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

NCT02493764 | Completed Phase 3 Results DMC

• 4 other identifiers: 7655A-0142015-000246-34163240MK-7655A-014
• Study Type: interventional
• Target: 537
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Bacterial Pneumonia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (21)

• Percentage of Participants in the MITT Population With a Favorable Clinical Response (FCR) at Early Follow-up (EFU) Visit

  Up to 16 days after end of therapy (up to 30 days)

• Percentage of Participants With ≥1 Adverse Event (AE)

  Up to 30 days

• Percentage of Participants Discontinuing Study Therapy Due to an AE

  Up to 14 days

• Percentage of Participants With ACM in the Microbiological Modified Intention-to-treat (mMITT) Population

  Up to 28 days

• Percentage of Participants With ACM at EFU in the MITT Population

  Up to 16 days after end of therapy (up to 30 days)

Study Arms (2)

IMI/REL

EXPERIMENTAL

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; Drug: Relebactam; Drug: Cilastatin; Drug: Linezolid

PIP/TAZ

ACTIVE COMPARATOR

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; Drug: Tazobactam; Drug: Linezolid

Interventions

Imipenem DRUG

Imipenem 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days

IMI/REL

Relebactam DRUG

Relebactam 250 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days

IMI/REL

Cilastatin DRUG

Cilastatin 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days

IMI/REL

Piperacillin DRUG

Piperacillin 4000 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days

PIP/TAZ

Tazobactam DRUG

Tazobactam 500 mg as part of a FDC administered by IV every 6 hours for a minimum of 7 days, up to 14 days

PIP/TAZ

Linezolid DRUG

Linezolid 600 mg administered open-label by IV every 12 hours for up to 14 days

IMI/REL; PIP/TAZ

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (3)

• Martin-Loeches I, Shorr AF, Kollef MH, Du J, Losada MC, Paschke A, DeRyke CA, Wong M, Jensen EH, Chen LF. Participant- and Disease-Related Factors as Independent Predictors of Treatment Outcomes in the RESTORE-IMI 2 Clinical Trial: A Multivariable Regression Analysis. Open Forum Infect Dis. 2023 May 4;10(6):ofad225. doi: 10.1093/ofid/ofad225. eCollection 2023 Jun.

  PMID: 37383243 DERIVED

• 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.

  PMID: 34704389 DERIVED

• 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.

  PMID: 32785589 DERIVED

MeSH Terms

Conditions

Pneumonia, Bacterial

Interventions

Imipenem; relebactam; Cilastatin; Piperacillin; Tazobactam; Linezolid

Condition Hierarchy (Ancestors)

Bacterial Infections; Bacterial Infections and Mycoses; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Ampicillin; Penicillin G; Penicillins; Sulfur Compounds; Penicillanic Acid; Sulfones; Acetamides; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 7, 2015
• First Posted: July 9, 2015
• Study Start: November 24, 2015
• Primary Completion: April 3, 2019
• Study Completion: April 3, 2019
• Last Updated: April 16, 2020
• Results First Posted: April 16, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share