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Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014) (RESTORE-IMI 2)

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ClinicalTrials.gov Identifier: NCT02493764
Recruitment Status : Completed
First Posted : July 9, 2015
Results First Posted : April 16, 2020
Last Update Posted : April 16, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Bacterial Pneumonia
Interventions Drug: Imipenem
Drug: Relebactam
Drug: Cilastatin
Drug: Piperacillin
Drug: Tazobactam
Drug: Linezolid
Enrollment 537
Recruitment Details Adult male and female participants requiring intravenous (IV) therapy for hospital-acquired bacterial pneumonia (HABP) or ventilator-assisted bacterial pneumonia (VABP) were recruited at 120 study centers in 28 countries.
Pre-assignment Details  
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a fixed dose combination (FDC) administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until methicillin-resistant Staphylococcus aureus (MRSA) was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Period Title: Overall Study
Started 268 269
Completed 185 187
Not Completed 83 82
Reason Not Completed
Adverse Event             2             2
Death             44             58
Lost to Follow-up             2             1
Protocol Violation             6             7
Physician Decision             1             1
Participant moved             17             5
Withdrawal parent/guardian             0             1
Withdrawal by Subject             11             7
Arm/Group Title IMI/REL PIP/TAZ Total
Hide Arm/Group Description Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. Total of all reporting groups
Overall Number of Baseline Participants 268 269 537
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 268 participants 269 participants 537 participants
60.4  (17.0) 58.9  (18.4) 59.7  (17.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 268 participants 269 participants 537 participants
Female
86
  32.1%
78
  29.0%
164
  30.5%
Male
182
  67.9%
191
  71.0%
373
  69.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 268 participants 269 participants 537 participants
Hispanic or Latino
56
  20.9%
55
  20.4%
111
  20.7%
Not Hispanic or Latino
209
  78.0%
205
  76.2%
414
  77.1%
Unknown or Not Reported
3
   1.1%
9
   3.3%
12
   2.2%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 268 participants 269 participants 537 participants
American Indian or Alaska Native
5
   1.9%
8
   3.0%
13
   2.4%
Asian
42
  15.7%
37
  13.8%
79
  14.7%
Native Hawaiian or Other Pacific Islander
0
   0.0%
1
   0.4%
1
   0.2%
Black or African American
4
   1.5%
6
   2.2%
10
   1.9%
White
208
  77.6%
209
  77.7%
417
  77.7%
More than one race
9
   3.4%
7
   2.6%
16
   3.0%
Unknown or Not Reported
0
   0.0%
1
   0.4%
1
   0.2%
1.Primary Outcome
Title Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population
Hide Description The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time Frame Up to 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline lower respiratory tract (LRT) specimen.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
15.9 21.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in all-cause mortality
Type of Statistical Test Non-Inferiority
Comments Non-inferiority was declared when the upper bound of the 2-sided 95% confidence interval (CI) for the difference in mortality (IMI/REL minus PIP/TAZ) was < 10 percentage points.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method t-test, 1 sided
Comments A one-sided alpha level of 0.025 was used to declare significance.
Method of Estimation Estimation Parameter Adjusted difference in ACM
Estimated Value -5.3
Confidence Interval (2-Sided) 95%
-11.9 to 1.2
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
2.Secondary Outcome
Title Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit
Hide Description The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame Up to 16 days after end of therapy (up to 30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline LRT specimen.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
61.0 55.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in FCR
Type of Statistical Test Non-Inferiority
Comments Non-inferiority was declared when the lower bound of the 2-sided 95% CI for the difference in FCR (IMI/REL minus PIP/TAZ) was > 12.5 percentage points.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method t-test, 1 sided
Comments A one-sided alpha level of 0.025 was used to declare significance.
