||
End point description |
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. The population analyzed was 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.
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End point type |
Secondary
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End point timeframe |
Up to 48 hours after last oral dose (Up to 19 days)
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | ||||||||||||
Statistical analysis description |
The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
95
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Percentage Difference | ||||||||||||
Point estimate |
-5.6
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-14.09 | ||||||||||||
upper limit |
8.88 |
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End point title |
Percentage of participants with microbiological eradication of all baseline pathogens at the Test of Cure Visit | ||||||||||||
End point description |
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. The population analyzed was 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.
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End point type |
Secondary
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End point timeframe |
Up to Test of Cure Visit (up to 35 days)
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | ||||||||||||
Statistical analysis description |
The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
95
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Percentage Difference | ||||||||||||
Point estimate |
-3
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-17.13 | ||||||||||||
upper limit |
17.4 |
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End point title |
Percentage of participants with microbiological eradication of all baseline pathogens at the End of Treatment Visit | ||||||||||||
End point description |
Microbiological eradication of all baseline pathogens is defined as a postbaseline urine culture shows all uropathogens found at baseline at ≥10^5 CFU/mL are reduced to <10^4 CFU/mL. The 95% CIs of each treatment are unstratified Wilson CIs.The population analyzed was 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.
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End point type |
Secondary
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End point timeframe |
Up to 48 hours after last oral dose (Up to 19 days)
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Statistical analysis title |
Difference in Percentage (C/T minus Mero) | ||||||||||||
Statistical analysis description |
The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel (CMH) weights was used. If there was a zero count in any class of the stratum, the groups with the lower count were pooled with its near age group stratum in the model.
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Comparison groups |
Ceftolozane/Tazobactam v Meropenem
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Number of subjects included in analysis |
95
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
Percentage Difference | ||||||||||||
Point estimate |
-3.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-12.67 | ||||||||||||
upper limit |
13.41 |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse Events (AEs): From treatment (Day 1) up to 88 days. All-cause mortality: From randomization (Day 1) up to 88 days.
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Adverse event reporting additional description |
For all-cause mortality the population analyzed was all randomized participants. For AEs the population analyzed was all randomized participants who received any amount of study treatment.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Meropenem
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Reporting group description |
Meropenem 20 mg/kg (maximum 1 g/dose) administered IV every 8 hours for 7-14 days | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Ceftolozane/Tazobactam
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Reporting group description |
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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 May 2019 |
Amendment 2 combined enrollment targets for groups 3-5 with a companion study of ceftolozane/tazobactam in pediatric complicated urinary tract infections. This allowed greater flexibility in enrollment targets for Groups 3-5 (the youngest cohort of children) and facilitated enrollment of a sufficient number of participants to evaluate safety and pharmacokinetics in both study populations and enabled timely completion of the studies. |
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08 Oct 2020 |
Amendment 3 removed the minimum number of at least 4 participants per study required to be enrolled in Groups 3, 4, and 5 and reduced minimum enrollment targets for Groups 3 and 5. Individual study age group minimum requirements for Groups 3-5 were removed to facilitate more timely availability of important pediatric data to health care providers and participants. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |