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Clinical Trial Results:
A Phase 3, Multi-Center, Randomized, Double-Blind, Double-Dummy Study to Evaluate The Efficacy, Safety, and Tolerability of Carbavance™ (Meropenem/RPX7009) Compared to Piperacillin/Tazobactam in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, in Adults
| Summary | |
EudraCT number | 2014-000545-78 |
Trial protocol | HU CZ SK IT ES PL SI BG GR |
Global end of trial date | 28 Apr 2016 |
| Results information | |
Results version number | v1(current) |
This version publication date | 08 Jun 2017 |
First version publication date | 08 Jun 2017 |
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 | |||
Sponsor protocol code | Rempex-505 | ||
| Additional study identifiers | |||
ISRCTN number | - | ||
US NCT number | NCT02166476 | ||
WHO universal trial number (UTN) | - | ||
Other trial identifiers | US-IND # : 120040 | ||
| Sponsors | |||
Sponsor organisation name | Rempex Pharmaceuticals, Inc. | ||
Sponsor organisation address | 3013 Science Park Rd, 1st Floor, San Diego, United States, | ||
Public contact | Elizabeth Morgan, Rempex Pharmaceuticals Inc., +1 8588756671, liz.morgan@themedco.com | ||
Scientific contact | Jeffery Loutit, Rempex Pharmaceuticals Inc., +1 8588756665, jeff.loutit@THEMEDCO.com | ||
| Paediatric regulatory details | |||
Is trial part of an agreed paediatric investigation plan (PIP) | No | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
| Results analysis stage | |||
Analysis stage | Final | ||
Date of interim/final analysis | 12 Jul 2016 | ||
Is this the analysis of the primary completion data? | Yes | ||
Primary completion date | 28 Apr 2016 | ||
Global end of trial reached? | Yes | ||
Global end of trial date | 28 Apr 2016 | ||
Was the trial ended prematurely? | No | ||
| General information about the trial | |||
Main objective of the trial | To assess the efficacy of meropenem/RPX7009 (meropenem/vaborbactam) administered by intravenous (IV) infusion in participants with complicated urinary tract infections (cUTIs) or acute pyelonephritis (AP); To assess the safety and tolerability of meropenem/vaborbactam administered by IV infusion in participants with cUTI or AP; and To assess the population pharmacokinetics (PK) of meropenem/vaborbactam in participants with cUTI or AP. | ||
Protection of trial subjects | This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which the study was conducted. | ||
Background therapy | - | ||
Evidence for comparator | - | ||
Actual start date of recruitment | 31 Jul 2014 | ||
Long term follow-up planned | No | ||
Independent data monitoring committee (IDMC) involvement? | Yes | ||
| Population of trial subjects | |||
Number of subjects enrolled per country | |||
Country: Number of subjects enrolled | Belarus: 74 | ||
Country: Number of subjects enrolled | Brazil: 14 | ||
Country: Number of subjects enrolled | Korea, Republic of: 1 | ||
Country: Number of subjects enrolled | Peru: 18 | ||
Country: Number of subjects enrolled | Taiwan: 8 | ||
Country: Number of subjects enrolled | Ukraine: 213 | ||
Country: Number of subjects enrolled | United States: 17 | ||
Country: Number of subjects enrolled | Poland: 9 | ||
Country: Number of subjects enrolled | Romania: 35 | ||
Country: Number of subjects enrolled | Slovakia: 31 | ||
Country: Number of subjects enrolled | Slovenia: 6 | ||
Country: Number of subjects enrolled | Spain: 7 | ||
Country: Number of subjects enrolled | Bulgaria: 46 | ||
Country: Number of subjects enrolled | Czech Republic: 26 | ||
Country: Number of subjects enrolled | Greece: 41 | ||
Country: Number of subjects enrolled | Hungary: 1 | ||
Country: Number of subjects enrolled | Italy: 3 | ||
Worldwide total number of subjects | 550 | ||
EEA total number of subjects | 205 | ||
Number of subjects enrolled per age group | |||
In utero | 0 | ||
Preterm newborn - gestational age | 0 | ||
Newborns (0-27 days) | 0 | ||
Infants and toddlers (28 days-23 months) | 0 | ||
Children (2-11 years) | 0 | ||
Adolescents (12-17 years) | 0 | ||
Adults (18-64 years) | 359 | ||
From 65 to 84 years | 174 | ||
85 years and over | 17 | ||
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| Recruitment | ||||||||||||||||||||||||||||||||||
Recruitment details | - | |||||||||||||||||||||||||||||||||
| Pre-assignment | ||||||||||||||||||||||||||||||||||
Screening details | Screening procedures were performed up to 24 hours prior to the first dose of study drug. All screening procedures were completed prior to randomization and the first dose of study drug. | |||||||||||||||||||||||||||||||||
| Period 1 | ||||||||||||||||||||||||||||||||||
Period 1 title | Rempex-505 (overall period) | |||||||||||||||||||||||||||||||||
