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

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

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.

Study Overview

• Status: Completed
• Conditions: Bacterial Pneumonia
• Intervention / Treatment: Drug: Imipenem; Drug: Relebactam; Drug: Cilastatin; Drug: Linezolid; Drug: Piperacillin; Drug: Tazobactam

• Study Type: Interventional
• Enrollment (Actual): 537
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	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
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.	Drug: Linezolid; Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days; 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 24, 2015
• Primary Completion (ACTUAL): April 3, 2019
• Study Completion (ACTUAL): April 3, 2019

Study Registration Dates

• First Submitted: July 7, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (ESTIMATE): July 9, 2015

Study Record Updates

• Last Update Posted (ACTUAL): April 16, 2020
• Last Update Submitted That Met QC Criteria: April 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Pneumonia; Pneumonia, Bacterial; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; beta-Lactamase Inhibitors; Linezolid; Imipenem; Relebactam; Cilastatin; Piperacillin; Tazobactam
• Other Study ID Numbers: 7655A-014; 2015-000246-34 (EUDRACT_NUMBER); 163240 (REGISTRY: JAPIC-CTI); MK-7655A-014 (OTHER: Merck Protocol Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf