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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02493764
Registration number
NCT02493764
Ethics application status
Date submitted
7/07/2015
Date registered
9/07/2015
Date last updated
16/04/2020
Titles & IDs
Public title
Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014)
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Scientific title
A Phase III, Randomized, Double-Blind, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Subjects With Hospital-Acquired Bacterial Pneumonia or Ventilator-Associated Bacterial Pneumonia
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Secondary ID [1]
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2015-000246-34
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Secondary ID [2]
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7655A-014
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Universal Trial Number (UTN)
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Trial acronym
RESTORE-IMI 2
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Bacterial Pneumonia
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Infection
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Other infectious diseases
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Infection
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Studies of infection and infectious agents
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Imipenem
Treatment: Drugs - Relebactam
Treatment: Drugs - Cilastatin
Treatment: Drugs - Piperacillin
Treatment: Drugs - Tazobactam
Treatment: Drugs - Linezolid
Experimental: IMI/REL - Imipenem 500 mg + relebactam 250 mg + cilastatin 500 mg as a FDC administered intravenously (IV) every 6 hours for a minimum of 7 days, up to 14 days. At study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.
Active Comparator: PIP/TAZ - 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 study entry open label linezolid 600 mg will also be administered by IV every 12 hours for up to 14 days.
Treatment: Drugs: Imipenem
Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
Treatment: Drugs: Relebactam
Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
Treatment: Drugs: Cilastatin
Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
Treatment: Drugs: Piperacillin
Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
Treatment: Drugs: Tazobactam
Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days
Treatment: Drugs: Linezolid
Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population
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Assessment method [1]
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The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
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Timepoint [1]
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Up to 28 days
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Secondary outcome [1]
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Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit
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Assessment method [1]
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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).
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Timepoint [1]
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Up to 16 days after end of therapy (up to 30 days)
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Secondary outcome [2]
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Percentage of Participants With =1 Adverse Event (AE)
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Assessment method [2]
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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.
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Timepoint [2]
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Up to 30 days
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Secondary outcome [3]
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Percentage of Participants Discontinuing Study Therapy Due to an AE
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Assessment method [3]
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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.
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Timepoint [3]
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Up to 14 days
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Secondary outcome [4]
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Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population
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Assessment method [4]
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The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
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Timepoint [4]
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Up to 28 days
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Secondary outcome [5]
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Percentage of Participants With ACM at EFU in the MITT Population
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Assessment method [5]
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The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.
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Timepoint [5]
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Up to 16 days after end of therapy (up to 30 days)
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Secondary outcome [6]
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Percentage of Participants With ACM at EFU in the mMITT Population
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Assessment method [6]
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The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.
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Timepoint [6]
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Up to 16 days after end of therapy (up to 30 days)
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Secondary outcome [7]
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Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3]
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Assessment method [7]
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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"]).
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Timepoint [7]
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Day 3 (OTX1)
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Secondary outcome [8]
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Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6)
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Assessment method [8]
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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"]).
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Timepoint [8]
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Day 6 (OTX2)
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Secondary outcome [9]
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Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10)
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Assessment method [9]
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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"]).
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Timepoint [9]
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Day 10 (OTX3)
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Secondary outcome [10]
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Percentage of Participants in the CE Population With a FCR at EOT Visit
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Assessment method [10]
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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).
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Timepoint [10]
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From Day 7 to Day 14
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Secondary outcome [11]
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Percentage of Participants in the CE Population With a FCR at Day 28
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Assessment method [11]
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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).
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Timepoint [11]
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Day 28
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Secondary outcome [12]
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Percentage of Participants in the CE Population With a FCR at EFU Visit
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Assessment method [12]
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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).
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Timepoint [12]
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Up to 16 days after end of therapy (up to Day 30)
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Secondary outcome [13]
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Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3)
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Assessment method [13]
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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"]).
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Timepoint [13]
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Day 3 (OTX1)
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Secondary outcome [14]
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Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6)
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Assessment method [14]
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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"]).
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Timepoint [14]
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Day 6 (OTX2)
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Secondary outcome [15]
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Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10)
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Assessment method [15]
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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"]).
