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Efficacy/Safety of Meropenem-Vaborbactam Compared to Piperacillin-Tazobactam in Adults With cUTI and AP

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ClinicalTrials.gov Identifier: NCT02166476
Recruitment Status : Completed
First Posted : June 18, 2014
Results First Posted : October 26, 2017
Last Update Posted : June 11, 2018
Sponsor:
Collaborator:
Department of Health and Human Services
Information provided by (Responsible Party):
Melinta Therapeutics, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Urinary Tract Infection Complicated
Acute Pyelonephritis
Interventions Drug: Meropenem-Vaborbactam
Drug: Piperacillin-Tazobactam
Drug: Levofloxacin
Drug: Saline
Enrollment 550
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/Group Description Meropenem-vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered intravenously (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 therapy could be administered IV. 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 therapy could be administered IV.
Period Title: Overall Study
Started [1] 272 273
Received at Least 1 Dose of Study Drug [2] 272 273
Completed 258 250
Not Completed 14 23
Reason Not Completed
Withdrawal by Subject             5             7
Adverse Event             3             3
Lost to Follow-up             5             10
Physician Decision             1             0
Unable to Come for Visit             0             3
[1]
5 participants were randomized but not dosed: 4 withdrew consent, 1 did not meet inclusion criteria.
[2]
Randomized participants included in the Safety and modified intent-to-treat [MITT] populations.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam Total
Hide Arm/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 therapy could be administered IV. 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 therapy could be administered IV. Total of all reporting groups
Overall Number of Baseline Participants 272 273 545
Hide Baseline Analysis Population Description
All randomized participants who received at least 1 dose of study drug (MITT population).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 272 participants 273 participants 545 participants
53.0  (19.42) 52.6  (20.93) 52.8  (20.17)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 272 participants 273 participants 545 participants
Female
181
  66.5%
180
  65.9%
361
  66.2%
Male
91
  33.5%
93
  34.1%
184
  33.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 272 participants 273 participants 545 participants
Hispanic or Latino
24
   8.8%
19
   7.0%
43
   7.9%
Not Hispanic or Latino
248
  91.2%
254
  93.0%
502
  92.1%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 272 participants 273 participants 545 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
5
   1.8%
5
   1.8%
10
   1.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
3
   1.1%
4
   1.5%
7
   1.3%
White
254
  93.4%
252
  92.3%
506
  92.8%
More than one race
10
   3.7%
12
   4.4%
22
   4.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Proportion Of Participants In The Microbiological Modified Intent-To-Treat (m-MITT) Population Who Achieved Overall Success At The End Of Intravenous Treatment Visit
Hide Description This was the primary outcome measure for the Food and Drug Administration (FDA). For this composite outcome measure, overall success was achieved with a clinical outcome of Cure or Improvement and microbiologic outcome of Eradication at the end of intravenous treatment (EOIVT). Cure was defined as the complete resolution or significant improvement of the baseline signs and symptoms. Improvement was defined as lessening, incomplete resolution, or no worsening of the baseline signs and symptoms. Eradication was defined using the FDA's colony-forming units (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).
Time Frame EOIVT (Days 5-14)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
189
  98.4%
171
  94.0%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Meropenem-Vaborbactam, Piperacillin-Tazobactam
Comments Treatment comparison of the m-MITT population
Type of Statistical Test Non-Inferiority or Equivalence
Comments The noninferiority margin was a difference of 15%. Noninferiority was concluded if the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference for overall success at EOIVT was >-15%.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 4.5
Confidence Interval (2-Sided) 95%
0.7 to 9.1
Estimation Comments 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.
2.Primary Outcome
Title Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication At The Test Of Cure Visit
Hide Description This was the primary outcome measure for the European Medicines Agency (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 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).
Time Frame Test of cure (TOC) (Days 15-23)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
128
  66.7%
105
  57.7%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Meropenem-Vaborbactam, Piperacillin-Tazobactam
Comments Treatment comparison of the m-MITT population
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 9.0
Confidence Interval (2-Sided) 95%
-0.9 to 18.7
Estimation Comments Treatment difference is the estimate of the difference in the Eradication rate between the two treatment arms. The difference estimates and the 95% CIs are obtained based on Miettinen and Nurminen method.
