A Pharmacokinetics Study of MK-7655A in Pediatric Participants With Gram-negative Infections (MK-7655A-020)

A Phase 1b, Open-label, Single-dose Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of MK-7655A in Pediatric Subjects From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-negative Infections

This study aims to obtain plasma pharmacokinetic (PK) data and characterize the PK profile of imipenem (IMI), cilastatin (CIL), and relebactam (REL) following administration of a single intravenous (IV) dose of MK-7655A (a fixed ratio combination of imipenem/cilastatin/relebactam), hereafter referred to as IMI/REL.

Study Overview

• Status: Completed
• Conditions: Suspected or Documented Gram-negative Bacterial Infection
• Intervention / Treatment: Drug: IMI/REL FDC

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Burgas, Bulgaria, 8127
    • UMHAT Deva Maria. EOOD ( Site 0209)
  • Pleven, Bulgaria, 5800
    • UMHAT Dr. Georgi Stranski EAD ( Site 0211)
  • Ruse, Bulgaria, 7002
    • UMHAT Kanev AD ( Site 0203)
  • Ruse, Bulgaria, 7002
    • UMHAT Kanev AD ( Site 0212)
  • Pazardzhik
    • Pazardjik, Pazardzhik, Bulgaria, 4400
      • MHAT Pazardjik AD ( Site 0208)
• Colombia
  • Antioquia
    • Medellin, Antioquia, Colombia, 050034
      • Hospital Pablo Tobon Uribe ( Site 0301)
    • Medellin, Antioquia, Colombia, 500515
      • Hospital General de Medellin Luz Castro de Gutierrez ( Site 0303)
  • Valle Del Cauca
    • Cali, Valle Del Cauca, Colombia, 760032
      • Fundacion Valle del Lili ( Site 0300)
• Greece
  • Thessaloniki, Greece, 546 42
    • General Hospital of Thessaloniki Hippokrateio ( Site 1402)
• Norway
  • Akershus
    • Loerenskog, Akershus, Norway, 1478
      • Akershus Universitetssykehus HF ( Site 0903)
  • Rogaland
    • Stavanger, Rogaland, Norway, 4011
      • Stavanger Universitetssykehus, Helse Stavanger ( Site 0901)
  • Sor-Trondelag
    • Trondheim, Sor-Trondelag, Norway, 7006
      • St. Olavs Hospital ( Site 0900)
  • Vestfold
    • Bergen, Vestfold, Norway, 5021
      • Haukeland Universitetssjukehus ( Site 0902)
• Poland
  • Lodzkie
    • Lodz, Lodzkie, Poland, 91-347
      • Wojewodzki Specjalistyczny Szpital im. Bieganskiego w Lodzi ( Site 1000)
  • Mazowieckie
    • Lomianki, Mazowieckie, Poland, 05-092
      • SPZOZ im. Dzieci Warszawy w Dziekanowie Lesnym ( Site 1002)
• Ukraine
  • Dnipropetrovska Oblast
    • Dnipro, Dnipropetrovska Oblast, Ukraine, 49100
      • SI Dnipropetrovsk Regional Children Clinical Hospital DOR ( Site 1214)
  • Kharkivska Oblast
    • Kharkiv, Kharkivska Oblast, Ukraine, 61075
      • Kharkiv City Children Hospital 16 ( Site 1200)
  • Kyivska Oblast
    • Kyiv, Kyivska Oblast, Ukraine, 04050
      • Institution of Pediatr Obstetr and Gynec NAMS of Ukraine ( Site 1213)
  • Odeska Oblast
    • Odesa, Odeska Oblast, Ukraine, 65031
      • Odessa Regional Children Clinical Hospital ( Site 1203)
  • Poltavska Oblast
    • Poltava, Poltavska Oblast, Ukraine, 36004
      • Children City Clinical Hospital ( Site 1215)
  • Zaporizka Oblast
    • Zaporizhzhya, Zaporizka Oblast, Ukraine, 69063
      • Zaporizhzhya Regional Clinical Childrens Hospital ( Site 1202)
• United Kingdom
  • Bristol, City Of
    • Bristol, Bristol, City Of, United Kingdom, BS2 8AF
      • Bristol Royal Hospital for Children ( Site 1101)
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • University Hospital Southampton NHS Foundation Trust ( Site 1100)
  • London, City Of
    • London, London, City Of, United Kingdom, SW17 0QT
      • St. Georges University Hospital NHS Foundation Trust ( Site 1103)
  • Newcastle Upon Tyne
    • Newcastle, Newcastle Upon Tyne, United Kingdom, NE1 4LP
      • Great Northern Children s Hospital ( Site 1102)
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital ( Site 1311)
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County ( Site 1301)
    • San Diego, California, United States, 92123
      • Rady Children's Hospital-San Diego ( Site 1305)
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Our Lady of the Lake Hospital ( Site 1304)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital ( Site 1322)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center ( Site 1317)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia ( Site 1318)
  • Washington
    • Seattle, Washington, United States, 98105
      • Seattle Childrens Hospital ( Site 1321)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has a parent or legally acceptable representative (LAR) who provides written informed consent for the trial on the participant's behalf.
• Aged from birth to <18 years old.
• Is hospitalized, currently receiving antibacterial treatment for confirmed or suspected Gram-negative bacterial infection, and expected to require hospitalization until at least 24 hours after completion of study drug administration.
• Is not of reproductive potential; but if of reproductive potential, agrees to avoid becoming pregnant or impregnating a partner from the time of consent through 24 hours after completion of study drug administration.
• Has clinically stable renal function at the time of screening that is judged to be within acceptable ranges.
• Has sufficient intravascular access to receive study drug through an existing peripheral or central line.

