Clinical trial NCT03230916: A Pharmacokinetics Study of MK-7655A in Pediatric Participants With Gram-negative Infections (MK-7655A-020)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Suspected or Documented Gram-negative Bacterial Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-07-27
Enrollment: 47
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Imipenem (IMI) Area Under the Concentration Time Curve From Time 0 to Infinity (AUC0-∞)
timeFrame: 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
measure: IMI Maximum Concentration (Cmax)
timeFrame: 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
measure: IMI Central Volume of Distribution (Vc)
timeFrame: 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
measure: IMI Clearance (CL)
timeFrame: 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
measure: IMI Percentage of Time Above the Minimum Concentration (%TMIC)
timeFrame: 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
measure: Relebactam (REL) AUC0-∞
timeFrame: 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
measure: REL Maximum Concentration (Cmax)
timeFrame: 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
measure: REL Clearance (CL)
timeFrame: 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
measure: REL Central Volume of Distribution (Vc)
timeFrame: 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
measure: Cilastatin (CIL) AUC0-∞
timeFrame: 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
measure: CIL Time to Maximum Concentration (Tmax)
timeFrame: 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
measure: CIL Concentration at End of Infusion (Ceoi)
timeFrame: 30 min after the start of infusion for Cohort 1; 60 min after the start of infusion for Cohorts 2-5
measure: CIL Terminal Half-Life (t1/2)
timeFrame: 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
measure: CIL Clearance (CL)
timeFrame: 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
measure: CIL Volume of Distribution (Vss)
timeFrame: 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 outcomes:
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to 17 days
measure: Number of Participants Who Discontinued Study Drug Due to an AE
timeFrame: Day 1
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Children's Hospital ( Site 1311)
state: Arkansas
city: Orange
country: United States
facility: Children's Hospital of Orange County ( Site 1301)
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital-San Diego ( Site 1305)
state: California
city: Baton Rouge
country: United States
facility: Our Lady of the Lake Hospital ( Site 1304)
state: Louisiana
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital ( Site 1322)
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center ( Site 1317)
state: North Carolina
city: Philadelphia
country: United States
facility: The Children's Hospital of Philadelphia ( Site 1318)
state: Pennsylvania
city: Seattle
country: United States
facility: Seattle Childrens Hospital ( Site 1321)
state: Washington
city: Pazardjik
country: Bulgaria
facility: MHAT Pazardjik AD ( Site 0208)
state: Pazardzhik
city: Burgas
country: Bulgaria
facility: UMHAT Deva Maria. EOOD ( Site 0209)
city: Pleven
country: Bulgaria
facility: UMHAT Dr. Georgi Stranski EAD ( Site 0211)
city: Ruse
country: Bulgaria
facility: UMHAT Kanev AD ( Site 0203)
city: Ruse
country: Bulgaria
facility: UMHAT Kanev AD ( Site 0212)
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe ( Site 0301)
state: Antioquia
city: Medellin
country: Colombia
facility: Hospital General de Medellin Luz Castro de Gutierrez ( Site 0303)
state: Antioquia
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0300)
state: Valle Del Cauca
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki Hippokrateio ( Site 1402)
city: Loerenskog
country: Norway
facility: Akershus Universitetssykehus HF ( Site 0903)
state: Akershus
city: Stavanger
country: Norway
facility: Stavanger Universitetssykehus, Helse Stavanger ( Site 0901)
state: Rogaland
city: Trondheim
country: Norway
facility: St. Olavs Hospital ( Site 0900)
state: Sor-Trondelag
city: Bergen
country: Norway
facility: Haukeland Universitetssjukehus ( Site 0902)
state: Vestfold
city: Lodz
country: Poland
facility: Wojewodzki Specjalistyczny Szpital im. Bieganskiego w Lodzi ( Site 1000)
state: Lodzkie
city: Lomianki
country: Poland
facility: SPZOZ im. Dzieci Warszawy w Dziekanowie Lesnym ( Site 1002)
state: Mazowieckie
city: Dnipro
country: Ukraine
facility: SI Dnipropetrovsk Regional Children Clinical Hospital DOR ( Site 1214)
state: Dnipropetrovska Oblast
city: Kharkiv
country: Ukraine
facility: Kharkiv City Children Hospital 16 ( Site 1200)
state: Kharkivska Oblast
city: Kyiv
country: Ukraine
facility: Institution of Pediatr Obstetr and Gynec NAMS of Ukraine ( Site 1213)
state: Kyivska Oblast
city: Odesa
country: Ukraine
facility: Odessa Regional Children Clinical Hospital ( Site 1203)
state: Odeska Oblast
city: Poltava
country: Ukraine
facility: Children City Clinical Hospital ( Site 1215)
state: Poltavska Oblast
city: Zaporizhzhya
country: Ukraine
facility: Zaporizhzhya Regional Clinical Childrens Hospital ( Site 1202)
state: Zaporizka Oblast
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children ( Site 1101)
state: Bristol, City Of
city: Southampton
country: United Kingdom
facility: University Hospital Southampton NHS Foundation Trust ( Site 1100)
state: Hampshire
city: London
country: United Kingdom
facility: St. Georges University Hospital NHS Foundation Trust ( Site 1103)
state: London, City Of
city: Newcastle
country: United Kingdom
facility: Great Northern Children s Hospital ( Site 1102)
state: Newcastle Upon Tyne
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.