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

Study Overview
=================
Brief Summary
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Suspected or Documented Gram-negative Bacterial Infection

Intervention / Treatment
-----------------
* Drug: IMI/REL
* Drug: Active Control


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Cohorts 4 and 5, participant is at least 37 weeks postmenstrual age at the time of signing the informed consent/assent. 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 (medications with only gram-positive activity [e.g., vancomycin, linezolid] are allowed). 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 reflux of ileal loop urinary diversion; 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 for suspected meningitis prior to initiation of IV study intervention. If 3 months of age or older, or <3 months of age without suspected meningitis, 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 <12 years of age) below that specified for the appropriate age range; or requires peritoneal dialysis, hemodialysis, or hemofiltration. 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.

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IMI/REL<br>Participants with cIAI or cUTI will receive imipenem/cilastatin/relebactam (IMI/REL) via IV infusion, once every 6 hours, for a minimum of 5 days (with optional oral switch after 3 days) up to a maximum of 14 days. Participants with HABP/VABP will receive IMI/REL via IV infusion, once every 6 hours, for a minimum of 7 days up to a maximum of 14 days. All oral switch medications will be chosen from a list of acceptable approved agents and will be administered per authorized Package Insert (PI), Summary of Product Characteristics (SPC), or international treatment guidelines. | Drug: IMI/REL<br>* Age-based dosing: 12 to <18 years, IMI 500 and REL 250 mg, IV infusion every 6 hours 2 to <12 years, IMI 15 and REL 7.5 mg/kg, IV infusion every 6 hours 3 months to <2 years, IMI 15 and REL 7.5 mg/kg, IV infusion every 6 hours Birth to <3 month, IMI 15 and REL 7.5 mg/kg, IV infusion every 8 hours NOTE: Participants with cIAI or cUTI may be switched to oral therapy after at least 3 days of IV study intervention.<br>* Other names: MK-7655A;|
| Active Comparator: Active Control<br>Participants with cIAI or cUTI will receive active control via IV infusion for a minimum of 5 days (with optional oral switch after 3 days) up to a maximum of 14 days. Participants with HABP/VABP will receive active control via IV infusion for a minimum of 7 days up to a maximum of 14 days. All active control and oral switch medications will be administered per authorized PI, SPC, or international treatment guidelines. All active control and oral switch medications will be chosen from a list of acceptable approved agents. | Drug: Active Control<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With One or More Adverse Event (AE) | 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. | Up to 28 days | 
| Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event (AE) | 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. | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Deaths by All Causes Through Day 28 | All-cause mortality up to 28 days post-randomization will be presented. | Up to Day 28 | 
| Percentage of Participants With a Favorable Clinical Response at End of Therapy (EOT) | The percentage of participants with a favorable clinical response at EOT will be presented. | Day 5 up to Day 14 | 
| Percentage of Participants With a Favorable Clinical Response at Early Follow-Up (EFU) | The percentage of participants with a favorable clinical response at EFU will be presented. | Day 12 up to Day 28 | 
| Percentage of Participants With a Favorable Clinical Response at Late Follow-Up (LFU) | The percentage of participants with a favorable clinical response at LFU will be presented. | Day 19 up to Day 42 | 
| Percentage of Participants With a Favorable Microbiological Response at End of Therapy (EOT) | The percentage of participants with a favorable microbiological response at EOT will be presented. | Day 5 up to Day 14 | 
| Percentage of Participants With a Favorable Microbiological Response at End of Follow-Up (EFU) | The percentage of participants with a favorable microbiological response at EFU will be presented. | Day 12 up to Day 28 | 
| Percentage of Participants With a Favorable Microbiological Response at Late Follow-Up (LFU) | Percentage of participants with a favorable microbiological response at LFU will be presented. | Day 19 up to Day 42 | 
| Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Imipenem Following Administration of IMI/REL | 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, within 10 minutes after the end of the first infusion, 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. | 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. | 
| Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Relebactam Following Administration of IMI/REL | 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, within 10 minutes after the end of the first infusion, 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. | 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. | 
| Concentration at End of Infusion (Ceoi) of Imipenem Following Administration of IMI/REL | Blood samples for Ceoi of imipenem analysis will be collected within 10 minutes after the end of the first infusion on Day 1. | At the end of the first infusion on Day 1. | 
| Concentration at End of Infusion (Ceoi) of Relabactam Following Administration of IMI/REL | Blood samples for Ceoi of relabactam analysis will be collected within 10 minutes after the end of the first infusion on Day 1. | At the end of the first infusion on Day 1. | 
| Percentage of Time Imipenem Concentration Is Above Minimum Inhibitory Concentration (%T>MIC of Imipenem) Following Administration of IMI/REL | 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, within 10 minutes after the end of the first infusion, 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. | 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. |