A trial to evaluate the pharmacokinetics, safety, and tolerability of MK-7655A in children less than 18 years old with confirmed or suspected gram-negative infections

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2016-004328-43-Outside-EU/EEA
• Date of registration: 12/06/2017
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: A trial to evaluate the pharmacokinetics, safety, and tolerability of MK-7655A in children less than 18 years old with confirmed or suspected gram-negative infections
• Scientific 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 - A Single-dose Pharmacokinetics Study of MK-7655A in Pediatric Subjects
• Target sample size: 44
• Recruitment status: NA
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-004328-43
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Colombia, Ukraine, United States

Contacts

• Name: Luke F. Chen
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

• Name: Luke F. Chen
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Have a parent or LAR who provides written informed consent for the trial on the subject’s behalf after understanding the study procedures, alternative treatments available, and risks involved with the study, and voluntarily agrees to allow the subject to participate. Assent is to be obtained from minors according to institutional practices. The subject, depending on their age and ability to understand the nature and intent of the study, must also assent to participate in the study main trial
2.Be able to comply with the protocol for the duration of the study
3.Be male or female from birth to <18 years of age at screening
4.For Cohorts 4 and 5, was born at or after 37 weeks of gestation
5.Be 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. Subjects who are not receiving antibacterial treatment for the qualifying infection at the time of screening are eligible for this trial if either (1) they will be initiating antibacterial treatment for the qualifying infection prior to study drug administration, or (2) they have recently (within 48 hours prior to study drug administration) completed antibacterial treatment for the qualifying infection
6.Meet 1 of the following categories: a)The subject is a male who is not of reproductive potential, defined as a male who has azoospermia; b)The subject is a female who is not of reproductive potential, defined as a female who either: (1) who has not undergone menarche, (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening, OR (3) has a congenital or acquired condition that prevents childbearing.; c) The subject is a female or a male who is of reproductive potential and agrees to avoid becoming pregnant or impregnating a partner from the time of consent through 24 hours after completion of study drug administration by complying with 1 of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have their partner use) acceptable contraception during heterosexual activity.Acceptable methods of contraception are:Single method (1 of the following is acceptable):a)intrauterine device,b)vasectomy of a female subject’s male partner C)contraceptive rod implanted into the skin. Combination method (requires use of 2 of the following):a)diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) b)cervical cap with spermicide (nulliparous women only) c)contraceptive sponge (nulliparous women only) d)male condom or female condom (cannot be used together) e)hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection. Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and Ethical Review Committee (ERCs)/Institutional Review Boards (IRBs). Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.
7. Have clinically stable renal function at the time of screening that is judged to
Exclusion criteria:
1.Has a personal history of hypersensitivity to IMI or to any of the following: a) Any carbapenem, cephalosporin, penicillin, or other ß-lactam agent b) Other BLIs (e.g., tazobactam, sulbactam, clavulanic acid, avibactam)
2.If female, is currently pregnant or breast feeding or has a positive serum ß-human chorionic gonadotropin (ß-hCG) pregnancy test prior to administration of the study drug.
3.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)
4.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
5.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
6.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
7.Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days prior to screening
8.Has enrolled previously in the current trial and been discontinued, or has received REL for any other reason
9.Has a current diagnosis of cystic fibrosis, meningitis, or severe sepsis
10.Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might expose the subject to risk by participating in the trial, confound the results of the trial, or interfere with the subject’s participation for the full duration of the trial
11.Is expected to survive less than 72 hours after completion of study drug administration
12.Has any of the following laboratory abnormalities at the time of screening: a) ALT or AST =3 × ULN, b)ALT or AST =2 × ULN accompanied by total bilirubin >ULN, c)Total bilirubin =2 × ULN, or d)Any other clinically significant abnormal laboratory test results not related to the underlying infection, as determined by the investigator.
13.Has a history of clinically significant renal, hepatic, or hemodynamic instability
14.Has planned use of cardiopulmonary bypass, extracorporeal membrane oxygenation, hemodialysis, or peritoneal dialysis during the study
15.Has weight outside of the 5th to 95th percentile based on age
16.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
17.Has a planned blood transfusion within 24 hours of study drug administration or expected before the end of the PK sampling
18.Has had significant blood loss (=5% of total blood volume) within 4 weeks before the screening visit. Total blood volume can be estimated as 80 mL/kg of body weight
19.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 trial


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Bacterial Infections and Mycoses [C01]

Treatment of bacterial infections in pediatric populations
MedDRA version: 20.0 Level: LLT Classification code 10071097 Term: Beta-lactam antibiotic resistance System Organ Class: 100000004862

Intervention(s)

Product Name: imipenem/cilastatin/relebactam
Product Code: MK-7655A
Pharmaceutical Form: Powder for injection
INN or Proposed INN: IMIPENEM
CAS Number: 64221-86-9
Other descriptive name: Imipenem is an active substance part of the marketed drug TIENAM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
INN or Proposed INN: CILASTATIN
CAS Number: 82009-34-5
Other descriptive name: Cilastatin is an active substance part of the marketed drug TIENAM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 500-
INN or Proposed INN: Relebactam
Other descriptive name: MK-7655
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 250-

Primary Outcome(s)

Secondary Objective: To evaluate the safety and tolerability profile of a single IV dose of IMI/REL in pediatric subjects from birth to less than 18 years of age receiving standard-of-care antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection.

Primary end point(s): Pharmacokinetic: Plasma PK concentration data; 4 PK samples per subject will be collected. Primary model-based endpoints for REL and imipenem and non-model-based endpoints for cilastatin are listed in protocol Section 8.4.1 -Pharmacokinetic/Pharmacodynamic Endpoints

Main Objective: To obtain plasma PK data and characterize the PK profile of imipenem, cilastatin, and relebactam (REL) following administration of a single IV dose of IMI/REL in pediatric subjects from birth to less than 18 years of age receiving standard-of-care antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection.

Timepoint(s) of evaluation of this end point: Samples for pharmacokinetic analysis will be collected at following timepoints
a)First sample (for cohorts 1-5): 30 min prior to drug infusion;
b) second sample (for cohort 1-5): 5 min after end of study drug infusion;
c) Third sample:
(Cohorts 1-4): 1.5-2.5 hours after start of study drug infusion,
(Cohort 5): 2-5 hours after start of study drug infusion and;
d) Fourth sample
(Cohort 1-4): 4.5-6 hours. after start of study drug infusion
(Cohort 5): 6-12 hours. after start of study drug infusion

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Safety endpoints will be assessed throughout the duration of the trial participation

Secondary end point(s): Safety: Safety evaluation will be based on the following endpoints: AEs (including ECIs), local tolerability assessments, clinical laboratory data, vital sign measurements, and physical examinations findings

Secondary ID(s)

108,754

MK-7655A-020

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.