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 5.0
Confidence Interval (2-Sided) 95%
-3.2 to 13.2
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
3.Secondary Outcome
Title Percentage of Participants With ≥1 Adverse Event (AE)
Hide Description An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time Frame Up to 30 days
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received ≥1 dose of study therapy are included.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 266 269
Measure Type: Number
Unit of Measure: Percentage of participants
85.0 86.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments [Not Specified]
Type of Statistical Test Other
Comments Difference in % with AE vs PIP/TAZ
Method of Estimation Estimation Parameter Difference in % with AE
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-7.7 to 4.3
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants Discontinuing Study Therapy Due to an AE
Hide Description An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time Frame Up to 14 days
Hide Outcome Measure Data
Hide Analysis Population Description
All participants who received ≥1 dose of study therapy are included.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 266 269
Measure Type: Number
Unit of Measure: Percentage of participants
5.6 8.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments [Not Specified]
Type of Statistical Test Other
Comments Difference in % discontinuing vs PIP/TAZ
Method of Estimation Estimation Parameter Difference in % discontinuing
Estimated Value -2.5
Confidence Interval (2-Sided) 95%
-7.1 to 1.8
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population
Hide Description The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Time Frame Up to 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 215 218
Measure Type: Number
Unit of Measure: Percentage of participants
16.7 20.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in all-cause mortality
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Adjusted difference in ACM
Estimated Value -3.5
Confidence Interval (2-Sided) 95%
-10.9 to 3.6
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
6.Secondary Outcome
Title Percentage of Participants With ACM at EFU in the MITT Population
Hide Description The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time Frame Up to 16 days after end of therapy (up to 30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci on Gram stain of the baseline specimen.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
14.8 19.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in all-cause mortality
Type of Statistical Test Non-Inferiority
Comments Non-inferiority was declared when the upper bound of the 2-sided 95% CI for the difference in mortality (IMI/REL minus PIP/TAZ) was ≥ 10 percentage points.
Method of Estimation Estimation Parameter Adjusted difference in ACM
Estimated Value -4.6
Confidence Interval (2-Sided) 95%
-11.0 to 1.7
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
7.Secondary Outcome
Title Percentage of Participants With ACM at EFU in the mMITT Population
Hide Description The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.
Time Frame Up to 16 days after end of therapy (up to 30 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population includes all randomized participants who received ≥1 dose of study treatment and did not have only gram-positive cocci only on baseline Gram stain and who have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 215 218
Measure Type: Number
Unit of Measure: Percentage of participants
15.3 18.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in all-cause mortality
Type of Statistical Test Other
Comments Adjusted difference in ACM
Method of Estimation Estimation Parameter Adjusted difference in ACM
Estimated Value -3.1
Confidence Interval (2-Sided) 95%
-10.2 to 3.8
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
8.Secondary Outcome
Title Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3]
Hide Description The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 3 (OTX1)
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 3 clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 171 165
Measure Type: Number
Unit of Measure: Percentage of participants
70.8 72.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-11.3 to 7.8
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
9.Secondary Outcome
Title Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6)
Hide Description The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 6 (OTX2)
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 6 clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 171 165
Measure Type: Number
Unit of Measure: Percentage of participants
85.5 87.8
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value -2.2
Confidence Interval (2-Sided) 95%
-9.8 to 5.5
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
10.Secondary Outcome
Title Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10)
Hide Description The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 10 (OTX3)
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 10 clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 171 165
Measure Type: Number
Unit of Measure: Percentage of participants
89.6 83.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in favorable clinical response
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 6.6
Confidence Interval (2-Sided) 95%
-4.6 to 18.4
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
11.Secondary Outcome
Title Percentage of Participants in the CE Population With a FCR at EOT Visit
Hide Description The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame From Day 7 to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EOT clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 171 165
Measure Type: Number
Unit of Measure: Percentage of participants
84.7 85.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value -0.4
Confidence Interval (2-Sided) 95%
-8.1 to 7.4
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
12.Secondary Outcome
Title Percentage of Participants in the CE Population With a FCR at Day 28
Hide Description The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have Day 28 clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 147 144
Measure Type: Number
Unit of Measure: Percentage of participants
70.5 75.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value -3.4
Confidence Interval (2-Sided) 95%
-14.3 to 7.5
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
13.Secondary Outcome
Title Percentage of Participants in the CE Population With a FCR at EFU Visit
Hide Description The percentage of participants with a FCR at EFU was determined for each arm. Favorable clinical response at EFU was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame Up to 16 days after end of therapy (up to Day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
The CE population is all randomized participants with ≥1 dose of study therapy; had not only gram-positive cocci on baseline Gram stain; met important entry criteria; had no protocol deviations; received minimum duration of IV therapy; and have EFU clinical response data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 147 144
Measure Type: Number
Unit of Measure: Percentage of participants
74.3 79.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value -3.7
Confidence Interval (2-Sided) 95%
-13.6 to 6.4
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
14.Secondary Outcome
Title Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3)
Hide Description The percentage of participants with a FCR at OTX1 was determined for each arm. Favorable clinical response at OTX1 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 3 (OTX1)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 3 data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
68.0 64.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 3.5
Confidence Interval (2-Sided) 95%
-4.6 to 11.6
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
15.Secondary Outcome
Title Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6)
Hide Description The percentage of participants with a FCR at OTX2 was determined for each arm. Favorable clinical response at OTX2 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 6 (OTX2)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 6 data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
83.5 83.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 0.5
Confidence Interval (2-Sided) 95%
-6.3 to 7.4
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
16.Secondary Outcome
Title Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10)
Hide Description The percentage of participants with a FCR at OTX3 was determined for each arm. Favorable clinical response at OTX3 was defined as "improved" (majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"]).