3.Primary Outcome
Title Proportion Of Participants In The Microbiological Evaluable (ME) Population Who Achieved A Microbiologic Outcome Of Eradication At The TOC Visit
Hide 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 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). The ME population included all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Time Frame TOC (Days 15-23)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
118
  66.3%
102
  60.4%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Meropenem-Vaborbactam, Piperacillin-Tazobactam
Comments Treatment comparison of the ME population
Type of Statistical Test Non-Inferiority or Equivalence
Comments 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 ME Population.
Method of Estimation Estimation Parameter Treatment Difference
Estimated Value 5.9
Confidence Interval (2-Sided) 95%
-4.2 to 16.0
Estimation Comments 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.
4.Secondary Outcome
Title Proportion Of Participants In The m-MITT Population With Overall Success
Hide 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).
Time Frame EOIVT (Days 5-14) and TOC (Days 15-23)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
EOIVT
189
  98.4%
171
  94.0%
TOC
143
  74.5%
128
  70.3%
5.Secondary Outcome
Title Proportion Of Participants In The ME Population With Overall Success
Hide Description This secondary outcome measure focused on the overall success in the ME population at the EOIVT and TOC visits. Overall success 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).
Time Frame EOIVT (Days 5-14) and TOC (Days 15-23)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
EOIVT
178
 100.0%
165
  97.6%
TOC
134
  75.3%
124
  73.4%
6.Secondary Outcome
Title Proportion Of Participants In The m-MITT Population Who Achieved A Microbiologic Outcome Of Eradication
Hide Description This secondary outcome measure focused on a microbiological outcome of Eradication in the m-MITT population at 5 time points: Day 3, EOIVT, end of treatment (EOT), TOC, and late follow up (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 a uropathogen (if repeated after positive at baseline blood culture).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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 piperacillin-tazobactam plus saline, if clinically indicated. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: FDA
189
  98.4%
167
  91.8%
EOIVT: FDA
188
  97.9%
168
  92.3%
EOT: FDA
172
  89.6%
158
  86.8%
TOC: FDA
132
  68.8%
113
  62.1%
LFU: FDA
132
  68.8%
103
  56.6%
Day 3: EMA
186
  96.9%
164
  90.1%
EOIVT: EMA
188
  97.9%
168
  92.3%
EOT: EMA
169
  88.0%
158
  86.8%
TOC: EMA
128
  66.7%
105
  57.7%
LFU: EMA
129
  67.2%
98
  53.8%
7.Secondary Outcome
Title Proportion Of Participants In The ME Population Who Achieved A Microbiologic Outcome Of Eradication
Hide Description This secondary outcome measure focused on a microbiological outcome of Eradication in 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).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: FDA
177
  99.4%
160
  94.7%
EOIVT: FDA
178
 100.0%
166
  98.2%
EOT: FDA
163
  91.6%
156
  92.3%
TOC: FDA
122
  68.5%
109
  64.5%
LFU: FDA
122
  68.5%
99
  58.6%
Day 3: EMA
174
  97.8%
157
  92.9%
EOIVT: EMA
178
 100.0%
166
  98.2%
EOT: EMA
160
  89.9%
156
  92.3%
TOC: EMA
118
  66.3%
102
  60.4%
LFU: EMA
120
  67.4%
94
  55.6%
8.Secondary Outcome
Title Proportion Of Participants With A Clinical Outcome Of Cure In The m-MITT Population
Hide 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.
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: Improvement
186
  96.9%
171
  94.0%
EOIVT: Cure
156
  81.3%
144
  79.1%
EOIVT: Improvement
33
  17.2%
30
  16.5%
EOT: Cure
179
  93.2%
167
  91.8%
EOT: Improvement
4
   2.1%
3
   1.6%
TOC: Cure
174
  90.6%
157
  86.3%
LFU: Cure
166
  86.5%
143
  78.6%
9.Secondary Outcome
Title Proportion Of Participants With A Clinical Outcome Of Cure In The Clinical Evaluable (CE) Population
Hide 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.