Is this the baseline period? | Yes | |||||||||||||||||||||||||||||||||
Allocation method | Randomised - controlled | |||||||||||||||||||||||||||||||||
Blinding used | Double blind | |||||||||||||||||||||||||||||||||
Roles blinded | Subject, Investigator, Assessor | |||||||||||||||||||||||||||||||||
Blinding implementation details | The investigator, site personnel, Sponsor, and Sponsor’s designees involved in monitoring, data management, medical review, and other study aspects were blinded. Only the site pharmacist/qualified designee was unblinded to treatment assignment to allow study drug preparation. The study drug supply was not blinded. The Sponsor and Sponsor’s designee involved in monitoring the pharmacy data were also unblinded. This monitor was independent from the primary monitor. | |||||||||||||||||||||||||||||||||
| Arms | ||||||||||||||||||||||||||||||||||
Are arms mutually exclusive | Yes | |||||||||||||||||||||||||||||||||
| Arm title | Meropenem/Vaborbactam | |||||||||||||||||||||||||||||||||
Arm description | Meropenem/vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered IV over 3 hours, every 8 hours (q8h), with 100 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-milligram (mg) dose every 24 hours (q24h) after a minimum of 15 doses of IV meropenem/vaborbactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | |||||||||||||||||||||||||||||||||
Arm type | Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name | Meropenem/Vaborbactam | |||||||||||||||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||||||||||||||
Other name | Meropenem/RPX7009, Meropenem 2 g-Vaborbactam 2 g , Carbavance | |||||||||||||||||||||||||||||||||
Pharmaceutical forms | Powder for concentrate for solution for injection/infusion | |||||||||||||||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||||||||||||||
Dosage and administration details | Participants in the meropenem/vaborbactam group received the following infusions q8h: meropenem/vaborbactam diluted in normal saline to a volume of 250 mL and infused over 3 hours and, to preserve the blind, 100 mL normal saline infused over 30 minutes. | |||||||||||||||||||||||||||||||||
Investigational medicinal product name | Levofloxacin | |||||||||||||||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||||||||||||||
Other name | ||||||||||||||||||||||||||||||||||
Pharmaceutical forms | Tablet | |||||||||||||||||||||||||||||||||
Routes of administration | Oral use | |||||||||||||||||||||||||||||||||
Dosage and administration details | If it was deemed clinically indicated and the participant had received a minimum of 15 doses of study drug, levofloxacin (500 mg) was administered orally q24h as a tablet(s). | |||||||||||||||||||||||||||||||||
| Arm title | Piperacillin/Tazobactam | |||||||||||||||||||||||||||||||||
Arm description | Piperacillin/tazobactam (piperacillin 4 g plus tazobactam 0.5 g), infused in 100 mL normal saline, administered IV over 30 minutes, q8h, with 250 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV piperacillin/tazobactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | |||||||||||||||||||||||||||||||||
Arm type | Active comparator | |||||||||||||||||||||||||||||||||
Investigational medicinal product name | Piperacillin/Tazobactam | |||||||||||||||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||||||||||||||
Other name | Piperacillin 4 g-Tazobactam 0.5 g | |||||||||||||||||||||||||||||||||
Pharmaceutical forms | Powder for concentrate for solution for injection/infusion | |||||||||||||||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||||||||||||||
Dosage and administration details | Participants in the piperacillin/tazobactam group received the following infusions q8h: piperacillin/tazobactam 4.5 g (piperacillin 4 g-tazobactam 0.5 g) diluted in normal saline to a volume of 100 mL and infused over 30 minutes and, to preserve the blind, 250 mL normal saline infused over 3 hours. | |||||||||||||||||||||||||||||||||
Investigational medicinal product name | Levofloxacin | |||||||||||||||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||||||||||||||
Other name | ||||||||||||||||||||||||||||||||||
Pharmaceutical forms | Tablet | |||||||||||||||||||||||||||||||||
Routes of administration | Oral use | |||||||||||||||||||||||||||||||||
Dosage and administration details | If it was deemed clinically indicated and the participant had received a minimum of 15 doses of study drug, levofloxacin (500 mg) was administered orally q24h as a tablet(s). | |||||||||||||||||||||||||||||||||
