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 |
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Recruitment Status :
Completed
First Posted : July 9, 2015
Results First Posted : April 16, 2020
Last Update Posted : April 16, 2020
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Sponsor:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Bacterial Pneumonia | Drug: Imipenem Drug: Relebactam Drug: Cilastatin Drug: Piperacillin Drug: Tazobactam Drug: Linezolid | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 537 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | November 24, 2015 |
| Actual Primary Completion Date : | April 3, 2019 |
| Actual Study Completion Date : | April 3, 2019 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Pneumonia
| Arm | Intervention/treatment |
|---|---|
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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.
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Drug: 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 Drug: 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 Drug: 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 Drug: Linezolid Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days |
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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.
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Drug: 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 Drug: 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 Drug: Linezolid Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days |
Primary Outcome Measures :
- Percentage of Participants With All-cause Mortality (ACM) Through Day 28 in the Modified Intention-to-treat (MITT) Population [ Time Frame: Up to 28 days ]The percentage of participants in the MITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
Secondary Outcome Measures :
- Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit [ Time Frame: Up to 16 days after end of therapy (up to 30 days) ]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).
- Percentage of Participants With ≥1 Adverse Event (AE) [ Time Frame: Up to 30 days ]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.
- Percentage of Participants Discontinuing Study Therapy Due to an AE [ Time Frame: Up to 14 days ]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.
- Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population [ Time Frame: Up to 28 days ]The percentage of participants in the mMITT population with mortality due to any cause from randomization through Day 28 was determined for each arm.
- Percentage of Participants With ACM at EFU in the MITT Population [ Time Frame: Up to 16 days after end of therapy (up to 30 days) ]The percentage of participants in the MITT population with mortality due to any cause from randomization through EFU was determined for each arm.
- Percentage of Participants With ACM at EFU in the mMITT Population [ Time Frame: Up to 16 days after end of therapy (up to 30 days) ]The percentage of participants in the mMITT population with mortality due to any cause from randomization through EFU was determined for each arm.
- Percentage of Participants in the Clinically Evaluable (CE) Population With a FCR at On-therapy Visit 1 (OTX1) [Day 3] [ Time Frame: Day 3 (OTX1) ]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"]).
- Percentage of Participants in the CE Population With a FCR at OTX2 (Day 6) [ Time Frame: Day 6 (OTX2) ]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"]).
- Percentage of Participants in the CE Population With a FCR at OTX3 (Day 10) [ Time Frame: Day 10 (OTX3) ]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"]).
- Percentage of Participants in the CE Population With a FCR at EOT Visit [ Time Frame: From Day 7 to Day 14 ]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).
- Percentage of Participants in the CE Population With a FCR at Day 28 [ Time Frame: 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).
- Percentage of Participants in the CE Population With a FCR at EFU Visit [ Time Frame: Up to 16 days after end of therapy (up to Day 30) ]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).
- Percentage of Participants in the MITT Population With a FCR at OTX1 (Day 3) [ Time Frame: Day 3 (OTX1) ]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"]).
- Percentage of Participants in the MITT Population With a FCR at OTX2 (Day 6) [ Time Frame: Day 6 (OTX2) ]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"]).
- Percentage of Participants in the MITT Population With a FCR at OTX3 (Day 10) [ Time Frame: Day 10 (OTX3) ]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"]).
- Percentage of Participants in the MITT Population With a FCR at EOT [ Time Frame: From Day 7 to Day 14 ]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).
- Percentage of Participants in the MITT Population With a FCR at Day 28 [ Time Frame: 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).
- Percentage of Participants in the mMITT Population With a Favorable Microbiological Response (FMR) at End of Treatment (EOT) Visit [ Time Frame: From Day 7 to Day 14 ]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).
- Percentage of Participants in the mMITT Population With a FMR at EFU Visit [ Time Frame: Up to 16 days after end of therapy (up to Day 30) ]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).
- Percentage of Participants in the Microbiologically Evaluable (ME) Population With a FMR at EOT Visit [ Time Frame: From Day 7 to Day 14 ]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).
- Percentage of Participants in the ME Population With a FMR at EFU Visit [ Time Frame: Up to 16 days after end of therapy (up to Day 30) ]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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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02493764
Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
| Study Director: | Medical Director | Merck Sharp & Dohme LLC |
Study Documents (Full-Text)
Documents provided by Merck Sharp & Dohme LLC:
Documents provided by Merck Sharp & Dohme LLC:
Study Protocol and Statistical Analysis Plan [PDF] September 6, 2018
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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 Posted: | July 9, 2015 Key Record Dates |
| Results First Posted: | April 16, 2020 |
| Last Update Posted: | April 16, 2020 |
| Last Verified: | March 2020 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf |
| URL: | http://engagezone.msd.com/ds_documentation.php |
Additional relevant MeSH terms:
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Pneumonia Pneumonia, Bacterial Respiratory Tract Infections Infections Lung Diseases Respiratory Tract Diseases Bacterial Infections Bacterial Infections and Mycoses Tazobactam Linezolid Piperacillin |
Imipenem Relebactam Cilastatin Anti-Bacterial Agents Anti-Infective Agents beta-Lactamase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Protein Synthesis Inhibitors Protease Inhibitors |