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
CE population: all participants who received ≥1 dose of drug (MITT), had no key inclusion/exclusion criteria violations, had a clinical outcome (Cure, Improvement, Failure) at EOIVT, received 80-120% of expected IV doses, missed ≤1 IV dose in the first 48 hours, missed ≤2 consecutive IV doses overall, received ≥6 doses (Failure) or ≥9 doses (Cure).
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 248 258
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: Improvement
243
  98.0%
250
  96.9%
EOIVT: Cure
202
  81.5%
206
  79.8%
EOIVT: Improvement
45
  18.1%
46
  17.8%
EOT: Cure
235
  94.8%
239
  92.6%
EOT: Improvement
7
   2.8%
6
   2.3%
TOC: Cure
231
  93.1%
224
  86.8%
LFU: Cure
220
  88.7%
209
  81.0%
10.Secondary Outcome
Title Proportion Of Participants With A Clinical Outcome Of Cure In The ME Population
Hide 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.
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: Improvement
175
  98.3%
164
  97.0%
EOIVT: Cure
148
  83.1%
138
  81.7%
EOIVT: Improvement
30
  16.9%
30
  17.8%
EOT: Cure
170
  95.5%
161
  95.3%
EOT: Improvement
3
   1.7%
3
   1.8%
TOC: Cure
164
  92.1%
153
  90.5%
LFU: Cure
156
  87.6%
139
  82.2%
11.Secondary Outcome
Title Per-Pathogen Microbiological Outcome (FDA) In The m-MITT Population
Hide Description This secondary outcome measure focused on the per-pathogen (Enterobacter cloacae [E. cloacae], Enterococcus faecalis [E. faecalis], Escherichia coli [E. coli], Klebsiella pneumoniae [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).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
3
  60.0%
EOIVT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
EOT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
TOC: E. cloacae Number Analyzed 10 participants 5 participants
9
  90.0%
3
  60.0%
LFU: E. cloacae Number Analyzed 10 participants 5 participants
8
  80.0%
2
  40.0%
Day 3: E. faecalis Number Analyzed 13 participants 14 participants
13
 100.0%
14
 100.0%
EOIVT: E. faecalis Number Analyzed 13 participants 14 participants
13
 100.0%
14
 100.0%
EOT: E. faecalis Number Analyzed 13 participants 14 participants
13
 100.0%
14
 100.0%
TOC: E. faecalis Number Analyzed 13 participants 14 participants
7
  53.8%
12
  85.7%
LFU: E. faecalis Number Analyzed 13 participants 14 participants
11
  84.6%
10
  71.4%
Day 3: E. coli Number Analyzed 125 participants 117 participants
124
  99.2%
106
  90.6%
EOIVT: E. coli Number Analyzed 125 participants 117 participants
123
  98.4%
107
  91.5%
EOT: E. coli Number Analyzed 125 participants 117 participants
113
  90.4%
100
  85.5%
TOC: E. coli Number Analyzed 125 participants 117 participants
91
  72.8%
73
  62.4%
LFU: E. coli Number Analyzed 125 participants 117 participants
91
  72.8%
69
  59.0%
Day 3: K. pneumoniae Number Analyzed 30 participants 28 participants
29
  96.7%
26
  92.9%
EOIVT: K. pneumoniae Number Analyzed 30 participants 28 participants
29
  96.7%
26
  92.9%
EOT: K. pneumoniae Number Analyzed 30 participants 28 participants
27
  90.0%
24
  85.7%
TOC: K. pneumoniae Number Analyzed 30 participants 28 participants
19
  63.3%
15
  53.6%
LFU: K. pneumoniae Number Analyzed 30 participants 28 participants
15
  50.0%
13
  46.4%
12.Secondary Outcome
Title Per-Pathogen Microbiological Outcome (FDA) In The ME Population
Hide 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).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/Group Description:
Meropenem-vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered intravenously (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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
3
  60.0%
EOIVT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
EOT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
TOC: E. cloacae Number Analyzed 10 participants 5 participants
9
  90.0%
3
  60.0%
LFU: E. cloacae Number Analyzed 10 participants 5 participants
8
  80.0%
2
  40.0%
Day 3: E. faecalis Number Analyzed 11 participants 14 participants
11
 100.0%
14
 100.0%
EOIVT: E. faecalis Number Analyzed 11 participants 14 participants
11
 100.0%
14
 100.0%
EOT: E. faecalis Number Analyzed 11 participants 14 participants
11
 100.0%
13
  92.9%
TOC: E. faecalis Number Analyzed 11 participants 14 participants
6
  54.5%
12
  85.7%
LFU: E. faecalis Number Analyzed 11 participants 14 participants
9
  81.8%
10
  71.4%
Day 3: E. coli Number Analyzed 117 participants 106 participants
117
 100.0%
101
  95.3%
EOIVT: E. coli Number Analyzed 117 participants 106 participants
117
 100.0%
106
 100.0%
EOT: E. coli Number Analyzed 117 participants 106 participants
108
  92.3%
99
  93.4%
TOC: E. coli Number Analyzed 117 participants 106 participants
84
  71.8%
71
  67.0%
LFU: E. coli Number Analyzed 117 participants 106 participants
84
  71.8%
67
  63.2%
Day 3: K. pneumoniae Number Analyzed 28 participants 27 participants
28
 100.0%
25
  92.6%
EOIVT: K. pneumoniae Number Analyzed 28 participants 27 participants
28
 100.0%
26
  96.3%
EOT: K. pneumoniae Number Analyzed 28 participants 27 participants
26
  92.9%
24
  88.9%
TOC: K. pneumoniae Number Analyzed 28 participants 27 participants
18
  64.3%
14
  51.9%
LFU: K. pneumoniae Number Analyzed 28 participants 27 participants
15
  53.6%
12
  44.4%
13.Secondary Outcome
Title Per-Pathogen Microbiological Outcome (EMA) In The m-MITT Population
Hide 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).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
The m-MITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline bacterial pathogen(s) of ≥10^5 CFU/mL of urine at baseline urine culture or the same bacterial pathogen present in concurrent blood and urine cultures.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/Group Description:
Meropenem-vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered intravenously (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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 192 182
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
3
  60.0%
EOIVT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
EOT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
TOC: E. cloacae Number Analyzed 10 participants 5 participants
9
  90.0%
3
  60.0%
LFU: E. cloacae Number Analyzed 10 participants 5 participants
8
  80.0%
2
  40.0%
Day 3: E. faecalis Number Analyzed 13 participants 14 participants
13
 100.0%
14
 100.0%
EOIVT: E. faecalis Number Analyzed 13 participants 14 participants
13
 100.0%
14
 100.0%
EOT: E. faecalis Number Analyzed 13 participants 14 participants
12
  92.3%
13
  92.9%
TOC: E. faecalis Number Analyzed 13 participants 14 participants
5
  38.5%
11
  78.6%
LFU: E. faecalis Number Analyzed 13 participants 14 participants
9
  69.2%
9
  64.3%
Day 3: E. coli Number Analyzed 125 participants 117 participants
124
  99.2%
106
  90.6%
EOIVT: E. coli Number Analyzed 125 participants 117 participants
123
  98.4%
107
  91.5%
EOT: E. coli Number Analyzed 125 participants 117 participants
112
  89.6%
100
  85.5%
TOC: E. coli Number Analyzed 125 participants 117 participants
89
  71.2%
68
  58.1%
LFU: E. coli Number Analyzed 125 participants 117 participants
90
  72.0%
68
  58.1%
Day 3: K. pneumoniae Number Analyzed 30 participants 28 participants
29
  96.7%
24
  85.7%
EOIVT: K. pneumoniae Number Analyzed 30 participants 28 participants
29
  96.7%
26
  92.9%
EOT: K. pneumoniae Number Analyzed 30 participants 28 participants
27
  90.0%
24
  85.7%
TOC: K. pneumoniae Number Analyzed 30 participants 28 participants
19
  63.3%
14
  50.0%
LFU: K. pneumoniae Number Analyzed 30 participants 28 participants
15
  50.0%
12
  42.9%
14.Secondary Outcome
Title Per-Pathogen Microbiological Outcome (EMA) In The ME Population
Hide 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).
