Clinical trial NCT02493764: Imipenem/Relebactam/Cilastatin Versus Piperacillin/Tazobactam for Treatment of Participants With Bacterial Pneumonia (MK-7655A-014)
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Bacterial Pneumonia
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-07-09
Enrollment: 537
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

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

Primary outcomes:
measure: Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population
timeFrame: Up to 28 days
Secondary outcomes:
measure: Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit
timeFrame: Up to 16 days after end of therapy (up to 30 days)
measure: Percentage of Participants With ≥1 Adverse Event (AE)
timeFrame: Up to 30 days
measure: Percentage of Participants Discontinuing Study Therapy Due to an AE
timeFrame: Up to 14 days
measure: Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population
timeFrame: Up to 28 days
measure: Percentage of Participants With ACM at EFU in the MITT Population
timeFrame: Up to 16 days after end of therapy (up to 30 days)
measure: Percentage of Participants With ACM at EFU in the mMITT Population
timeFrame: Up to 16 days after end of therapy (up to 30 days)
measure: Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3]
timeFrame: Day 3 (OTX1)
measure: Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6)
timeFrame: Day 6 (OTX2)
measure: Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10)
timeFrame: Day 10 (OTX3)
measure: Percentage of Participants in the CE Population With a FCR at EOT Visit
timeFrame: From Day 7 to Day 14
measure: Percentage of Participants in the CE Population With a FCR at Day 28
timeFrame: Day 28
measure: Percentage of Participants in the CE Population With a FCR at EFU Visit
timeFrame: Up to 16 days after end of therapy (up to Day 30)
measure: Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3)
timeFrame: Day 3 (OTX1)
measure: Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6)
timeFrame: Day 6 (OTX2)
measure: Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10)
timeFrame: Day 10 (OTX3)
measure: Percentage of Participants in the MITT Population With a FCR at EOT
timeFrame: From Day 7 to Day 14
measure: Percentage of Participants in the MITT Population With a FCR at Day 28
timeFrame: Day 28
measure: Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit
timeFrame: From Day 7 to Day 14
measure: Percentage of Participants in the mMITT Population With a FMR at EFU Visit
timeFrame: Up to 16 days after end of therapy (up to Day 30)
measure: Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit
timeFrame: From Day 7 to Day 14
measure: Percentage of Participants in the ME Population With a FMR at EFU Visit
timeFrame: Up to 16 days after end of therapy (up to Day 30)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Patel M, Bellanti F, Daryani NM, Noormohamed N, Hilbert DW, Young K, Kulkarni P, Copalu W, Gheyas F, Rizk ML. Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital-acquired/ventilator-associated bacterial pneumonia. Clin Transl Sci. 2022 Feb;15(2):396-408. doi: 10.1111/cts.13158. Epub 2021 Oct 27.
citation: Titov I, Wunderink RG, Roquilly A, Rodriguez Gonzalez D, David-Wang A, Boucher HW, Kaye KS, Losada MC, Du J, Tipping R, Rizk ML, Patel M, Brown ML, Young K, Kartsonis NA, Butterton JR, Paschke A, Chen LF. A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. 2021 Dec 6;73(11):e4539-e4548. doi: 10.1093/cid/ciaa803.