Time Frame Day 10 (OTX3)
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 10 data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
83.5 80.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 3.4
Confidence Interval (2-Sided) 95%
-7.1 to 14.2
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
17.Secondary Outcome
Title Percentage of Participants in the MITT Population With a FCR at EOT
Hide Description The percentage of participants with a FCR at EOT was determined for each arm. Favorable clinical response at EOT was defined as either "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required) or "improved" (the majority of pre-therapy signs and symptoms of the index infection have improved or resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame From Day 7 to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have EOT data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
74.2 69.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 4.4
Confidence Interval (2-Sided) 95%
-3.1 to 12.0
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
18.Secondary Outcome
Title Percentage of Participants in the MITT Population With a FCR at Day 28
Hide Description The percentage of participants with a FCR at Day 28 was determined for each arm. Favorable clinical response at Day 28 was defined as either "sustained cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] with no evidence of resurgence and no additional antibiotics are required) or "cure" (all pre-therapy signs and symptoms of the index infection have resolved [or returned to "pre-infection status"] and no additional antibiotics are required).
Time Frame Day 28
Hide Outcome Measure Data
Hide Analysis Population Description
The MITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci on Gram stain of the baseline specimen, and have Day 28 data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 264 267
Measure Type: Number
Unit of Measure: Percentage of participants
51.9 50.6
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable clinical response
Type of Statistical Test Other
Comments Difference in FCR
Method of Estimation Estimation Parameter Adjusted difference in FCR
Estimated Value 1.1
Confidence Interval (2-Sided) 95%
-7.2 to 9.4
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
19.Secondary Outcome
Title Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit
Hide Description The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame From Day 7 to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EOT data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 215 218
Measure Type: Number
Unit of Measure: Percentage of participants
77.2 67.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable microbiological response
Type of Statistical Test Other
Comments Difference in FMR
Method of Estimation Estimation Parameter Adjusted difference in FMR
Estimated Value 9.7
Confidence Interval (2-Sided) 95%
1.6 to 17.9
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
20.Secondary Outcome
Title Percentage of Participants in the mMITT Population With a FMR at EFU Visit
Hide Description The percentage of participants with a FMR at EFU was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EFU showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame Up to 16 days after end of therapy (up to Day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
The mMITT population includes all randomized participants who received ≥1 dose of study treatment, did not have only gram-positive cocci only on baseline Gram stain, have a baseline bacterial pathogen identified as the cause of HABP/VABP against which IMI/REL has been shown to have antibacterial activity, and have EFU data.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 215 218
Measure Type: Number
Unit of Measure: Percentage of participants
67.9 61.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable microbiological response
Type of Statistical Test Other
Comments Difference in FMR
Method of Estimation Estimation Parameter Adjusted difference in FMR
Estimated Value 6.2
Confidence Interval (2-Sided) 95%
-2.7 to 15.0
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
21.Secondary Outcome
Title Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit
Hide Description The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame From Day 7 to Day 14
Hide Outcome Measure Data
Hide Analysis Population Description
The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EOT data and LRT culture available.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 140 133
Measure Type: Number
Unit of Measure: Percentage of participants
87.1 85.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable microbiological response
Type of Statistical Test Other
Comments Difference in FMR
Method of Estimation Estimation Parameter Adjusted difference in FMR
Estimated Value 2.5
Confidence Interval (2-Sided) 95%
-5.5 to 11.0
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
22.Secondary Outcome
Title Percentage of Participants in the ME Population With a FMR at EFU Visit
Hide Description The percentage of participants with a FMR at EOT was determined for each arm. Favorable microbiological response at EOT was defined as either "eradication" (a lower respiratory tract culture taken at EOT showing eradication of baseline pathogen) or "presumed eradication" (no specimen collected because the participant deemed clinically cured or improved).
