Clinical trial NCT03969901: Safety, Tolerability, Efficacy and Pharmacokinetics of Imipenem/Cilastatin/Relebactam (MK-7655A) in Pediatric Participants With Gram-negative Bacterial Infection (MK-7655A-021)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Suspected or Documented Gram-negative Bacterial Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-05-31
Enrollment: 115
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

Inclusion Criteria include but are not limited to:

* Requires hospitalization and treatment with intravenous (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: Hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP); complicated intra-abdominal infection (cIAI); or complicated urinary tract infection (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:

Exclusion Criteria include but are not limited to:

* Is expected to survive less than 72 hours.
* Has a concurrent infection that would interfere with evaluation of response to the study antibacterials (imipenem/cilastatin/relebactam (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 (i.e., 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 (e.g., anaphylaxis), or any serious reaction to IMI, or to any carbapenem, cephalosporin, penicillin, or other β-lactam agent, or to other β-lactamase inhibitors (e.g., 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.
* For all Age Cohorts, provided all other eligibility criteria are met, the following participants may be enrolled:

  * A participant failing prior antibiotic therapy for a current episode of cUTI or HABP/VABP who: Has received the prior antibacterial treatment for at least 48 hours; Has persistent clinical or radiographic findings clearly indicating ongoing infection; Fulfills other laboratory or microbiology criteria for enrollment
  * A participant failing prior antibiotic therapy for a current episode of cIAI who: Has received the prior antibacterial treatment for at least 48 hours; Has persistent clinical or radiographic findings clearly indicating ongoing infection; Fulfills other laboratory or microbiology criteria for enrollment; Has planned operative intervention no more than 24 hours after first dose of study treatment; Has not received any further nonstudy antibiotics postoperatively
* If 3 months of age or older, or \<3 months of age without suspected meningitis, has received potentially therapeutic antibacterial therapy (e.g., 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 (e.g., spouse, parent/legal guardian, sibling, or child) who is investigational site or Sponsor staff directly involved with this study.