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Between the 2 Arms, 5 participants were randomized but never dosed: 4 participants withdrew consent and 1 participant did not meet the inclusion criteria and as such, was ineligible to be dosed. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Between the 2 Arms, 5 participants were randomized but never dosed: 4 participants withdrew consent and 1 participant did not meet the inclusion criteria and as such, was ineligible to be dosed. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Between the 2 Arms, 5 participants were randomized but never dosed: 4 participants withdrew consent and 1 participant did not meet the inclusion criteria and as such, was ineligible to be dosed. | ||||||||||||||||||||||||||||||||||
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| Baseline characteristics reporting groups | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Meropenem/Vaborbactam | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Meropenem/vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered IV over 3 hours, every 8 hours (q8h), with 100 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-milligram (mg) dose every 24 hours (q24h) after a minimum of 15 doses of IV meropenem/vaborbactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Piperacillin/Tazobactam | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Piperacillin/tazobactam (piperacillin 4 g plus tazobactam 0.5 g), infused in 100 mL normal saline, administered IV over 30 minutes, q8h, with 250 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV piperacillin/tazobactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| End points reporting groups | |||
Reporting group title | Meropenem/Vaborbactam | ||
Reporting group description | Meropenem/vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered IV over 3 hours, every 8 hours (q8h), with 100 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-milligram (mg) dose every 24 hours (q24h) after a minimum of 15 doses of IV meropenem/vaborbactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||
Reporting group title | Piperacillin/Tazobactam | ||
Reporting group description | Piperacillin/tazobactam (piperacillin 4 g plus tazobactam 0.5 g), infused in 100 mL normal saline, administered IV over 30 minutes, q8h, with 250 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV piperacillin/tazobactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||
Subject analysis set title | Microbiological Modified Intent-To-Treat (m-MITT) Population | ||
Subject analysis set type | Modified intention-to-treat | ||
Subject analysis set description | The m-MITT Population included all participants who met the modified intent-to-treat (MITT) criteria (screened, randomized, and received at least 1 dose of study drug) and had a baseline bacterial pathogen(s) of ≥10^5 colony-forming units (CFU)/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures. | ||
Subject analysis set title | Microbiological Evaluable (ME) Population | ||
Subject analysis set type | Modified intention-to-treat | ||
Subject analysis set description | The ME Population included all participants who met MITT criteria and all of the following criteria: a bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture for evaluation or have the same bacterial pathogen present in concurrent blood and urine cultures; no key inclusion or exclusion violations; a clinical outcome (Cure, Improvement, or Failure) and microbiologic outcome (eradication or persistence) at end of intravenous treatment (EOIVT), unless criteria for Failure on clinical outcome were met at an earlier time point; received ≥80% or ≤120% of expected IV doses; missed no more than 1 IV dose in the first 48 hours, missed no more than 2 consecutive IV doses; received no less than 6 doses for failure or no less than 9 doses for cure; only had an identified gram-positive pathogen in the urine and had received >48 hours of an antibiotic, with only gram-positive coverage not included in the m-MITT Population. | ||
Subject analysis set title | Clinical Evaluable (CE) Population | ||
Subject analysis set type | Modified intention-to-treat | ||
Subject analysis set description | The CE Population includes participants who meet the MITT criteria (screened, randomized, and received at least 1 dose of study drug), as well as the following criteria: have no key inclusion or exclusion violations; obtained a clinical outcome (Cure, Improvement, or Failure) at EOIVT, unless criteria for Failure on clinical outcome were met at an earlier time point; received ≥80% and ≤120% of expected IV doses for the completed treatment duration, missed no more than 1 IV dose in the first 48 hours of treatment, and missed no more than 2 consecutive IV doses overall; received ≥6 doses of study drug if classified as a Failure on clinical outcome, or received ≥9 doses of study drug if classified as a Cure on clinical outcome. These criteria were reviewed to identify which participants should be excluded from the CE Population prior to unblinding. | ||