Time Frame Day 3, EOIVT (Days 5-14), EOT (Days 10-14), TOC (Days 15-23), and LFU (Days 22-30)
Hide Outcome Measure Data
Hide Analysis Population Description
ME population: all participants who met m-MITT criteria and had a clinical outcome and microbiologic outcome at EOIVT or earlier; 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.
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/Group Description:
Meropenem-vaborbactam (meropenem 2 grams [g] plus vaborbactam 2 g), infused in 250 milliliters (mL) normal saline, administered intravenously (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. Treatment was administered for up to 14 days.
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. Treatment was administered for up to 14 days.
Overall Number of Participants Analyzed 178 169
Measure Type: Count of Participants
Unit of Measure: Participants
Day 3: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
3
  60.0%
EOIVT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
EOT: E. cloacae Number Analyzed 10 participants 5 participants
10
 100.0%
5
 100.0%
TOC: E. cloacae Number Analyzed 10 participants 5 participants
9
  90.0%
3
  60.0%
LFU: E. cloacae Number Analyzed 10 participants 5 participants
8
  80.0%
2
  40.0%
Day 3: E. faecalis Number Analyzed 11 participants 14 participants
11
 100.0%
14
 100.0%
EOIVT: E. faecalis Number Analyzed 11 participants 14 participants
11
 100.0%
14
 100.0%
EOT: E. faecalis Number Analyzed 11 participants 14 participants
10
  90.9%
13
  92.9%
TOC: E. faecalis Number Analyzed 11 participants 14 participants
4
  36.4%
11
  78.6%
LFU: E. faecalis Number Analyzed 11 participants 14 participants
8
  72.7%
9
  64.3%
Day 3: E. coli Number Analyzed 117 participants 106 participants
117
 100.0%
101
  95.3%
EOIVT: E. coli Number Analyzed 117 participants 106 participants
117
 100.0%
106
 100.0%
EOT: E. coli Number Analyzed 117 participants 106 participants
107
  91.5%
99
  93.4%
TOC: E. coli Number Analyzed 117 participants 106 participants
82
  70.1%
67
  63.2%
LFU: E. coli Number Analyzed 117 participants 106 participants
83
  70.9%
66
  62.3%
Day 3: K. pneumoniae Number Analyzed 28 participants 27 participants
28
 100.0%
23
  85.2%
EOIVT: K. pneumoniae Number Analyzed 28 participants 27 participants
28
 100.0%
26
  96.3%
EOT: K. pneumoniae Number Analyzed 28 participants 27 participants
26
  92.9%
24
  88.9%
TOC: K. pneumoniae Number Analyzed 28 participants 27 participants
18
  64.3%
13
  48.1%
LFU: K. pneumoniae Number Analyzed 28 participants 27 participants
15
  53.6%
11
  40.7%
15.Secondary Outcome
Title Pharmacokinetic (PK) Characterization Of Plasma Exposure Of Meropenem/Vaborbactam
Hide 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. Sparse PK sampling on Day 1 was performed 3-3.5 hours and 5-6 hours after the start of the first 3-h 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 curve (AUC) was generated using a Population PK model and post hoc estimates of each participants' PK parameters, including AUC0-24, were generated.

The AUC during 24 hours (AUC0-24) for Day 1 and at steady-state are presented in micrograms (ug)·hour/mL.

Time Frame Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: Participants in the MITT population (all participants screened, randomized, and 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 (1 g meropenem/1 g vaborbactam).
Arm/Group Title Meropenem-Vaborbactam
Hide Arm/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. Treatment was administered for up to 14 days.

AUC0-24 Steady-State estimates not available for 2 participants who received >3 doses.