Primary outcomes:
measure: Percentage of Participants With One or More Adverse Event (AE)
timeFrame: Up to 28 days
measure: Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event (AE)
timeFrame: Up to 14 days
Secondary outcomes:
measure: Percentage of Participants With All-cause Mortality Through Day 28
timeFrame: Up to Day 28
measure: Percentage of Participants With a Favorable Clinical Response at End of Therapy (EOT)
timeFrame: Day 5 up to Day 14
measure: Percentage of Participants With a Favorable Clinical Response at Early Follow-Up (EFU)
timeFrame: Day 12 up to Day 28
measure: Percentage of Participants With a Favorable Clinical Response at Late Follow-Up (LFU)
timeFrame: Baseline and Day 19 up to Day 42
measure: Percentage of Participants With a Favorable Microbiological Response at End of Therapy (EOT)
timeFrame: Day 5 up to Day 14
measure: Percentage of Participants With a Favorable Microbiological Response at End of Follow-Up (EFU)
timeFrame: Day 12 up to Day 28
measure: Percentage of Participants With a Favorable Microbiological Response at Late Follow-Up (LFU)
timeFrame: Day 19 up to Day 42
measure: Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Imipenem Following Administration of IMI/REL
timeFrame: 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.
measure: Area Under the Curve From Time 0 to 24 Hours (AUC0-24) of Relebactam Following Administration of IMI/REL
timeFrame: 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.
measure: Concentration at End of Infusion (Ceoi) of Imipenem Following Administration of IMI/REL
timeFrame: At the end of the first infusion on Day 1.
measure: Concentration at End of Infusion (Ceoi) of Relebactam Following Administration of IMI/REL
timeFrame: At the end of the first infusion on Day 1.
measure: Percentage of Time Imipenem Concentration Is Above Minimum Inhibitory Concentration (%T>MIC of Imipenem) Following Administration of IMI/REL
timeFrame: 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.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Banner University Medical Center ( Site 0356)
state: Arizona
city: Long Beach
country: United States
facility: Miller Children's & Women's Hospital ( Site 0349)
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital-San Diego ( Site 0347)
state: California
city: Boston
country: United States
facility: Tufts Medical Center-Floating Hospital for Children ( Site 0350)
state: Massachusetts
city: Albuquerque
country: United States
facility: University of New Mexico ( Site 0358)
state: New Mexico
city: San Antonio
country: United States
facility: University Hospital ( Site 0360)
state: Texas
city: Richmond
country: United States
facility: Children's Hospital of Richmond at VCU ( Site 0359)
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Ruby Memorial Hospital ( Site 0344)
state: West Virginia
city: Burgas
country: Bulgaria
facility: UMHAT Deva Maria. EOOD ( Site 0165)
city: Montana
country: Bulgaria
facility: MHAT City Clinic Sv. Georgi EOOD ( Site 0167)
city: Pleven
country: Bulgaria
facility: UMHAT Dr. Georgi Stranski EAD ( Site 0174)
city: Ruse
country: Bulgaria
facility: UMHAT Kanev AD ( Site 0168)
city: Ruse
country: Bulgaria
facility: UMHAT Kanev AD ( Site 0169)
city: Sliven
country: Bulgaria
facility: MHAT Dr. Ival Seliminski ( Site 0173)
city: Santiago
country: Chile
facility: Hospital Roberto del Río ( Site 0802)
state: Region M. De Santiago
city: Medellin
country: Colombia
facility: Fundacion Hospital San Vicente de Paul ( Site 0269)
state: Antioquia
city: Barranquilla
country: Colombia
facility: Clinica de la Costa S.A.S. ( Site 0264)
state: Atlantico
city: Bogota
country: Colombia
facility: Sociedad de Cirugía de Bogotá - Hospital de San Jose ( Site 0265)
state: Distrito Capital De Bogota
city: Bogota
country: Colombia
facility: Fundacion Hospital Infantil Universitario de San Jose ( Site 0268)
state: Distrito Capital De Bogota
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0266)
state: Valle Del Cauca
city: Tallinn
country: Estonia
facility: Tallinn Children Hospital ( Site 0209)
state: Harjumaa
city: Nice
country: France
facility: Hopitaux Pediatriques CHU Lenval ( Site 0143)
state: Alpes-Maritimes
city: Dijon
country: France
facility: Hopital Francois Mitterand ( Site 0146)
state: Cote-d Or
city: Lille
country: France
facility: Hopital Jeanne de Flandre ( Site 0145)
state: Nord-Pas-de-Calais
city: Athens
country: Greece
facility: University of Athens - Aghia Sophia Childrens Hospital ( Site 0243)
state: Attiki
city: Athens
country: Greece
facility: Pan and Aglaia Kyriakou Children s Hospital ( Site 0247)
state: Attiki
city: Thessaloniki
country: Greece