Subject analysis set title | PK Population | ||
Subject analysis set type | Sub-group analysis | ||
Subject analysis set description | The PK Population included participants in the MITT Population (only participants screened and randomized to study drug [meropenem/vaborbactam] and those who received at least 1 dose of study drug) and had at least 1 plasma PK sample drawn. Due to renal impairment, 28 participants received a reduced dose of the study drug (meropenem 1 g plus vaborbactam 1 g). | ||
Subject analysis set title | m-MITT by Pathogen | ||
Subject analysis set type | Modified intention-to-treat | ||
Subject analysis set description | Analysis by pathogen in the m-MITT Population using both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) microbiologic outcome criteria at Day 3, EOIVT (Days 5-14), end of treatment (EOT) (Days 10-14), test of cure (TOC) (Days 15-23), and late follow-up (LFU) (Days 22- 30). Pathogens: Enterobacter cloacae (E. cloacae); Enterococcus faecalis (E. faecalis); Escherichia coli (E. coli); Klebsiella pneumoniae (K. pneumoniae) | ||
Subject analysis set title | ME by Pathogen | ||
Subject analysis set type | Modified intention-to-treat | ||
Subject analysis set description | Analysis by pathogen in the ME Population using both the FDA and EMA microbiologic outcome criteria at Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22- 30). Pathogens: E. cloacae; E. faecalis; E. coli; K. pneumoniae | ||
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End point title | Proportion Of Participants In The m-MITT Population Who Achieved Overall Success At The EOIVT Visit | |||||||||
End point description | This was the primary outcome measure for the FDA. For this composite outcome measure, overall success was achieved with a clinical outcome of Cure or Improvement and microbiologic outcome of Eradication at EOIVT. Cure was defined as the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms of cUTI or AP, but continued IV therapy was warranted. Eradication was defined using the FDA’s CFU/mL criteria that the bacterial pathogen(s) found at baseline was/were reduced to <10^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||
End point type | Primary | |||||||||
End point timeframe | EOIVT (Days 5-14) | |||||||||
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Statistical analysis title | m-MITT and Overall Success | |||||||||
Statistical analysis description | Treatment difference is the estimate of the difference in the overall success rate between the 2 treatment arms. The difference estimates and the 95% confidence interval (CI) are obtained based on Miettinen and Nurminen method. | |||||||||
Comparison groups | Meropenem/Vaborbactam v Piperacillin/Tazobactam | |||||||||
Number of subjects included in analysis | 374 | |||||||||
Analysis specification | Pre-specified | |||||||||
Analysis type | non-inferiority [1] | |||||||||
Method | ||||||||||
Parameter type | Treatment Difference | |||||||||
Point estimate | 4.5 | |||||||||
Confidence interval | ||||||||||
level | 95% | |||||||||
sides | 2-sided | |||||||||
lower limit | 0.7 | |||||||||
upper limit | 9.1 | |||||||||
| Notes [1] - The non-inferiority margin was a difference of 15%. Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference for overall success at EOIVT was ≥-15%. | ||||||||||
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End point title | Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication At The TOC Visit | |||||||||
End point description | This was the primary outcome measure for the EMA. For this measure, a microbiologic outcome of Eradication was defined using the EMA’s CFU/mL criteria: bacterial pathogen(s) found at baseline was/were reduced to <10^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||
End point type | Primary | |||||||||
End point timeframe | TOC (Days 15-23) | |||||||||
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Statistical analysis title | m-MITT and Eradication | |||||||||
Statistical analysis description | Treatment difference is the estimate of the difference in the Eradication rate between the 2 treatment arms. The difference estimates and the 95% CIs are obtained based on Miettinen and Nurminen method. | |||||||||
Comparison groups | Meropenem/Vaborbactam v Piperacillin/Tazobactam | |||||||||
Number of subjects included in analysis | 374 | |||||||||
Analysis specification | Pre-specified | |||||||||
Analysis type | non-inferiority [2] | |||||||||
Method | ||||||||||
Parameter type | Treatment Difference | |||||||||
