| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of bacterial infections in pediatric populations |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of bacterial infections in pediatric populations |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071097 |
| E.1.2 | Term | Beta-lactam antibiotic resistance |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To obtain plasma PK data and characterize the pharmacokinetic (PK) profile of imipenem, cilastatin (IMI), and relebactam (REL) following administration of a single IV dose of IMI/REL in pediatric participants from birth to less than 18 years of age receiving standard-of-care antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the safety and tolerability profile of a single IV dose of IMI/REL in pediatric participants from birth to less than 18 years of age receiving standard-of-care antibacterial therapy for a confirmed or suspected Gram-negative bacterial infection. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 as applicable according to institutional practices.
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, is at least 37 weeks postmenstrual age at the time of screening. Postmenstrual age is calculated by adding the gestational age at the time of birth to the chronological age at the time of screening.
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. Participants 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 be within acceptable ranges for age, as measured by creatinine clearance and as defined in the protocol
8.Have sufficient intravascular access to receive study drug through an existing peripheral or central line. |
|
| E.4 | Principal exclusion criteria |
1.Has a personal history of hypersensitivity to IMI or to any of the following: a) Any carbapenem, cephalosporin, penicillin, or other β-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 β-human chorionic gonadotropin (β-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, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), angiotensin receptor blockers, (eg, valsartan), 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 (with the exception of values, as determined by the investigator, that would be part of normal physiologic process for a particular age group [eg, physiologic hyperbilirubinemia in a newborn]): 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.For Cohorts 1 through 3 only: 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 |
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| E.5 End points |
| E.5.1 | 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 |
|
| E.5.1.1 | 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): 10 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
|
|
| E.5.2 | 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety endpoints will be assessed throughout the duration of the trial participation |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Pharmacokinetics, Safety, and Tolerability in Pediatric Participants |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Colombia |
| Greece |
| Norway |
| Poland |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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