Clinical trial NCT03583333: Imipenem/Cilastatin/Relebactam (MK-7655A) Versus Piperacillin/Tazobactam in Participants With Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia (MK-7655A-016)
Official title: A Multi-national Phase 3, 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hospital-Acquired Bacterial Pneumonia
Ventilator-Associated Bacterial Pneumonia
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-07-11
Enrollment: 274
Sex: ALL
Minimum age (years): 18
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the efficacy and safety of a FDC of imipenem/cilastatin (IMI) and relebactam (REL) \[IMI/REL, MK-7655A\] compared to piperacillin/tazobactam (PIP/TAZ) in the treatment of adults diagnosed with Hospital-Acquired Bacterial Pneumonia (HABP) or Ventilator-Associated Bacterial Pneumonia (VABP). The primary hypothesis is that IMI/REL is non-inferior to PIP/TAZ as measured by the incidence rate of all-cause mortality through Day 28 post-randomization.


Eligibility criteria: Inclusion Criteria:

* Requires treatment with IV antibiotic therapy for HABP or VABP
* Fulfills clinical and radiographic criteria within 48 hours prior to randomization, with onset of criteria occurring after more than 2 days of hospitalization or within 7 days after discharge from a hospital for HABP; or at least 2 days after mechanical ventilation (for VABP)
* Has an adequate baseline (at or within 2 days of screening) lower respiratory tract specimen obtained for Gram stain and culture
* Has an infection known or thought to be, in the opinion of the investigator, 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 and long-term storage
* Males agree to use contraception as detailed in protocol from the time of providing informed consent through completion of the study and refrain from donating sperm during this period
* Females are not pregnant, not breastfeeding, and are either: a.) Not a woman of childbearing potential (WOCBP) OR b.) A WOCBP who agrees to follow the contraceptive guidance from the time of providing informed consent through completion of the study
* If a penicillin skin test is required by local clinical practice, the participant must have a negative skin test result for allergy to penicillin

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 caused by Mycoplasma, Chlamydia, or Legionella, or of viral, fungal, or parasitic etiology
* Has HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction
* Has a carcinoid tumor or carcinoid syndrome
* Has active immunosuppression
* Is expected to die during the 7- to 14-day treatment period, despite adequate antibiotic therapy
* Has a concurrent condition or infection that, in the investigator's judgment, would preclude evaluation of therapeutic response
* Has a history of serious allergy, hypersensitivity, or any serious reaction to any β-lactams or β-lactamase inhibitors
* Has a history of a seizure disorder which has required ongoing treatment with anticonvulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years
* Is currently undergoing hemodialysis or peritoneal dialysis
* A WOCBP who has a positive urine pregnancy test at screening
* Has received effective antibacterial drug therapy with known coverage of pathogens that cause HABP/VABP for a continuous duration of more than 48 hours during the previous 72 hours
* Is anticipated to be treated with any of the prohibited medications during the course of study therapy
* Is currently participating in, or has participated in, any other clinical study involving the administration of investigational or experimental medication (not licensed by regulatory agencies) at the time of the presentation or during the previous 90 days prior to screening or is anticipated to participate in such a clinical study during the course of this trial
* Has previously participated in this study at any time

Primary outcomes:
measure: Percentage of Participants With All-cause Mortality Through Day 28 in the Modified Intent to Treat (MITT) Population
timeFrame: Up to approximately 28 days
Secondary outcomes:
measure: Percentage of Participants Achieving a Favorable Clinical Response at Early Follow-up (EFU) Visit in the MITT Population
timeFrame: Up to approximately 27 days
measure: Percentage of Participants Achieving a Favorable Clinical Response at EFU Visit in the Clinically Evaluable (CE) Population
timeFrame: Up to approximately 27 days
measure: Percentage of Participants Achieving a Favorable Clinical Response at End of Therapy (EOT) Visit in the MITT Population
timeFrame: Up to approximately 14 days
measure: Percentage of Participants Achieving a Favorable Clinical Response at EOT Visit in the Clinically Evaluable (CE) Population
timeFrame: Up to approximately 14 days
measure: Percentage of Participants Achieving a Favorable Microbiological Response at EOT Visit in Microbiological Modified Intent-To-Treat Population (mMITT) Population
timeFrame: Up to approximately 14 days
measure: Percentage of Participants Achieving a Favorable Microbiological Response at EFU Visit in Microbiological-evaluable (ME) Population.