Exclusion Criteria:

• Has a personal history of hypersensitivity to imipenem/cilastatin (IMI) or to any of the following: any carbapenem, cephalosporin, penicillin, or other β-lactam agent; or other β-lactamase inhibitors (BLIs) e.g. tazobactam, sulbactam, clavulanic acid, avibactam.
• Female is currently pregnant or breast feeding or has a positive serum β-human chorionic gonadotropin (β-hCG) pregnancy test.
• Has a history of a seizure disorder requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years.
• Has used or plans to use valproic acid or divalproex sodium within 2 weeks prior to screening or at any point between screening and 24 hours after the completion of study drug infusion.
• Has received treatment or plans to receive treatment with any carbapenem antibiotic within 48 hours prior to initiation of study drug infusion or at any point between administration of study drug and the last PK sample collection.
• Has used or plans to use any of the following medications, which are organic anion transporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at any point between screening and the last PK sample collection: cimetidine, probenecid, indomethacin, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), angiotensin receptor blockers (eg, valsartan), and ketorolac.
• Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to screening.
• Has enrolled previously in the current trial and been discontinued, or has received REL for any other reason.
• Has a current diagnosis of cystic fibrosis, meningitis, or severe sepsis.
• Is expected to survive less than 72 hours after completion of study drug administration.
• Has a history of clinically significant renal, hepatic, or hemodynamic instability.
• Plans to use cardiopulmonary bypass, extracorporeal membrane oxygenation, hemodialysis, or peritoneal dialysis during the study.
• For participants that are 2 to 17 years of age only: weighs outside of the 5th to 95th percentile based on age.
• Is, at the time of signing informed consent, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence.
• Has a planned blood transfusion within 24 hours of study drug administration or expected before the end of the PK sampling.
• Has had significant blood loss (≥5% of total blood volume) within 4 weeks before the screening visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IMI/REL FDC; Imipenem/Cilastatin/Relebactam (IMI/REL) administered as a single fixed 2:1 ratio of imipenem/cilastatin to relebactam, with a maximum dose of 15 mg/kg IMI and 15 mg/kg CIL (up to 500 mg IMI and 500 mg CIL) and 7.5 mg/kg REL (up to 250 mg REL).	Drug: IMI/REL FDC; IMI/REL is supplied as a single fixed dose combination (FDC) vial; which is administered at a maximum dose of 15 mg/kg IMI and 15 mg/kg CIL (up to 500 mg IMI and 500 mg CIL) and 7.5 mg/kg REL (up to 250 mg REL).; Other Names: MK-7655A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞)	Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma imipenem (IMI) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
IMI Maximum Concentration (Cmax)	Maximum plasma concentration (Cmax) of IMI was calculated. Cmax is the peak plasma concentration of study drug after administration.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
IMI Central Volume of Distribution (Vc)	Central volume of distribution (Vc) of plasma IMI was calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
IMI Clearance (CL)	Systemic clearance (CL) of plasma IMI was calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