facility: Hippokration General Hospital of Thessaloniki ( Site 0244)
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont ( Site 0100)
state: Hajdu-Bihar
city: Nyiregyhaza
country: Hungary
facility: Szabolcs-Szatmar-Bereg Megyei Kórházak és Egyetemi Otatókórház-Gyermekosztály ( Site 0105)
state: Szabolcs-Szatmar-Bereg
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 0189)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Hebrew University Medical Center ( Site 0188)
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center ( Site 0187)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 0190)
city: Tijuana
country: Mexico
facility: Hospital General de Tijuana ( Site 0284)
state: Baja California
city: Emiliano Zapata
country: Mexico
facility: Hospital del Nino y Adolescente Morelense ( Site 0286)
state: Morelos
city: Aguascalientes
country: Mexico
facility: Centenario Hospital Miguel Hidalgo-Pediatrics Department ( Site 0290)
city: Ciudad de Mexico
country: Mexico
facility: Instituto Nacional de Pediatria ( Site 0291)
city: Bergen
country: Norway
facility: Haukeland Universitetssjukehus ( Site 0500)
state: Hordaland
city: Manila
country: Philippines
facility: University of the Philippines-Philippine General Hospital ( Site 0318)
state: National Capital Region
city: Quezon City
country: Philippines
facility: Philippine Children s Medical Center ( Site 0317)
state: National Capital Region
city: Torun
country: Poland
facility: Wojewodzki Szpital Zespolony im. Rydgiera ( Site 0220)
state: Kujawsko-pomorskie
city: Lodz
country: Poland
facility: Instytut Centrum Zdrowia Matki Polki ( Site 0223)
state: Lodzkie
city: Lomianki
country: Poland
facility: SPZOZ im. Dzieci Warszawy w Dziekanowie Lesnym ( Site 0226)
state: Mazowieckie
city: Moscow
country: Russian Federation
facility: Pediatric Hematology Oncology and Immunology Centre n.a. D.Rogachev. ( Site 0233)
state: Moskva
city: Moscow
country: Russian Federation
facility: Morozovskaya Children City Clinical Hospital ( Site 0241)
state: Moskva
city: Novosibirsk
country: Russian Federation
facility: State Budgetary Healthcare Institution of Novosibirsk Region City Childrens Clinical Emergency Hospi
state: Novosibirskaya Oblast
city: Saint Petersburg
country: Russian Federation
facility: St.Petersburg State Pediatric Medical University ( Site 0236)
state: Sankt-Peterburg
city: Saint Petersburg
country: Russian Federation
facility: Children's City Clinical Hospital #1 ( Site 0237)
state: Sankt-Peterburg
city: St. Petersburg
country: Russian Federation
facility: Children s City Clinical Hospital 5 n.a. N.F. Filatov ( Site 0235)
state: Sankt-Peterburg
city: Smolensk
country: Russian Federation
facility: Smolensk Regional Clinical Hospital ( Site 0231)
state: Smolenskaya Oblast
city: Vologda
country: Russian Federation
facility: Regional Childrens Clinical Hospital ( Site 0400)
state: Vologodskaya Oblast
city: Johannesburg
country: South Africa
facility: Empilweni Services and Research Unit ( Site 1557)
state: Gauteng
city: Johannesburg
country: South Africa
facility: Chris Hani Baragwanath Academic Hospital ( Site 0156)
state: Gauteng
city: Pretoria
country: South Africa
facility: Molotlegi Street ( Site 0155)
state: Gauteng
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus ( Site 0114)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz ( Site 0113)
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio ( Site 0115)
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty ( Site 0200)
city: Ankara
country: Turkey
facility: Ankara Universitesi Tip Fakultesi. ( Site 0202)
city: Eskisehir
country: Turkey
facility: Eskisehir Osmangazi University Medical ( Site 0201)
city: Istanbul
country: Turkey
facility: SBU Sariyer Hamidiye Etfal Egitim ve Arastirma Hastanesi ( Site 0198)
city: Izmir
country: Turkey
facility: Ege Universitesi Tıp Fakultesi Hastanesi ( Site 0199)
city: Dnipro
country: Ukraine
facility: SI Dnipropetrovsk Regional Children Clinical Hospital DOR ( Site 0121)
state: Dnipropetrovska Oblast
city: Kryvyy Rig
country: Ukraine
facility: Communal non-commercial enterprise "Kryvorizka city clinical hospital 16" of Kryvyy Rig city council
state: Dnipropetrovska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk Regional Children Clinical Hospital ( Site 0131)
state: Ivano-Frankivska Oblast
city: Kharkiv
country: Ukraine
facility: Kharkiv City Children Hospital 16 ( Site 0130)
state: Kharkivska Oblast
city: Poltava
country: Ukraine
facility: Municipal Enterprise Children's City Clinical Hospital in Poltava City Council ( Site 0122)
state: Poltavska Oblast
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: