Safety, Tolerability, Efficacy and Pharmacokinetics of Imipenem/Cilastatin/Relebactam (MK-7655A) in Pediatric Participants With Gram-negative Bacterial Infection (MK-7655A-021)

PHRR190731-002168

MK-7655A-021

2019-CT0491

A Phase 2/3 Open-label, Randomized, Active-controlled Clinical Study to Evaluate the Safety, Tolerability, Efficacy and Pharmacokinetics of MK-7655A in Pediatric Participants From Birth to Less Than 18 Years of Age With Confirmed or Suspected Gram-negative Bacterial Infection

The primary purpose of this study is to evaluate the safety and tolerability of imipenem/cilastatin/relebactam (IMI/REL) in participants from birth to less than 18 years of age with confirmed or suspected gram-negative bacterial infection. Participants are expected to require hospitalization through completion of intravenous (IV) study intervention, and have at least one of the following primary infection types: hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP); complicated intra-abdominal infection (cIAI); or complicated urinary tract infection (cUTI). Participants will be randomized in a 3:1 ratio to receive IMI/REL or active control. This study will also evaluate the efficacy of IMI/REL by assessing all-cause mortality at Day 28 post-randomization, as well as clinical and microbiological response to treatment. It will also evaluate the pharmacokinetics of IMI/REL.

Start Date Duration in Months Target Completion Date Actual Completion Date
2022-08-31 60 2027-08-31 0000-00-00

Terminated

The sites were declared site ready but did not enroll any patients over the past two plus years in the MK7655A-021, thus early site closure has been conducted.

Institution Classification Region LTO #
Merck Sharp & Dohme (I.A.) LLC Private Business NCR CDRR-NCR-S-16
Institution Classification Region LTO #
Merck Sharp & Dohme (I.A.) LLC Private Business NCR CDRR-NCR-S-16
Institution Region
Merck Sharp & Dohme (I.A.) LLC NCR
Name E-Mail Institution and Institution Address
Priscila Perez priscila.d.perez@merck.com 26/F Philamlife Tower , 8767 Paseo de Roxas, Makati City, 1226 Philippines
Name E-Mail Institution and Institution Address
Priscila Perez priscila.d.perez@merck.com 26/F Philamlife Tower , 8767 Paseo de Roxas, Makati City, 1226 Philippines
Name Expertise Affiliation
Anna Lisa Ong-Lim, MD Principal Investigator University of the Philippines - Philippine General Hospital
David Bolong, MD Principal Investigator Philippine Children's Medical Center
Name of Trial Site Address Principal Investigator Research Ethics Committee
NAME EXPERTISE REC Name Status of Approval
University of the Philippines - Philippine General Hospital University of the Philippines-Philippine General Hospital, Pedia Office Ground Floor Taft Avenue. Ermita, 1000 IRB for UP-PGH UPMREB Anna Lisa Ong-Lim, MD Principal Investigator
Philippine Children's Medical Center Philippine Children's Medical Center, Quezon Avenue, Quezon City Philippine Children's Medical Center IRB - Ethics Committee David Bolong, MD Principal Investigator
Project Location Institutional Ethics Review Board
University of the Philippines - Philippine General Hospital IRB for UP-PGH UPMREB
Philippine Children's Medical Center Philippine Children's Medical Center IRB - Ethics Committee

Clinical Trial

Unspecified

Suspected or Documented Gram-negative Bacterial Infection

1. Percentage of Participants With One or More Adverse Event (AE) [ Time Frame: Up to 28 days ]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants with AEs will be presented.

2. Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event (AE) [ Time Frame: Up to 14 days ] 

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study medication due to an AE will be presented.

1. Number of Deaths by All Causes Through Day 28 [ Time Frame: Up to Day 28 ]
All-cause mortality up to 28 days post-randomization will be presented.

2. Percentage of Participants With a Favorable Clinical Response at End of Therapy (EOT) [ Time Frame: Day 5 up to Day 14 ]
The percentage of participants with a favorable clinical response at EOT will be presented.

3. Percentage of Participants With a Favorable Clinical Response at Early Follow-Up (EFU) [ Time Frame: Day 12 up to Day 28 ]
The percentage of participants with a favorable clinical response at EFU will be presented.

4. Percentage of Participants With a Favorable Clinical Response at Late Follow-Up (LFU) [ Time Frame: Day 19 up to Day 42 ]
The percentage of participants with a favorable clinical response at LFU will be presented.

5. Percentage of Participants With a Favorable Microbiological Response at End of Therapy (EOT) [ Time Frame: Day 5 up to Day 14 ]
The percentage of participants with a favorable microbiological response at EOT will be presented.