Point estimate | 9 | |||||||||
Confidence interval | ||||||||||
level | 95% | |||||||||
sides | 2-sided | |||||||||
lower limit | -0.9 | |||||||||
upper limit | 18.7 | |||||||||
| Notes [2] - The noninferiority margin was a difference of 15%. Meropenem/vaborbactam was claimed to be noninferior only if noninferiority was demonstrated for microbial eradication at TOC in the m-MITT Population. | ||||||||||
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End point title | Proportion Of Participants In The ME Population Who Achieved A Microbiologic Outcome Of Eradication | |||||||||
End point description | This was the primary outcome measure for the EMA. For this measure, a microbiologic outcome of Eradication was defined using the EMA’s CFU/mL criteria: bacterial pathogen(s) found at baseline was/were reduced to <10^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||
End point type | Primary | |||||||||
End point timeframe | TOC (Days 15-23) | |||||||||
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Statistical analysis title | ME and Eradication | |||||||||
Statistical analysis description | Treatment difference is the estimate of the difference in the overall success rate between the two treatment arms. The difference estimates and the 95% CIs are obtained based on Miettinen and Nurminen method. | |||||||||
Comparison groups | Meropenem/Vaborbactam v Piperacillin/Tazobactam | |||||||||
Number of subjects included in analysis | 347 | |||||||||
Analysis specification | Pre-specified | |||||||||
Analysis type | non-inferiority [3] | |||||||||
Method | ||||||||||
Parameter type | Treatment Difference | |||||||||
Point estimate | 5.9 | |||||||||
Confidence interval | ||||||||||
level | 95% | |||||||||
sides | 2-sided | |||||||||
lower limit | -4.2 | |||||||||
upper limit | 16 | |||||||||
| Notes [3] - The noninferiority margin was a difference of 15%. Meropenem/vaborbactam was claimed to be non-inferior only if non-inferiority was demonstrated for microbial eradication at TOC in the ME Population. | ||||||||||
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End point title | Proportion Of Participants In The m-MITT Population With Overall Success | |||||||||||||||
End point description | This secondary outcome measure, evaluated only for the FDA, focused on the overall success in the m-MITT population at the EOIVT and TOC visits. Overall success at TOC was defined as a clinical outcome of Cured and a microbiologic outcome of Eradication. Overall success at EOIVT was defined as a clinical outcome of Cured or Improvement and a microbiologic outcome of Eradication. Cured was defined as the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms of cUTI or AP, but continued IV therapy was warranted. Eradication was defined using the FDA's CFU/mL criteria that the bacterial pathogen(s) found at baseline was/were reduced to <10^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||
End point type | Secondary | |||||||||||||||
End point timeframe | EOIVT (Days 5-14) and TOC (Days 15-23) | |||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||
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End point title | Proportion Of Participants In The ME Population With Overall Success | |||||||||||||||
End point description | This secondary outcome measure focused on the overall success in the ME population at the EOIVT and TOC visits. Overall success at TOC was defined as a clinical outcome of Cured and a microbiologic outcome of Eradication. Overall success at EOIVT was defined as a clinical outcome of Cured or Improvement and a microbiologic outcome of Eradication. Cured was defined as the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms of cUTI or AP, but continued IV therapy was warranted. Eradication was defined using the FDA's CFU/mL criteria that the bacterial pathogen(s) found at baseline was/were reduced to <10^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||
End point type | Secondary | |||||||||||||||
End point timeframe | EOIVT (Days 5-14) and TOC (Days 15-23) | |||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||
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End point title | Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication At The TOC Visit | |||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on a microbiological outcome of Eradication in the m-MITT Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture (FDA) or <10^3 CFU/mL (EMA), and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||
End point title | Proportion Of Participants In The ME Population Who Achieved A Microbiologic Outcome Of Eradication | |||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on a microbiological outcome of Eradication the ME Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture (FDA) or <10^3 CFU/mL (EMA), and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
