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

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ClinicalTrials.gov Identifier: NCT03230916
Recruitment Status : Recruiting
First Posted : July 27, 2017
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

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.

Condition or disease Intervention/treatment Phase
Suspected or Documented Gram-negative Bacterial Infection Drug: IMI/REL FDC Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 44 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 6, 2017
Estimated Primary Completion Date : August 13, 2020
Estimated Study Completion Date : August 13, 2020

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 Name: MK-7655A




Primary Outcome Measures :
  1. REL Plasma Exposure [ Time Frame: Within 30 minutes before start of drug infusion (DI); within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma relebactam (REL)

  2. REL Maximum Concentration [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Maximum plasma concentration (Cmax) of REL

  3. REL Clearance [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Systemic clearance (CL) of plasma REL

  4. REL Volume of Distribution [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Central volume of distribution (Vc) of plasma REL

  5. IMI Plasma Exposure [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma imipenem (IMI)

  6. IMI Maximum Concentration [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Maximum plasma concentration (Cmax) of IMI

  7. IMI Clearance [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Systemic clearance (CL) of plasma IMI

  8. IMI Volume of Distribution [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Central volume of distribution (Vc) of plasma IMI

  9. IMI Percentage of Time [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Percentage of time spent above the minimum inhibitory concentration (%TMIC) of plasma IMI

  10. CIL Plasma Exposure [ Time Frame: Within 30 minutes before start of drug infusion (DI); within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Area under the concentration time curve from time 0 to infinity (AUC0-∞) of plasma cilastatin (CIL)

  11. CIL Time to Maximum Concentration [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Time to maximum plasma concentration (Tmax) of CIL

  12. CIL Concentration at End of Infusion [ Time Frame: At the end of DI, up to 35 minutes ]
    Concentration at end of infusion (CEOI) of plasma CIL

  13. CIL Half-Life [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Terminal half-life (t1/2) of plasma CIL

  14. CIL Clearance [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Systemic clearance (CL) of plasma CIL

  15. CIL Volume of Distribution [ Time Frame: Within 30 minutes before start of DI; within 5 minutes after the end of DI; 1.5 to 2.5 hours or 2 to 5 hours after the start of DI; 4.5 to 6 hours or 6 to 12 hours after the start of DI ]
    Volume of distribution (Vss) of plasma CIL


Secondary Outcome Measures :
  1. Adverse Events (AEs) [ Time Frame: Up to Day 17 ]
    Number of participants with one or more AEs

  2. Discontinuations [ Time Frame: Day 1 ]
    Number of participants who discontinued study drug due to an AE



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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; or was born at or after 37 weeks of gestation.
  • 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, furosemide or other loop diuretics, angiotensin receptor blockers, 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.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03230916


Contacts
Contact: Toll Free Number 1-888-577-8839 Trialsites@merck.com

Locations
United States, Arkansas
Arkansas Children's Hospital ( Site 1311) Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Study Coordinator    501-364-1416      
United States, California
Children's Hospital of Orange County ( Site 1301) Recruiting
Orange, California, United States, 92868
Contact: Study Coordinator    714-509-4064      
Rady Children's Hospital-San Diego ( Site 1305) Recruiting
San Diego, California, United States, 92123
Contact: Study Coordinator    858-966-7785      
United States, Louisiana
Our Lady of the Lake Hospital ( Site 1304) Recruiting
Baton Rouge, Louisiana, United States, 70808
Contact: Study Coordinator    225-765-5956      
United States, North Carolina
Duke University Medical Center ( Site 1317) Recruiting
Durham, North Carolina, United States, 27710
Contact: Study Coordinator    919-681-1504      
United States, Pennsylvania
The Children's Hospital of Philadelphia ( Site 1318) Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Study Coordinator    215-590-4024      
United States, Washington
Seattle Childrens Hospital ( Site 1321) Recruiting
Seattle, Washington, United States, 98105
Contact: Study Coordinator    206-884-5086      
Colombia
Fundacion Valle del Lili ( Site 0300) Recruiting
Cali, Valle Del Cauca, Colombia, 760032
Contact: Study Coordinator    +57233190904022      
Hospital Pablo Tobon Uribe ( Site 0301) Recruiting
Medellin, Colombia, 050034
Contact: Study Coordinator    +5744459753      
Hospital General de Medellin Luz Castro de Gutierrez ( Site 0303) Recruiting
Medellin, Colombia, 500515
Contact: Study Coordinator    +573104902491      
Norway
Haukeland Universitetssjukehus ( Site 0902) Recruiting
Bergen, Norway, 5021
Contact: Study Coordinator    +4755975200      
Akershus Universitetssykehus HF ( Site 0903) Recruiting
Loerenskog, Norway, 1478
Contact: Study Coordinator    +4723074587      
Stavanger Universitetssykehus, Helse Stavanger ( Site 0901) Recruiting
Stavanger, Norway, 4011
Contact: Study Coordinator    +4751519940      
St. Olavs Hospital ( Site 0900) Recruiting
Trondheim, Norway, 7006
Contact: Study Coordinator    +4772571241      
Poland
Wojewodzki Specjalistyczny Szpital im. Bieganskiego w Lodzi ( Site 1000) Recruiting
Lodz, Poland, 91-347
Contact: Study Coordinator    +48601272443      
SPZOZ im. Dzieci Warszawy w Dziekanowie Lesnym ( Site 1002) Recruiting
Lomianki, Poland, 05-092
Contact: Study Coordinator    +48227657153      
Ukraine
Kharkiv City Children Hospital 16 ( Site 1200) Recruiting
Kharkiv, Ukraine, 50082
Contact: Study Coordinator    +380662571720      
Institution of Pediatr Obstetr and Gynec NAMS of Ukraine ( Site 1213) Recruiting
Kyiv, Ukraine, 04050
Contact: Study Coordinator    +380444836220      
Odessa Regional Children Clinical Hospital ( Site 1203) Recruiting
Odesa, Ukraine, 65031
Contact: Study Coordinator    +380503169076      
Zaporizhzhya Regional Clinical Childrens Hospital ( Site 1202) Recruiting
Zaporizhzhya, Ukraine, 69063
Contact: Study Coordinator    +380617646726      
United Kingdom
University Hospital Southampton NHS Foundation Trust ( Site 1100) Recruiting
Southampton, Hampshire, United Kingdom, SO16 6YD
Contact: Study Coordinator    +442381206883      
Bristol Royal Hospital for Children ( Site 1101) Recruiting
Bristol, United Kingdom, BS2 8AF
Contact: Study Coordinator    +441173427534      
St. Georges University Hospital NHS Foundation Trust ( Site 1103) Recruiting
London, United Kingdom, SW17 0QT
Contact: Study Coordinator    +442087255382      
Great Northern Children s Hospital ( Site 1102) Recruiting
Newcastle, United Kingdom, NE1 4LP
Contact: Study Coordinator    +441912825984      
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03230916     History of Changes
Other Study ID Numbers: 7655A-020
2016-004328-43 ( EudraCT Number )
First Posted: July 27, 2017    Key Record Dates
Last Update Posted: January 4, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Infection
Communicable Diseases
Bacterial Infections
Gram-Negative Bacterial Infections
MK-7655
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Bacterial Agents
Anti-Infective Agents