6. Percentage of Participants With a Favorable Microbiological Response at End of Follow-Up (EFU) [ Time Frame: Day 12 up to Day 28 ]
The percentage of participants with a favorable microbiological response at EFU will be presented.

7. Percentage of Participants With a Favorable Microbiological Response at Late Follow-Up (LFU) [ Time Frame: Day 19 up to Day 42 ]
Percentage of participants with a favorable microbiological response at LFU will be presented.

8. Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Imipenem Following Administration of IMI/REL [ Time Frame: On Day 1 at 30 minutes prior to start of first IV infusion of study drug, at end of first infusion, and 2 to 6 hours after start of first infusion; and once at on-therapy visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day. ]
Blood samples for AUC0-24 of imipenem analysis will be collected on Day 1 at 30 minutes prior to start of first dose of IV study intervention, at the end of the first infusion (±5 min), and 2 to 6 hours after the start of first infusion; and once at the on-therapy (OTX) visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day.

9. Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Relebactam Following Administration of IMI/REL [ Time Frame: On Day 1 at 30 minutes prior to start of first IV infusion of study drug, at end of first infusion, and 2 to 6 hours after start of first infusion; and once at on-therapy visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day. ]
Blood samples for AUC0-24 of relebactam analysis will be collected on Day 1 at 30 minutes prior to start of first dose of IV study intervention, at the end of the first infusion (±5 min), and 2 to 6 hours after the start of first infusion; and once at the on-therapy (OTX) visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day.

10. Concentration at End of Infusion (Ceoi) of Imipenem Following Administration of IMI/REL [ Time Frame: At the end of the first infusion on Day 1. ]
Blood samples for Ceoi of imipenem analysis will be collected at the end of the first infusion on Day 1.

11. Concentration at End of Infusion (Ceoi) of Relabactam Following Administration of IMI/REL [ Time Frame: At the end of the first infusion on Day 1. ]
Blood samples for Ceoi of relabactam analysis will be collected at the end of the first infusion (±5 min) on Day 1.

12. Percentage of Time Imipenem Concentration Is Above Minimum Inhibitory Concentration (%T>MIC of Imipenem) Following Administration of IMI/REL [ Time Frame: On Day 1 at 30 minutes prior to start of first IV infusion of study drug, at end of first infusion, and 2 to 6 hours after start of first infusion; and once at on-therapy visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day. ]
Blood samples for %T>MIC of imipenem analysis will be collected on Day 1 at 30 minutes prior to start of first dose of IV study intervention, at the end of the first infusion (±5 min), and 2 to 6 hours after the start of first infusion; and once at the on-therapy (OTX) visit (Day 2 or Day 3) at 2 to 6 hours after start of any infusion that day.

Terminated

  • Bulgaria
  • Colombia
  • France
  • Greece
  • Israel
  • Mexico
  • Philippines
  • Poland
  • Russia
  • South Africa
  • Spain
  • Turkey
  • Ukraine
  • United States

MK-7655A-021

20190313084412

2019-06-10

0000-00-00

Protocol Code Number MK-7655A-021
Protocol Version Unspecified
Date of Protocol Version Unspecified

8

Unspecified

N/A

Unspecified

2022-08-31

Inclusion Criteria:
-Requires hospitalization and treatment with IV antibacterial therapy for confirmed or suspected gram-negative bacterial infection (in the absence of meningitis), and is expected to require hospitalization through completion of IV study intervention, with at least 1 of the following primary infection types: HABP or VABP; cIAI; or cUTI.
-For Age Cohort 4 and 5,  participant is at least 37 weeks postmenstrual age at the time of signing the informed consent
-If female, must not be pregnant or breastfeeding, and at least 1 of the following conditions must apply: must not be a woman of childbearing potential (WOCBP); OR, if a WOCBP, must agree to follow contraceptive guidance during the intervention period and for at least 24 hours after the last dose of study intervention.
-Has sufficient intravascular access to receive study drug through an existing peripheral or central line.