timeFrame: Up to approximately 27 days
measure: Percentage of Participants Achieving a Favorable Microbiological Response at EOT Visit in the ME Population
timeFrame: Up to approximately 14 days
measure: Percentage of Participants Experiencing Adverse Events (AEs)
timeFrame: Up to approximately 98 days
measure: Percentage of Participants Discontinuing Study Drug Due to AEs
timeFrame: Up to approximately 14 days
Other outcomes:
Locations:
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte ( Site 0300)
state: Minas Gerais
city: Sao Jose Do Rio Preto - SP
country: Brazil
facility: Hospital de Base de Sao Jose de Rio Preto ( Site 0301)
state: Sao Paulo
city: Beijing
country: China
facility: Beijing Chaoyang Hospital ( Site 0126)
state: Beijing
city: Beijing
country: China
facility: Peking University First Hospital ( Site 0131)
state: Beijing
city: Beijing
country: China
facility: Aero Space center hospital ( Site 0118)
state: Beijing
city: Beijing
country: China
facility: The Seventh Medical Center of PLA General Hospital-Intensive medicine ( Site 0157)
state: Beijing
city: Beijing
country: China
facility: Peking University Third Hospital ( Site 0115)
state: Beijing
city: Beijing
country: China
facility: Beijing Hospital ( Site 0127)
state: Beijing
city: Fuzhou
country: China
facility: The First Affiliated Hospital Of Fujian Medical University-Respiratory ( Site 0136)
state: Fujian
city: Xiamen
country: China
facility: Zhongshan Hospital Affiliated to Xiamen University ( Site 0133)
state: Fujian
city: Zhangzhou
country: China
facility: Zhangzhou Municipal Hospital of Fujian Province-Neurosurgery Department ( Site 0150)
state: Fujian
city: GuangZhou
country: China
facility: The First Affiliated Hospital ( Site 0100)
state: Guangdong
city: Guangzhou
country: China
facility: The First Affiliated Hospital of Guangzhou Medical University ( Site 0123)
state: Guangdong
city: Guangzhou
country: China
facility: Guangzhou First People's Hospital ( Site 0101)
state: Guangdong
city: Guangzhou
country: China
facility: Zhujiang Hospital of Southern Medical University ( Site 0148)
state: Guangdong
city: Guangzhou
country: China
facility: Southern Medical University Nanfang Hospital ( Site 0120)
state: Guangdong
city: Huizhou
country: China
facility: Huizhou Municipal Central Hospital ( Site 0140)
state: Guangdong
city: Shenzhen
country: China
facility: Shenzhen People s Hospital ( Site 0134)
state: Guangdong
city: Nanning
country: China
facility: The first people s hospital of Nanning ( Site 0138)
state: Guangxi
city: Nanning
country: China
facility: The first people s hospital of Nanning ( Site 0141)
state: Guangxi
city: Haikou
country: China
facility: Hainan General Hospital ( Site 0106)
state: Hainan
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University ( Site 0121)
state: Henan
city: Shiyan
country: China
facility: Shiyan City People's Hospital-Neurosurgery ( Site 0155)
state: Hubei
city: Changsha
country: China
facility: Changsha Central Hospital ( Site 0119)
state: Hunan
city: Changsha
country: China
facility: Hunan Provincial People Hospital ( Site 0122)
state: Hunan
city: Changzhou
country: China
facility: The First People's Hospital of Changzhou ( Site 0139)
state: Jiangsu
city: Huai'an
country: China
facility: First Huai'an Hospital Affiliated to Nanjing Medical University-Neurosurgery Department ( Site 0153)
state: Jiangsu
city: Suzhou
country: China
facility: First Hospital Affiliated to Suzhou University ( Site 0111)
state: Jiangsu
city: Wuxi
country: China
facility: Wuxi People's Hospital ( Site 0124)
state: Jiangsu
city: Zhenjiang
country: China
facility: Affiliated Hospital of Jiangsu University ( Site 0147)
state: Jiangsu
city: Nanchang
country: China
facility: Jiangxi Provincial People's Hospital ( Site 0129)
state: Jiangxi
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University ( Site 0132)
state: Jiangxi
city: Nanchang
country: China
facility: The Second Affiliated Hospital of Nanchang University-Neurosurgery Department ( Site 0151)
state: Jiangxi
city: Shenyang
country: China
facility: The First Affiliated Hospital of China Medical University ( Site 0116)
state: Liaoning
city: Yinchuan
country: China
facility: General Hospital of Ningxia Medical University ( Site 0135)
