A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of Cefiderocol in Hospitalized Pediatric Participants

Sponsor

Shionogi (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04335539

Collaborator

(none)

Enrollment

Locations

Arms

27.8

Anticipated Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objectives of this study are:

To assess the safety and tolerability of cefiderocol after single-dose administration in hospitalized paediatric participants 3 months to < 18 years of age with suspected or confirmed aerobic Gram-negative bacterial infections
To assess the pharmacokinetics (PK) of cefiderocol after single-dose administration of cefiderocol in hospitalized paediatric participants 3 months to < 18 years of age with suspected or confirmed aerobic Gram-negative bacterial infections
To assess the safety and tolerability of cefiderocol after multiple-dose administration in hospitalized paediatric participants 3 months to < 12 years of age with suspected or confirmed aerobic Gram-negative bacterial infections
To assess the PK of cefiderocol after multiple-dose administration in hospitalized paediatric participants 3 months to < 12 years of age with suspected or confirmed aerobic Gram-negative bacterial infections

Condition or Disease	Intervention/Treatment	Phase
Gram-negative Bacterial Infections Bloodstream Infections (BSI) Complicated Intra-abdominal Infection (cIAI) Hospital Acquired Pneumonia (HAP) Ventilator-acquired Pneumonia Complicated Urinary Tract Infection (cUTI) Sepsis	Drug: Cefiderocol Drug: Standard of Care	Phase 2

Detailed Description

This is a multicenter, single-arm, open-label, single- and multiple-dose study to assess the safety, tolerability, and PK of cefiderocol in hospitalized paediatric participants.

The single-dose phase will include 4 separate cohorts of participants, grouped according to age range:

Cohort 1: 12 to < 18 years
Cohort 2: 6 to < 12 years
Cohort 3: 2 to < 6 years
Cohort 4: 3 months to < 2 years Cohorts 1, 2, and 3 in the single-dose phase will be initiated in parallel. Cohort 4 will begin after safety and PK data from at least 6 participants from the single-dose Cohorts 1, 2, and 3 (with a minimum of 3 participants from Cohort 3) have been assessed.

The multiple-dose phase will include 3 cohorts according to age range (Cohorts 2, 3, and 4) and will begin after safety and PK data from 6 participants in the corresponding single-dose cohort have been assessed.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

54 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Single Arm, Open-label Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of Cefiderocol in Hospitalized Paediatric Subjects 3 Months to <18 Years of Age With Suspected or Confirmed Aerobic Gram-negative Bacterial Infections

Actual Study Start Date :

Aug 21, 2020

Anticipated Primary Completion Date :

Dec 15, 2022

Anticipated Study Completion Date :

Dec 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single Dose Phase: Cefiderocol Participants will receive a single dose of cefiderocol administered intravenously (IV) on Day 1, in addition to standard of care. Participants weighing less than 34 kilograms (kg) will receive 60 milligrams (mg)/kg of cefiderocol and participants ≥34 kg will receive 2000 mg.	Drug: Cefiderocol Administered intravenously over 3 hours Other Names: S-649266 Fetroja Drug: Standard of Care Standard of care antibiotics will be selected by the investigator based on the suspected or confirmed pathogen(s) for the infection in accordance with local standards.
Experimental: Multiple Dose Phase: Cefiderocol Participants will receive cefiderocol administered via IV every 8 hours on Day 1 and continuing for 5 to 14 days in addition to standard of care. Participants weighing less than 34 kg will receive 60 mg/kg of cefiderocol and participants ≥34 kg will receive 2000 mg. Dosage may be adjusted based on renal function.	Drug: Cefiderocol Administered intravenously over 3 hours Other Names: S-649266 Fetroja Drug: Standard of Care Standard of care antibiotics will be selected by the investigator based on the suspected or confirmed pathogen(s) for the infection in accordance with local standards.

Arm

Intervention/Treatment

Experimental: Single Dose Phase: Cefiderocol

Participants will receive a single dose of cefiderocol administered intravenously (IV) on Day 1, in addition to standard of care. Participants weighing less than 34 kilograms (kg) will receive 60 milligrams (mg)/kg of cefiderocol and participants ≥34 kg will receive 2000 mg.

Drug: Cefiderocol

Administered intravenously over 3 hours

Other Names:

S-649266

Fetroja

Drug: Standard of Care

Standard of care antibiotics will be selected by the investigator based on the suspected or confirmed pathogen(s) for the infection in accordance with local standards.

Experimental: Multiple Dose Phase: Cefiderocol

Participants will receive cefiderocol administered via IV every 8 hours on Day 1 and continuing for 5 to 14 days in addition to standard of care. Participants weighing less than 34 kg will receive 60 mg/kg of cefiderocol and participants ≥34 kg will receive 2000 mg. Dosage may be adjusted based on renal function.