End point title | Proportion Of Participants With A Clinical Outcome Of Cure In The m-MITT Population | ||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on a clinical outcome of Cure in the m-MITT Population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at Day 3, EOIVT, and EOT visits. | ||||||||||||||||||||||||||||||
End point type | Secondary | ||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | ||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
End point title | Proportion Of Participants With A Clinical Outcome Of Cure In The CE Population | ||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on a clinical outcome of Cure in the CE Population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at the Day 3, EOIVT, and EOT visits. | ||||||||||||||||||||||||||||||
End point type | Secondary | ||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | ||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
End point title | Proportion Of Participants With A Clinical Outcome Of Cure In The ME Population | ||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on a clinical outcome of Cure in the ME Population. A clinical outcome of Cure was defined as the following: at EOIVT, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP; at EOT, TOC, and LFU, the complete resolution or significant improvement of the baseline signs and symptoms of cUTI or AP such that no further antimicrobial therapy was warranted. Symptom resolution did not necessarily include baseline symptoms associated with anatomic abnormalities that predisposed to cUTI, such as symptoms associated with the presence of an indwelling urinary catheter. The clinical outcome of Cure was reported only at the EOIVT, EOT, TOC, and LFU visits, and improvement was reported only at the Day 3, EOIVT, and EOT visits. | ||||||||||||||||||||||||||||||
End point type | Secondary | ||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | ||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title | Per-Pathogen Microbiological Outcome (FDA) In The m-MITT Population | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the m-MITT Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the FDA criteria as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [4] - E. cloacae (N=10); E. faecalis (N=13); E. coli (N=125); K. pneumoniae (N=30) [5] - E. cloacae (N=5); E. faecalis (N=14); E. coli (N=117); K. pneumoniae (N=28) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title | Per-Pathogen Microbiological Outcome (FDA) In The ME Population | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the ME Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the FDA criteria as a reduction in baseline bacterial pathogen(s) to <10^4 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [6] - E. cloacae (N=10); E. faecalis (N=11); E. coli (N=117); K. pneumoniae (N=28) [7] - E. cloacae (N=5); E. faecalis (N=14); E. coli (N=106); K. pneumoniae (N=27) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title | Per-Pathogen Microbiological Outcome (EMA) In The m-MITT Population | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the m-MITT Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the EMA criteria as a reduction in baseline bacterial pathogen(s) to <10^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [8] - E. cloacae (N=10); E. faecalis (N=13); E. coli (N=125); K. pneumoniae (N=30) [9] - E. cloacae (N=5); E. faecalis (N=14); E. coli (N=117); K. pneumoniae (N=28) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title | Per-Pathogen Microbiological Outcome (EMA) In The ME Population | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description | This secondary outcome measure focused on the per-pathogen (E. cloacae, E. faecalis, E. coli, K. pneumoniae) microbiological outcome of Eradication in the ME Population at 5 time points: Day 3, EOIVT, EOT, TOC, and LFU. Eradication was defined per the EMA criteria as a reduction in baseline bacterial pathogen(s) to <10^3 CFU/mL of urine culture and a negative blood culture for an organism that was identified as an uropathogen (if repeated after positive at baseline blood culture). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe | Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [10] - E. cloacae (N=10); E. faecalis (N=11); E. coli (N=117); K. pneumoniae (N=28) [11] - E. cloacae (N=5); E. faecalis (N=14); E. coli (N=106); K. pneumoniae (N=27) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||
End point title | PK Characterization Of Plasma Exposure Of Meropenem/Vaborbactam [12] | ||||||||||||