Time Frame Up to 16 days after end of therapy (up to Day 30)
Hide Outcome Measure Data
Hide Analysis Population Description
The ME population is all randomized participants with ≥1 dose of study therapy; not only gram-positive cocci on baseline Gram stain; IMI/REL-sensitive baseline pathogen as cause of HABP/VABP; met entry criteria; no protocol deviations; received minimum duration of IV therapy; have microbiological EFU data and LRT culture available.
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description:
Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
Overall Number of Participants Analyzed 121 117
Measure Type: Number
Unit of Measure: Percentage of participants
89.9 86.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection IMI/REL, PIP/TAZ
Comments Adjusted difference in favorable microbiological response
Type of Statistical Test Other
Comments Difference in FMR
Method of Estimation Estimation Parameter Adjusted difference in FMR
Estimated Value 4.7
Confidence Interval (2-Sided) 95%
-4.0 to 14.1
Estimation Comments Adjusted difference and 95% CI are based on the Miettinen & Nurminen method.
Time Frame Up to 30 days
Adverse Event Reporting Description An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All randomized participants who received ≥1 dose of IV study therapy are included in the analysis.
 
Arm/Group Title IMI/REL PIP/TAZ
Hide Arm/Group Description Participants received imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of IMI/REL treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total. Participants received piperacillin 4000 mg + tazobactam 500 mg as a FDC administered IV every 6 hours for a minimum of 7 days, up to 14 days. At the start of PIP/TAZ treatment, participants were treated empirically with 600 mg open-label linezolid administered IV every 12 hours until MRSA was ruled out. Participants with confirmed MRSA infection continued to receive 600 mg linezolid every 12 hours for a minimum of 7 days, up to 14 days total.
All-Cause Mortality
IMI/REL PIP/TAZ
Affected / at Risk (%) Affected / at Risk (%)
Total   44/266 (16.54%)      58/269 (21.56%)    
Hide Serious Adverse Events
IMI/REL PIP/TAZ
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   71/266 (26.69%)      86/269 (31.97%)    
Blood and lymphatic system disorders     
Splenic lesion † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Thrombocytopenia † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Cardiac disorders     
Acute myocardial infarction † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Atrial fibrillation † 1  1/266 (0.38%)  1 2/269 (0.74%)  2
Atrioventricular block complete † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Bradycardia † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Cardiac arrest † 1  10/266 (3.76%)  12 7/269 (2.60%)  9
Cardiac failure † 1  2/266 (0.75%)  2 2/269 (0.74%)  2
Cardiac failure acute † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Cardiac failure congestive † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Cardio-respiratory arrest † 1  1/266 (0.38%)  1 2/269 (0.74%)  2
Cardiopulmonary failure † 1  2/266 (0.75%)  2 2/269 (0.74%)  2
Cardiovascular insufficiency † 1  3/266 (1.13%)  3 4/269 (1.49%)  4
Myocardial infarction † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Supraventricular tachycardia † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Tachyarrhythmia † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Gastrointestinal disorders     
Colitis ischaemic † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Diarrhoea † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Duodenal ulcer perforation † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Gastrointestinal haemorrhage † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Intestinal ischaemia † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Intestinal ulcer † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Large intestine perforation † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Mesenteric vein thrombosis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Small intestinal perforation † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
General disorders     
Brain death † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Death † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Multiple organ dysfunction syndrome † 1  1/266 (0.38%)  1 6/269 (2.23%)  6
Vascular stent thrombosis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Hepatobiliary disorders     
Hypertransaminasaemia † 1  0/266 (0.00%)  0 2/269 (0.74%)  2
Ischaemic hepatitis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Infections and infestations     
Bacteraemia † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Brain abscess † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Bronchitis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Carbuncle † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Endocarditis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Endocarditis bacterial † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Fungaemia † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Infectious pleural effusion † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Intervertebral discitis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Lung abscess † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Meningitis † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Neurological infection † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Peritonitis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Pneumonia † 1  6/266 (2.26%)  6 3/269 (1.12%)  3
Pneumonia acinetobacter † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Pneumonia staphylococcal † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Post procedural sepsis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Sepsis † 1  3/266 (1.13%)  3 3/269 (1.12%)  3
Septic shock † 1  7/266 (2.63%)  7 4/269 (1.49%)  4
Skin infection † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Spinal cord infection † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Tracheitis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Tuberculosis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Urinary tract infection † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Wound infection staphylococcal † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Injury, poisoning and procedural complications     
Endotracheal intubation complication † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Implant tissue necrosis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Spinal shock † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Splenic rupture † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Subdural haematoma † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Traumatic haemothorax † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Wound complication † 1  0/266 (0.00%)  0 1/269 (0.37%)  2
Wound evisceration † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Investigations     
Alanine aminotransferase increased † 1  3/266 (1.13%)  3 1/269 (0.37%)  1
Aspartate aminotransferase increased † 1  2/266 (0.75%)  2 1/269 (0.37%)  1
Hepatic enzyme increased † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Metabolism and nutrition disorders     
Diabetic ketoacidosis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Hyperkalaemia † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Gastric cancer † 1  0/266 (0.00%)  0 2/269 (0.74%)  2
Nervous system disorders     
Basilar artery thrombosis † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Brain dislocation syndrome † 1  1/266 (0.38%)  1 3/269 (1.12%)  3
Brain oedema † 1  0/266 (0.00%)  0 3/269 (1.12%)  3
Cerebral infarction † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Cerebrovascular accident † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Coma † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Generalised tonic-clonic seizure † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Haemorrhage intracranial † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Haemorrhagic stroke † 1  1/266 (0.38%)  1 3/269 (1.12%)  3
Hydrocephalus † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Intracranial pressure increased † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Ischaemic stroke † 1  1/266 (0.38%)  1 1/269 (0.37%)  1
Lethargy † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Seizure † 1  0/266 (0.00%)  0 1/269 (0.37%)  2
Subarachnoid haemorrhage † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Renal and urinary disorders     
Acute kidney injury † 1  0/266 (0.00%)  0 8/269 (2.97%)  8
Renal failure † 1  2/266 (0.75%)  2 1/269 (0.37%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Acute respiratory failure † 1  2/266 (0.75%)  2 1/269 (0.37%)  1
Aspiration † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Atelectasis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Haemothorax † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Hydrothorax † 1  2/266 (0.75%)  2 0/269 (0.00%)  0
Pleural effusion † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Pleural fibrosis † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Pneumonia aspiration † 1  4/266 (1.50%)  4 0/269 (0.00%)  0
Pneumothorax † 1  1/266 (0.38%)  1 2/269 (0.74%)  2
Pneumothorax spontaneous † 1  2/266 (0.75%)  2 0/269 (0.00%)  0
Pulmonary congestion † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Pulmonary embolism † 1  0/266 (0.00%)  0 2/269 (0.74%)  2
Pulmonary hypertension † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Respiratory depression † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Respiratory distress † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Respiratory failure † 1  2/266 (0.75%)  3 3/269 (1.12%)  3
Skin and subcutaneous tissue disorders     
Decubitus ulcer † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Vascular disorders     
Circulatory collapse † 1  3/266 (1.13%)  3 2/269 (0.74%)  2
Haematoma † 1  1/266 (0.38%)  1 0/269 (0.00%)  0
Haemodynamic instability † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Hypovolaemic shock † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
Shock haemorrhagic † 1  0/266 (0.00%)  0 1/269 (0.37%)  1
1
Term from vocabulary, MedDRA 22.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
IMI/REL PIP/TAZ
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   98/266 (36.84%)      105/269 (39.03%)    
Blood and lymphatic system disorders     
Anaemia † 1  28/266 (10.53%)  30 27/269 (10.04%)  28
Gastrointestinal disorders     
Diarrhoea † 1  21/266 (7.89%)  22 29/269 (10.78%)  32
General disorders     
Pyrexia † 1  11/266 (4.14%)  19 20/269 (7.43%)  29
Investigations     
Alanine aminotransferase increased † 1  23/266 (8.65%)  25 18/269 (6.69%)  18
Aspartate aminotransferase increased † 1  29/266 (10.90%)  31 19/269 (7.06%)  19
Metabolism and nutrition disorders     
Hypokalaemia † 1  18/266 (6.77%)  19 24/269 (8.92%)  25
Hyponatraemia † 1  14/266 (5.26%)  15 3/269 (1.12%)  3
Respiratory, thoracic and mediastinal disorders     
Hydrothorax † 1  11/266 (4.14%)  11 14/269 (5.20%)  17
1
Term from vocabulary, MedDRA 22.0
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp.
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme LLC
ClinicalTrials.gov Identifier: NCT02493764    
Other Study ID Numbers: 7655A-014
2015-000246-34 ( EudraCT Number )
163240 ( Registry Identifier: JAPIC-CTI )
MK-7655A-014 ( Other Identifier: Merck Protocol Number )
First Submitted: July 7, 2015
First Posted: July 9, 2015
Results First Submitted: April 3, 2020
Results First Posted: April 16, 2020
Last Update Posted: April 16, 2020