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)

NCT01506271 | Completed Phase 2 Results

• 3 other identifiers: 7655-0042011-005686-20MK-7655-004
• Study Type: interventional
• Target: 351
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Intra-abdominal Infections

Keywords

Complicated Intra-abdominal Infections

Outcome Measures

Primary Outcomes (12)

• 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 Outcomes (6)

• Percentage of Participants With a Favorable Clinical Response at Completion of IV Study Therapy in Participants Who Have Imipenem-resistant, Gram-negative cIAI Infections.

  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

  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

  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

  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

  Up to 42 days following completion of all study therapy (up to Day 56)

Study Arms (3)

Relebactam 250 mg with imipenem/cilastatin

EXPERIMENTAL

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; Drug: Imipenem/cilastatin

Relebactam 125 mg with imipenem/cilastatin

EXPERIMENTAL

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; Drug: Imipenem/cilastatin

Placebo to relebactam with imipenem/cilastatin

PLACEBO COMPARATOR

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; Drug: Matching placebo to relebactam

Interventions

Relebactam 250 mg DRUG

Relebactam 250 mg IV every 6 hours for a minimum of 96 hours

Also known as: MK-7655

Relebactam 250 mg with imipenem/cilastatin

Relebactam 125 mg DRUG

Relebactam 125 mg IV every 6 hours for a minimum of 96 hours

Also known as: MK-7655

Relebactam 125 mg with imipenem/cilastatin

Imipenem/cilastatin DRUG

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.

Placebo to relebactam with imipenem/cilastatin; Relebactam 125 mg with imipenem/cilastatin; Relebactam 250 mg with imipenem/cilastatin

Matching placebo to relebactam DRUG

Placebo-matching infusion of IV normal saline (0.9%) once every 6 hours.

Placebo to relebactam with imipenem/cilastatin

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Lucasti C, Vasile L, Sandesc D, Venskutonis D, McLeroth P, Lala M, Rizk ML, Brown ML, Losada MC, Pedley A, Kartsonis NA, Paschke A. Phase 2, Dose-Ranging Study of Relebactam with Imipenem-Cilastatin in Subjects with Complicated Intra-abdominal Infection. Antimicrob Agents Chemother. 2016 Sep 23;60(10):6234-43. doi: 10.1128/AAC.00633-16. Print 2016 Oct.

  PMID: 27503659 RESULT

MeSH Terms

Conditions

Intraabdominal Infections

Interventions

relebactam; Cilastatin, Imipenem Drug Combination

Condition Hierarchy (Ancestors)

Infections

Intervention Hierarchy (Ancestors)

Imipenem; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Cilastatin; Cyclopropanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Fatty Acids; Lipids; Drug Combinations; Pharmaceutical Preparations

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 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 5, 2012
• First Posted: January 9, 2012
• Study Start: June 1, 2012
• Primary Completion: August 12, 2014
• Study Completion: August 12, 2014
• Last Updated: June 10, 2019
• Results First Posted: June 10, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share