End point description | This outcome measure focused on PK assessment of participants in the meropenem/vaborbactam group who met MITT criteria and had at least 1 plasma PK sample drawn. PK samples on Day 1 were taken 3-3.5 hours and 5-6 hours after the start of the first 3-hour IV study drug infusion. Samples were not collected around the 30-minute infusions. Samples were collected from both groups to maintain the blind; however, only PK samples for the meropenem/vaborbactam group were analyzed. The area under the concentration-time curve during 24 hours (AUC0-24) for Day 1 and at steady-state are presented in micrograms (ug)·hour/mL. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | Day 1 | ||||||||||||
| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Blood samples for analysis of plasma concentrations were collected from both groups to maintain the blind; however, only PK samples for the Meropenem/Vaborbactam Arm were analyzed. | |||||||||||||
| |||||||||||||
| Notes [13] - PK Population. AUC0-24 Steady-State estimates not available for 2 participants who received >3 doses | |||||||||||||
| No statistical analyses for this end point | |||||||||||||
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| Adverse events information | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events | Day 1 (Screening) through Day 30 (Follow Up). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type | Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dictionary used for adverse event reporting | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name | MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version | 17.0 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Reporting groups | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Meropenem/Vaborbactam | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Meropenem/vaborbactam (meropenem 2 g plus vaborbactam 2 g), infused in 250 mL normal saline, administered IV over 3 hours, q8h, with 100 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV meropenem/vaborbactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Piperacillin/Tazobactam | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Piperacillin/tazobactam (piperacillin 4 g plus tazobactam 0.5 g), infused in 100 mL normal saline, administered IV over 30 minutes, q8h, with 250 mL saline administered over 30 minutes q8h. Levofloxacin tablets administered orally as a 500-mg dose q24h after a minimum of 15 doses of IV piperacillin/tazobactam plus saline, if clinically indicated. Total treatment was 10 days, unless a participant had baseline bacteremia where up to 14 days of IV therapy could be administered. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| |||
Substantial protocol amendments (globally) | |||
| Were there any global substantial amendments to the protocol? Yes | |||
Date | Amendment | ||
06 Aug 2014 | The original protocol was dated 06 May 2014. The protocol was amended 3 times. Key changes in the first amendment included: • Added dose adjustment for renally impaired participants. • Permitted the use of trimethoprim/sulfamethoxazole, cefdinir, and cefpodoxime as step-down therapy for levofloxacin-resistant participants. • Included a Data Safety Monitoring Board. • Required an Acute Physiology and Chronic Health Evaluation (APACHE) II score <30 in participants who have a calculated APACHE II score. • Removed urinary incontinence, pyuria, and lower back pain from the list of signs and symptoms. | ||
02 Apr 2015 | The original protocol was dated 06 May 2014. The protocol was amended 3 times. Key changes in the second amendment included: • Modified weight criteria up to 185 kilograms. • Permitted the use of 1 dose of a short-acting antibiotic within 24 hours of randomization (up to 25% of participants). • Modified the proportion of participants with AP to at least 30%. • Excluded participants that could not tolerate the IV fluid volume of 1050 mL per day related to study drug infusions. • Excluded participants that have recent history of trauma to the pelvis or urinary tract. • Added collection of presence or history of Charlson Comorbidity Components to the participant's medical history. • Allowed for antibiotic coverage of any gram-positive organisms. | ||
14 Jan 2016 | The original protocol was dated 06 May 2014. The protocol was amended 3 times. The key change in the third amendment was: • Changing the sample size from 850 participants to 500 participants, with corresponding changes to the noninferiority margin from 10% to 15%. | ||
Interruptions (globally) | |||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats | |||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||