Exclusion Criteria:
-Is expected to survive less than 72 hours.
-Has a concurrent infection that would interfere with evaluation of response to the study antibacterials (IMI/REL or Active Control), including any of the following: endocarditis; osteomyelitis; meningitis; prosthetic joint infection; active pulmonary tuberculosis; disseminated fungal infection; concomitant infection at the time of randomization that requires non-study systemic antibacterial therapy in addition to IV study treatment or oral step-down therapy.
-Has HABP/VABP caused by an obstructive process, including lung cancer (or other malignancy metastatic to the lungs resulting in pulmonary obstruction) or other known obstruction.
-Has a cUTI, with any of the following: complete obstruction of any portion of the urinary tract (ie, requiring a permanent indwelling urinary catheter or instrumentation); documented ileal loop reflux; suspected or confirmed perinephric or intrarenal abscess; suspected or confirmed prostatitis, urethritis, or epididymitis; trauma to pelvis/urinary tract; presence of indwelling urinary catheter which cannot be removed at study entry.
-Has any of the following medical conditions at screening: history of a seizure disorder (requiring ongoing treatment with anti-convulsive therapy or prior treatment with anti-convulsive therapy within the last 3 years); cystic fibrosis; history of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to IMI, or to any carbapenem, cephalosporin, penicillin, or other β-lactam agent, or to other β-lactamase inhibitors (eg, tazobactam, sulbactam, clavulanic acid, avibactam).
-Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might expose the participant to risk by participating in the study, confound study results, or interfere with the participant's participation for the full duration of the study.
-If less than 3 months of age, has received more than 72 hours of empiric antibacterial treatment until meningitis has been ruled out prior to initiation of IV study intervention.
-If 3 months of age or older, has received potentially therapeutic antibacterial therapy (eg, with gram-negative activity), including bladder infusions with topical urinary antiseptics or antibacterial agents, for a duration of more than 24 hours during the 48 hours preceding the first dose of study intervention.
-Is anticipated to be treated with any of the following medications: valproic acid or divalproex sodium (or has used valproic acid or divalproex sodium in the 2 weeks prior to screening) through 24 hours after completion of the final dose of IV study intervention for participants who receive IMI/REL or carbapenem; concomitant IV, oral, or inhaled antimicrobial agents with gram-negative activity, in addition to those designated in the study intervention groups, during the course of all (IV/oral) study intervention; planned receipt of suppressive/prophylactic antibiotics with gram-negative activity after completion of study intervention.
-Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 30 days prior to screening.
-Has enrolled previously in the current study and been discontinued, or has received REL for any other reason.
-Has an estimated creatinine clearance (based on the Cockcroft-Gault equation, for participants ≥12 years of age) or estimated glomerular filtration rate (eGFR, based on the modified Schwartz equation, for participants

-Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥5 × upper limit of normal (ULN) at the time of screening. NOTE: Patients with acute hepatic failure or acute decompensation of chronic hepatic failure should also be excluded.

-Is a user of recreational or illicit drugs or has had a recent history of drug or alcohol abuse or dependence.

-Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study. 

Interventional

1. Drug: IMI/REL 2. Drug: Active Control

  1. Drug: IMI/REL

Age-based dosing:

  • 12 to
  • 2 to
  • 3 months to
  • Birth to

Other Name: MK-7655A

 

  1. Drug: Active Control

All active control medications will be chosen from a list of acceptable approved agents for each infection type (HABP or VABP, cIAI, and UTI) and will be given via IV infusion, per authorized Package Insert (PI), Summary of Product Characteristics (SPC), or international treatment guidelines.

NOTE: Participants with cIAI or cUTI may be switched to oral therapy after at least 3 days of IV study intervention. All oral switch medications will be chosen from a list of acceptable approved agents.

Date Amendment Type Amendment Classification Reason
2020-01-07 Unspecified Amendments related to the protocol To decrease the planned enrollment numbers (including overall, by age group, and by infection site).
2022-02-07 Unspecified Amendments related to the protocol • To communicate the dosing regimen of MK-7655A for participants enrolled in Age Cohorts 4 and 5, based on the interim review of safety, tolerability, and PK data from PN20 and Age Cohorts 1 through 3 of PN021, and • To add piperacillin/tazobactam IV to the list of comparator medications allowed for participants with cIAI.

Method of Allocation

Randomized

Masking or Blinding

Open Label

Masking Details

None/OPEN LABEL

Control

Unspecified

Assignment

Parallel

Phase

Phase II/III

Purpose of the Study

Treatment

Detailed purpose of the study

Unspecified

Plan to Share IPD

Unspecified

IPD Description

Unspecified

Date of posting of result summaries

Unspecified

Date of the first journal publication of results

Unspecified

URL hyperlinks related to results and publications

Unspecified

URL link to protocol files(s) with version and data

Unspecified

Baseline Characteristics

Unspecified

Participant Flow

Unspecified

Adverse Events

Unspecified

Outcome Measures

Unspecified

Brief Summary

Unspecified

Utilization Utilization Info
Publication
Oral Presentation
Drug Literature
Posters
Others
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