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Completed

NCT Number: NCT02493764

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

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.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

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

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

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

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

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

Linezolid

Drug

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

Primary outcomes

  1. 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 outcomes

  1. 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).

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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"]).

  8. 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"]).

  9. 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"]).

  10. 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).

  11. 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).

  12. 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).

  13. 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"]).

  14. 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"]).

  15. 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"]).

  16. 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).

  17. 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).

  18. 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).

  19. 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).

  20. 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).

  21. 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).

Sponsors and collaborators

Lead sponsor

Merck Sharp & Dohme LLC

Industry

Registry information

Official study 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

Acronym: RESTORE-IMI 2

Important dates

Study start
2015
Primary completion
2019
Study completion
2019
First posted
Jul 9, 2015
Registry last updated
Apr 16, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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