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Timepoint [15]
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Day 10 (OTX3)
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Secondary outcome [16]
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Percentage of Participants in the MITT Population With a FCR at EOT
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Assessment method [16]
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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).
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Timepoint [16]
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From Day 7 to Day 14
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Secondary outcome [17]
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Percentage of Participants in the MITT Population With a FCR at Day 28
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Assessment method [17]
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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).
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Timepoint [17]
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Day 28
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Secondary outcome [18]
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Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit
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Assessment method [18]
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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).
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Timepoint [18]
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From Day 7 to Day 14
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Secondary outcome [19]
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Percentage of Participants in the mMITT Population With a FMR at EFU Visit
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Assessment method [19]
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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).
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Timepoint [19]
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Up to 16 days after end of therapy (up to Day 30)
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Secondary outcome [20]
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Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit
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Assessment method [20]
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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).
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Timepoint [20]
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From Day 7 to Day 14
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Secondary outcome [21]
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Percentage of Participants in the ME Population With a FMR at EFU Visit
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Assessment method [21]
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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).
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Timepoint [21]
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Up to 16 days after end of therapy (up to Day 30)
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Eligibility
Key inclusion criteria
- Requires treatment with IV antibiotic therapy for hospital-acquired bacterial
pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP)
- Fulfills clinical and radiographic criteria, with onset of criteria occurring after
more than 48 hours of hospitalization or within 7 days after discharge from a hospital
(for HABP); or at least 48 hours after mechanical ventilation (for VABP)
- Has an adequate baseline lower respiratory tract specimen obtained for Gram stain and
culture
- Has an infection known or thought to be caused by microorganisms susceptible to the IV
study therapy
- Agrees to allow any bacterial isolates obtained from protocol-required specimens
related to the current infection to be provided to the Central Microbiology Reference
Laboratory for study-related microbiological testing, long term storage, and other
future testing
- Is not of reproductive potential; or if of reproductive potential agrees to avoid
impregnating a partner or avoid becoming pregnant, by practicing abstinence or using
acceptable contraception
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Has a baseline lower respiratory tract specimen Gram stain that shows the presence of
Gram-positive cocci only
- Has confirmed or suspected community-acquired bacterial pneumonia (CABP)
- Has confirmed or suspected pneumonia of viral, fungal or parasitic origin
- Has HABP/VABP caused by an obstructive process, including lung cancer or other known
obstruction
- Has a carcinoid tumor or carcinoid syndrome
- Has active immunosuppression defined as either receiving immunosuppressive medications
or having a medical condition associated with immunodeficiency
- Is expected to survive for less than 72 hours
- Has a concurrent condition or infection that would preclude evaluation of therapeutic
response
- Has received effective antibacterial drug therapy for the index infection of HABP/VABP
for more than 24 hours continuously, during the previous 72 hours
- Has a history of serious allergy, hypersensitivity or a serious reaction to any
penicillin or beta-lactamase inhibitors
- Female is pregnant, expecting to conceive, is breastfeeding or plans to breastfeed
- Has a history of seizure disorder requiring ongoing prior treatment with
anti-convulsive therapy within the last 3 years
- Anticipates treatment with the following: valproic acid or divalproex sodium,
serotonin re-uptake inhibitors, tricyclic antidepressants, or serotonin receptor
antagonists, meperidine, buspirone, concomitant systemic antibacterial agents,
antifungal or antiviral therapy for the index infection of HABP/VABP
- Is currently undergoing hemodialysis or peritoneal dialysis
- Is currently participating in, has participated in during the previous 30 days, or
anticipates to participate in any other clinical study involving the administration of
experimental medication
- Has previously participated in this study
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
24/11/2015
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
3/04/2019
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Sample size
Target
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Accrual to date
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Final
537
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Recruitment in Australia
Recruitment state(s)
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Merck Sharp & Dohme LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This study aims to compare treatment with a fixed-dose combination (FDC) of
imipenem/relebactam/cilastatin (IMI/REL) with a FDC of piperacillin/tazobactam (PIP/TAZ) in
participants with hospital-acquired or ventilator-associated bacterial pneumonia (HABP or
VAPB, respectively). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ in the
incidence rate of all-cause mortality.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02493764
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
Name
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02493764
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