state: Ningxia
city: Liaocheng
country: China
facility: People's Hospital of Liaocheng City-Neurology ( Site 0154)
state: Shandong
city: Shanghai
country: China
facility: Ruijin Hospital Shanghai Jiao Tong University School of Medicine ( Site 0104)
state: Shanghai
city: Shanghai
country: China
facility: Huadong Hospital Affiliated Fudan University ( Site 0103)
state: Shanghai
city: Shanghai
country: China
facility: Huashan Hospital of Fudan University ( Site 0105)
state: Shanghai
city: Shanghai
country: China
facility: Shanghai General Hospital ( Site 0125)
state: Shanghai
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital ( Site 0108)
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital ( Site 0113)
state: Tianjin
city: Hangzhou
country: China
facility: The First Affiliated Hospital.Zhejiang University ( Site 0102)
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital School of Medicine Zhejiang University ( Site 0110)
state: Zhejiang
city: Lishui
country: China
facility: People s Hospital of Lishui City ( Site 0137)
state: Zhejiang
city: Ningbo
country: China
facility: Ningbo First Hospital-neurosurgery ( Site 0152)
state: Zhejiang
city: Wenzhou
country: China
facility: The 2nd Affiliated Hospital of Wenzhou Medical University ( Site 0130)
state: Zhejiang
city: Lille
country: France
facility: Hopital Roger Salengro du Lille ( Site 0601)
state: Nord
city: Nantes
country: France
facility: CHU de Nantes - Hotel Dieu ( Site 0600)
state: Pays-de-la-Loire
city: Pierre Benite
country: France
facility: Hospices Civils de Lyon ( Site 0603)
state: Rhone
city: Le Kremlin-Bicetre
country: France
facility: Hopital Bicetre ( Site 0605)
state: Val-de-Marne
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 0800)
state: Jalisco
city: Guadalajara
country: Mexico
facility: Hospital Civil Nuevo de Guadalajara Dr. Juan I. Menchaca ( Site 0804)
state: Jalisco
city: Metro Manila
country: Philippines
facility: Mary Johnston Hospital ( Site 0901)
state: National Capital Region
city: Quezon
country: Philippines
facility: Lung Center of the Philippines ( Site 0903)
state: National Capital Region
city: Iloilo
country: Philippines
facility: West Visayas State University Medical Center ( Site 0900)
city: Timisoara
country: Romania
facility: Spitalul Clinic Judetean de Urgenta Pius Branzeu ( Site 1103)
state: Timis
city: Bucuresti
country: Romania
facility: Spitalul Clinic de Urgenta Bagdasar-Arseni ( Site 1101)
city: Arkhangelsk
country: Russian Federation
facility: First City Clinical Hospital n.a. E.E.Volosevich ( Site 1016)
state: Arkhangel Skaya Oblast
city: Severodvinsk
country: Russian Federation
facility: City Hospital #2 Severodvinsk ( Site 1017)
state: Arkhangel Skaya Oblast
city: Saint Petersburg
country: Russian Federation
facility: Research Institute of Emergency Medicine n.a. I.I.Dzhanelidze ( Site 1011)
state: Sankt-Peterburg
city: Saint Petersburg
country: Russian Federation
facility: Clinical Hospital #122 L.G. Sokolova FMBA ( Site 1015)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: City Hospital #26 ( Site 1002)
state: Sankt-Peterburg
city: Dnipro
country: Ukraine
facility: ME Dnipropetrovsk Clinical Joinder of Emergency Care of DRC ( Site 1304)
state: Dnipropetrovska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk regional clinical hospital ( Site 1301)
state: Ivano-Frankivska Oblast
city: Kharkiv
country: Ukraine
facility: City Clinical Hospital No13 of Kharkiv City Council ( Site 1303)
state: Kharkivska Oblast
city: Kiev
country: Ukraine
facility: Kiyv city municipal hospital 17 ( Site 1300)
state: Kyivska Oblast
city: Poltava
country: Ukraine
facility: Reg. Clin. Hospital ( Site 1306)
state: Poltavska Oblast
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Li J, Wei F, Xiang P, Tang Z, Ding L, Chen LF, Losada M, Iamboliyska Z, Sun F, Zhu M, Guo X, Du X, Chen C, Bruno C, Koseoglu S, Young K, Zhou M, Qu J. A phase III, randomized, controlled noninferiority trial to study the efficacy and safety of imipenem/cilastatin/relebactam (IMI/REL) vs piperacillin/tazobactam (PIP/TAZ) in patients with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). Int J Infect Dis. 2025 Apr;153:107357. doi: 10.1016/j.ijid.2024.107357. Epub 2024 Dec 12.