IMI Percentage of Time Above the Minimum Concentration (%TMIC)	Percentage of time spent above the minimum inhibitory concentration (%TMIC) of plasma IMI was calculated. %TMIC is defined as the percentage of time (in hours) in which the lowest concentration of a study drug, completely inhibits growth of the specific organism being tested.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Relebactam (REL) AUC0-∞	Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma relebactam (REL) was calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
REL Maximum Concentration (Cmax)	Maximum plasma concentration (Cmax) of REL was calculated. Cmax is the peak plasma concentration of study drug after administration.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
REL Clearance (CL)	Systemic clearance (CL) of plasma REL was calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
REL Central Volume of Distribution (Vc)	Central volume of distribution (Vc) of plasma REL was calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
Cilastatin (CIL) AUC0-∞	Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma cilastatin (CIL) was not calculated. AUC0-∞ is the area under the plasma concentration versus time curve from time zero (pre-dose) to extrapolated infinite time.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
CIL Time to Maximum Concentration (Tmax)	Time to maximum plasma concentration (Tmax) of CIL was determined. Tmax is defined as the time after drug administration at which peak drug concentration in plasma occurs.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
CIL Concentration at End of Infusion (Ceoi)	Concentration at end of infusion (Ceoi) of plasma CIL was determined.	30 min after the start of infusion for Cohort 1; 60 min after the start of infusion for Cohorts 2-5
CIL Terminal Half-Life (t1/2)	Terminal half-life (t1/2) of plasma CIL was not calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
CIL Clearance (CL)	Systemic clearance (CL) of plasma CIL was not calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to 12 hrs after start of DI for Cohort 5
CIL Volume of Distribution (Vss)	Volume of distribution (Vss) of plasma CIL was not calculated.	30 minutes (min) before start of drug infusion (DI) and 10 min after the end of DI for all cohorts; 1.5 to 2.5 hours (hrs) and 4.5 to 6 hrs after start of DI for Cohorts 1-4; 2 to 5 hrs and 6 to12 hrs after start of DI for Cohort 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced an Adverse Event (AE)	Number of participants with one or more AEs was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug.	Up to 17 days
Number of Participants Who Discontinued Study Drug Due to an AE	Number of participants who discontinued study drug due to an AE was calculated. An AE is defined as any untoward medical occurrence in a participant administered study drug and which may or may not have a causal relationship to the study drug.	Day 1

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Bradley JS, Makieieva N, Tondel C, Roilides E, Kelly MS, Patel M, Vaddady P, Maniar A, Zhang Y, Paschke A, Chen LF. Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial. J Clin Pharmacol. 2023 Dec;63(12):1387-1397. doi: 10.1002/jcph.2334. Epub 2023 Sep 2.

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2017
• Primary Completion (Actual): July 28, 2020
• Study Completion (Actual): August 11, 2020

Study Registration Dates

• First Submitted: July 17, 2017
• First Submitted That Met QC Criteria: July 26, 2017
• First Posted (Actual): July 27, 2017

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Bacterial Infections and Mycoses; Infections; Communicable Diseases; Bacterial Infections; Gram-Negative Bacterial Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Relebactam
• Other Study ID Numbers: 7655A-020; 2016-004328-43 (EudraCT Number); MK-7665A-020 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No