Overall Number of Participants Analyzed 272
Mean (Standard Deviation)
Unit of Measure: ug·hour/mL
AUC0-24: Day 1 803  (45.3)
AUC0-24: Steady-State 798  (60.6)
Time Frame Days 1 (Screening) through 30 (Follow Up).
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Meropenem-Vaborbactam Piperacillin-Tazobactam
Hide Arm/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 therapy could be administered IV. 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 therapy could be administered IV.
All-Cause Mortality
Meropenem-Vaborbactam Piperacillin-Tazobactam
Affected / at Risk (%) Affected / at Risk (%)
Total   2/272 (0.74%)   2/273 (0.73%) 
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Meropenem-Vaborbactam Piperacillin-Tazobactam
Affected / at Risk (%) Affected / at Risk (%)
Total   11/272 (4.04%)   12/273 (4.40%) 
Cardiac disorders     
Cardiac failure congestive  1  1/272 (0.37%)  0/273 (0.00%) 
General disorders     
Sudden cardiac death  1  1/272 (0.37%)  0/273 (0.00%) 
Infections and infestations     
Bacterial sepsis  1  0/272 (0.00%)  1/273 (0.37%) 
Pneumonia  1  0/272 (0.00%)  1/273 (0.37%) 
Postoperative wound infection  1  0/272 (0.00%)  1/273 (0.37%) 
Pyelonephritis  1  0/272 (0.00%)  1/273 (0.37%) 
Salpingo-oophoritis  1  1/272 (0.37%)  0/273 (0.00%) 
Sepsis  1  1/272 (0.37%)  0/273 (0.00%) 
Septic shock  1  1/272 (0.37%)  1/273 (0.37%) 
Urinary tract infection  1  0/272 (0.00%)  2/273 (0.73%) 
Injury, poisoning and procedural complications     
Infusion related reaction  1  1/272 (0.37%)  0/273 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Colon cancer  1  1/272 (0.37%)  1/273 (0.37%) 
Rectal neoplasm  1  1/272 (0.37%)  0/273 (0.00%) 
Nervous system disorders     
Cerebrovascular accident  1  0/272 (0.00%)  1/273 (0.37%) 
Convulsion  1  0/272 (0.00%)  1/273 (0.37%) 
Renal and urinary disorders     
Azotaemia  1  1/272 (0.37%)  0/273 (0.00%) 
Calculus ureteric  1  1/272 (0.37%)  0/273 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Aspiration  1  1/272 (0.37%)  0/273 (0.00%) 
Pulmonary embolism  1  0/272 (0.00%)  1/273 (0.37%) 
Vascular disorders     
Deep vein thrombosis  1  1/272 (0.37%)  0/273 (0.00%) 
Thrombophlebitis superficial  1  0/272 (0.00%)  1/273 (0.37%) 
1
Term from vocabulary, MedDRA version 17.0
Indicates events were collected by systematic assessment
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Frequency Threshold for Reporting Other Adverse Events 2%
Meropenem-Vaborbactam Piperacillin-Tazobactam
Affected / at Risk (%) Affected / at Risk (%)
Total   36/272 (13.24%)   31/273 (11.36%) 
Gastrointestinal disorders     
Diarrhoea  1  9/272 (3.31%)  12/273 (4.40%) 
General disorders     
Infusion Site Phlebitis  1  6/272 (2.21%)  2/273 (0.73%) 
Infections and infestations     
Vaginal Infection  1  1/272 (0.37%)  6/273 (2.20%) 
Nervous system disorders     
Headache  1  24/272 (8.82%)  12/273 (4.40%) 
1
Term from vocabulary, MedDRA version 17.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Global Health Science Center
Organization: The Medicines Company
Phone: 888-977-6326
Responsible Party: Melinta Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT02166476     History of Changes
Other Study ID Numbers: Rempex 505
First Submitted: June 16, 2014
First Posted: June 18, 2014
Results First Submitted: April 18, 2017
Results First Posted: October 26, 2017
Last Update Posted: June 11, 2018