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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Bacterial Pneumonia

Intervention / Treatment
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* Drug: Imipenem
* Drug: Relebactam
* Drug: Cilastatin
* Drug: Piperacillin
* Drug: Tazobactam
* Drug: Linezolid


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMI/REL<br>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. | Drug: Imipenem<br>* Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days<br>Drug: Relebactam<br>* Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days<br>Drug: Cilastatin<br>* Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days<br>Drug: Linezolid<br>* Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days<br>|
| Active Comparator: PIP/TAZ<br>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. | Drug: Piperacillin<br>* Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days<br>Drug: Tazobactam<br>* Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days<br>Drug: Linezolid<br>* Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population | The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit | 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). | Up to 16 days after end of therapy (up to 30 days) | 
| Percentage of Participants With ≥1 Adverse Event (AE) | 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. | Up to 30 days | 
| Percentage of Participants Discontinuing Study Therapy Due to an AE | 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. | Up to 14 days | 
| Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population | The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm. | Up to 28 days | 
| Percentage of Participants With ACM at EFU in the MITT Population | The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm. | Up to 16 days after end of therapy (up to 30 days) | 
| Percentage of Participants With ACM at EFU in the mMITT Population | The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm. | Up to 16 days after end of therapy (up to 30 days) | 
| Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] | 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]). | Day 3 (OTX1) | 
| Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) | 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]). | Day 6 (OTX2) | 
| Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) | 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]). | Day 10 (OTX3) | 
| Percentage of Participants in the CE Population With a FCR at EOT Visit | 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). | From Day 7 to Day 14 | 
| Percentage of Participants in the CE Population With a FCR at Day 28 | 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). | Day 28 | 
| Percentage of Participants in the CE Population With a FCR at EFU Visit | 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). | Up to 16 days after end of therapy (up to Day 30) | 
| Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) | 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]). | Day 3 (OTX1) | 
| Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) | 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]). | Day 6 (OTX2) | 
| Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) | 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]). | Day 10 (OTX3) | 
| Percentage of Participants in the MITT Population With a FCR at EOT | 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). | From Day 7 to Day 14 | 
| Percentage of Participants in the MITT Population With a FCR at Day 28 | 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). | Day 28 | 
| Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit | 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). | From Day 7 to Day 14 | 
| Percentage of Participants in the mMITT Population With a FMR at EFU Visit | 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). | Up to 16 days after end of therapy (up to Day 30) | 
| Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit | 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). | From Day 7 to Day 14 | 
| Percentage of Participants in the ME Population With a FMR at EFU Visit | 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). | Up to 16 days after end of therapy (up to Day 30) |