Study of the Safety, Tolerability, and Efficacy of Relebactam (MK-7655) + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone to Treat Complicated Intra-Abdominal Infection [cIAI] (MK-7655-004)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and tolerability of adding 125 mg or 250 mg doses of relebactam (MK-7655) to imipenem/cilastatin in adults 18 years or older with Complicated Intra-Abdominal Infection (cIAI). The primary hypothesis is that the relebactam + imipenem/cilastatin treatment regimen is non-inferior to treatment with imipenem/cilastatin alone with respect to the percentage of participants with a favorable clinical response at completion of intravenous (IV) study therapy.

Official Title
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A Phase II, Randomized, Active Comparator-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of MK-7655 + Imipenem/Cilastatin Versus Imipenem/Cilastatin Alone in Patients With Complicated Intra-Abdominal Infection [cIAI]

Conditions
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Intra-abdominal Infections

Intervention / Treatment
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* Drug: Relebactam 250 mg
* Drug: Relebactam 125 mg
* Drug: Imipenem/cilastatin
* Drug: Matching placebo to relebactam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically suspected and/or bacteriologically documented cIAI requiring hospitalization and treatment with IV antibiotic therapy. Enrolled intraoperatively or postoperatively on the basis of operative findings OR enrolled preoperatively on the basis of compelling preoperative clinical findings. Exclusion Criteria: Infection which should be managed by Staged Abdominal Repair (STAR) or open abdomen technique. Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 30. Any amount of effective antibiotic therapy after obtaining the culture for admission to this study and prior to the administration of the first dose of IV study therapy. An infection which has been treated with >24 hours of systemic antibiotic therapy known to be effective against the presumed or documented etiologic pathogen(s) within the 72-hour period immediately prior to consideration for entry into the study. History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to carbapenem antibiotics, any cephalosporins, penicillins, or other β-lactam agents. History of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to other β-lactamase inhibitors (e.g., tazobactam, sulbactam, clavulanic acid). History of a seizure disorder (requiring ongoing treatment with anticonvulsive therapy or prior treatment with anti-convulsive therapy in the last 3 years). Currently being treated with valproic acid or has used valproic acid in the 2 weeks prior to screening. Rapidly progressive or terminal illness (unlikely to survive the approximately 6- to 8-week study period). Pregnant or expecting to conceive, breastfeeding, or plans to breast feed within 1 month of completion of the study. Participant in whom a response to IV study therapy within the timeframe of treatment specified in this protocol is considered unlikely. Concurrent infection that would interfere with evaluation of response to the study antibiotics. Need for concomitant systemic antimicrobial agents in addition to those designated in the various study treatment groups. cIAI due to a confirmed fungal pathogen. Currently receiving immunosuppressive therapy, including use of high-dose corticosteroids. Prior recipient of a renal transplantation. Estimated or actual creatinine clearance of <50 mL/minute. History of any other illness that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering the study drug to the patient. Laboratory abnormalities as specified in protocol. 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 presentation or during the previous 30 days prior to screening or is anticipated to participate in such a clinical study during the course of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Relebactam 250 mg with imipenem/cilastatin<br>Participants randomized to receive relebactam 250 mg will be administered 250 mg doses of relebactam IV in a blinded fashion once every 6 hours with each dose infused over a 30-minute interval. A 500 mg dose of imipenem/cilastatin will be administered in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval. | Drug: Relebactam 250 mg<br>* Relebactam 250 mg IV every 6 hours for a minimum of 96 hours<br>* Other names: MK-7655;Drug: Imipenem/cilastatin<br>* A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval.<br>|
| Experimental: Relebactam 125 mg with imipenem/cilastatin<br>Participants randomized to receive relebactam 125 mg will be administered 125 mg doses of relebactam IV, in a blinded-treatment fashion once every 6 hours with each dose infused over a 30-minute interval. A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval. | Drug: Relebactam 125 mg<br>* Relebactam 125 mg IV every 6 hours for a minimum of 96 hours<br>* Other names: MK-7655;Drug: Imipenem/cilastatin<br>* A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval.<br>|
| Placebo Comparator: Placebo to relebactam with imipenem/cilastatin<br>Participants randomized to receive placebo for relebactam will receive a placebo-matching infusion of IV normal saline (0.9%) once every 6 hours. A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval. | Drug: Imipenem/cilastatin<br>* A 500 mg dose of imipenem/cilastatin will be administered IV in an open-label fashion once every 6 hours with each dose infused over a 30-minute interval.<br>Drug: Matching placebo to relebactam<br>* Placebo-matching infusion of IV normal saline (0.9%) once every 6 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy | A favorable clinical response was assessed by the clinical investigator as a cure, and was defined as a situation where all or most pre-therapy signs and symptoms of the index infection had resolved, or returned to pre-infection status, and no additional antibiotic therapy was required. | 4 to 14 days post initiation of intravenous (IV) study therapy (up to postrandomization Day 14) | 
| Percentage of Participants With an Elevated Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) Laboratory Values That Are Greater Than or Equal to 5X the Upper Limit of Normal (ULN) | Pre-specified events of interest were confirmed (i.e., verified by repeat testing) elevated AST or ALT laboratory value that is greater than or equal to 5 X ULN as a result of within-protocol-specific testing or unscheduled testing. | Up to 14 days following completion of all study therapy (up to Day 28) | 
| Percentage of Participants With Elevated AST or ALT Laboratory Values >= 3X the ULN, Total Bilirubin >= 2X the ULN, and Alkaline Phosphatase Values < 2X the ULN | Pre-specified events of interest were a confirmed (i.e., verified by repeat testing) elevated AST or ALT laboratory value that is greater than or equal to 3X ULN, as well as elevated total bilirubin greater than or equal to 2X the ULN, and alkaline phosphatase values that are less than 2X the ULN, as a result of within-protocol-specific testing or unscheduled testing. | Up to 14 days following completion of all study therapy (up to Day 28) | 
| Percentage of Participants With Any Adverse Event (AE) | An adverse event (AE) is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. | Up to 14 days following completion of all study therapy (up to Day 28) | 
| Percentage of Participants With Any Serious Adverse Event (SAE) | A serious adverse event (SAE) is any AE occurring at any dose that is life threatening; results in a persistent or significant disability/incapacity; prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; or results in death. | Up to 14 days following completion of all study therapy (up to Day 28) | 
| Percentage of Participants With Any Drug-related AE | An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. A drug-related AE is a AE determined by the investigator to be possibly, probably or definitely related to drug treatment. | Up to 14 days following completion of all study therapy (up to Day 28) | 
| Percentage of Participants With Any Drug-related SAE | A SAE is any AE occurring at any dose that is life threatening; results in a persistent or significant disability/incapacity; prolongs an existing inpatient hospitalization; is a congenital anomaly/birth defect; or results in death. A drug-related SAE is a SAE determined by the investigator to be possibly, probably or definitely related to drug treatment. | Up to 42 days following completion of all study therapy (up to Day 56) | 
| Percentage of Participants Who Discontinued IV Study Therapy Due to an AE | An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. AEs assessed by the investigator that caused discontinuation of participant treatment are presented. | Up to 14 days post initiation of IV study therapy (up to 14 days) | 
| Percentage of Participants Who Discontinued IV Study Therapy Due to a Drug-related AE | An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. A drug-related AE is an AE determined by the investigator to be possibly, probably or definitely related to drug treatment. Drug-related AEs assessed by the investigator that caused discontinuation of participant treatment are presented. | Up to 14 days post initiation of IV study therapy (up to 14 days) | 
| Percentage of Participants With Specific AEs With Incidence of >= 4 Participants in One Treatment Group | An AE is any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the medicinal product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the medicinal product, is also an AE. AE preferred terms, with incidence greater than or equal to 4 in one treatment group are presented. AEs preferred terms which did not achieve this threshold are not reported. AE preferred terms are based on MedDRA version 17.0. | Up to 42 days following completion of all study therapy (up to Day 56) | 
| Percentage of Participants With Predefined Limit of Change (PDLC) With Incidence of >= 4 Participants in One Treatment Group | Predefined limit of change (PDLC) are presented based on values from the following laboratory tests on serum: alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Bil), and alkaline phosphatase (AP). Results are presented for PDLC from tests with reported incidence greater than or equal to 4 participants in one treatment group. Laboratory tests which did not achieve the PDLC threshold are not reported. | Up to 42 days following completion of all study therapy (up to Day 56) | 
| Percentage of Participants With System Organ Class (SOC) With AEs With Incidence of >= 4 Participants in One Treatment Group | A system organ class (SOC) is the highest level of terminology used to describe disorders of the human body, and distinguishes by either anatomical or physiological systems, disease origin or purpose. SOCs with AE incidence greater than or equal to 4 in one treatment group are presented. SOCs with AE incidence which did not achieve this threshold are not reported. SOCs are based on MedDRA version 17.0. | Up to 42 days following completion of all study therapy (up to Day 56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy in Participants Who Have Imipenem-resistant, Gram-negative cIAI Infections. | A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. | 4 to 14 days post initiation of IV study therapy (up to postrandomization day 14). | 
| Percentage of Participants With a Favorable Clinical Response at Early Follow-up | A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. | Up to 9 days following completion of all study therapy (up to Day 23) | 
| Percentage of Participants With a Favorable Microbiological Response at Completion of IV Study Therapy | A favorable microbiological response is assessed by the clinical investigator, and is defined as the eradication or presumptive eradication of all bacterial pathogens identified at baseline. | Up to 14 days post initiation of IV study therapy (up to postrandomization day 14) | 
| Percentage of Participants With a Favorable Microbiological Response at Early Follow-up | A favorable microbiological response is assessed by the clinical investigator, and is defined as the eradication or presumptive eradication of all bacterial pathogens identified at baseline. | Up to 9 days following completion of all study therapy (up to Day 23) | 
| Percentage of Participants With a Favorable Clinical Response at Late Follow-up | A favorable clinical response is assessed by the clinical investigator as a cure, and is defined as a situation where all or most pre-therapy signs and symptoms of the index infection have resolved, or returned to pre-infection status, and no additional antibiotic therapy is required. | Up to 42 days following completion of all study therapy (up to Day 56) | 
| Percentage of Participants With a Favorable Microbiological Response at Late Follow-up | A favorable microbiological response is assessed by the clinical investigator, and is defined as the eradication or presumptive eradication of all bacterial pathogens identified at baseline. | Up to 42 days following completion of all study therapy (up to Day 56) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complicated Intra-abdominal Infections