Drug: Cefiderocol

Administered intravenously over 3 hours

Other Names:

S-649266

Fetroja

Drug: Standard of Care

Standard of care antibiotics will be selected by the investigator based on the suspected or confirmed pathogen(s) for the infection in accordance with local standards.

Outcome Measures

Primary Outcome Measures

Number of Participants with Adverse Events in the Single Dose Phase [28 days]
Maximum Observed Plasma Concentration (Cmax) of Cefiderocol in the Single Dose Phase [Cohorts 1 and 2: Day 1 at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: Day 1 at 3, 5, and 8 hours after the start of infusion.]
Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to Infinity (AUCinf) of Cefiderocol in the Single Dose Phase [Cohorts 1 and 2: Day 1 at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: Day 1 at 3, 5, and 8 hours after the start of infusion.]
Apparent Terminal Elimination Half-life of Cefiderocol in the Single Dose Phase [Cohorts 1 and 2: Day 1 at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: Day 1 at 3, 5, and 8 hours after the start of infusion.]
Number of Participants with Adverse Events in the Multiple Dose Phase [Up to 28 days after last dose (33 to 42 days depending on treatment duration)]
Maximum Observed Plasma Concentration (Cmax) of Cefiderocol in the Multiple Dose Phase [During one of the dosing intervals from the 6th to the 12th dose of cefiderocol: Cohort 2: at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: at 3, 5, and 8 hours after start of infusion.]
Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to Infinity (AUCinf) of Cefiderocol in the Multiple Dose Phase [During one of the dosing intervals from the 6th to the 12th dose of cefiderocol: Cohort 2: at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: at 3, 5, and 8 hours after start of infusion.]
Apparent Terminal Elimination Half-life of Cefiderocol in the Multiple Dose Phase [During one of the dosing intervals from the 6th to the 12th dose of cefiderocol: Cohort 2: at 1, 3, 3.5, 5, and 8 hours after start of infusion. Cohorts 3 and 4: at 3, 5, and 8 hours after start of infusion.]

Secondary Outcome Measures

Percentage of Participants with a Clinical Response in the Multiple Dose Phase [At 7 and 28 days after the end of treatment]
Percentage of Participants with a Microbiological Response Per Pathogen in the Multiple Dose Phase [At 7 and 28 days after the end of treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

3 Months to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant's parent(s) or legally authorized representative (LAR) provides written informed consent in accordance with regional and country-specific laws and regulations.
Participant provides written informed assent, when feasible (age of assent to be determined by institutional review boards/independent ethics committees [IRB's/IEC's] or be consistent with local legal requirements).
Hospitalized participant is 3 months to <18 years of age at the time written informed consent/assent is obtained for the single-dose phase. Hospitalized participant is 3 months to <12 years of age at the time written informed consent/assent is obtained for the multiple-dose phase. Premature babies will not be restricted, but the participant must have an adjusted or postnatal age of 3 months.
Participant has a suspected or confirmed infection (including but not limited to complicated urinary tract infection [cUTI], complicated intra-abdominal infection [cIAI], hospital-acquired pneumonia [HAP] /ventilator-acquired pneumonia [VAP], sepsis, or bloodstream infections [BSI]) that requires hospitalization for treatment with IV antibiotics.
If participant is a sexually active female of childbearing potential and has reached menarche or Tanner stage 3, participant agrees to use barrier contraception (including condom, diaphragm, or cervical cap) with spermicide or agrees to use a highly effective method of contraception (including contraceptive implant, injectable contraceptive, combination oral contraceptive, or an intrauterine [IUD] contraceptive device) from Screening up to 28 days after administration of the last dose of cefiderocol.

Exclusion Criteria:

Participant has a documented history of any hypersensitivity or allergic reaction to any β-lactam antibiotic (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment).
Multiple-dose only: Participant has an infection caused only by a confirmed Gram-positive pathogen.
Participant has a suspected or confirmed central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection) or osteomyelitis (which would require prolonged antibiotic therapy).
Participant has cystic fibrosis.
Single-dose phase: Participant has moderate or severe renal impairment based on estimated glomerular filtration rate (eGFR) (based on Schwartz equation if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation if ≥ 1 to < 18 years of age) of < 60 milliliter (mL) per minute (min)/1.73 ^2² at Screening.

Multiple-dose phase: Participant has an eGFR (based on Schwartz equation if ≥ 3 months to < 1 year of age and modified Bedside Schwartz equation if ≥ 1 to < 18 years of age) of < 15 mL/min/1.73 ^2² at Screening.

Participant has end-stage renal disease (ESRD), is on hemodialysis (HD), or receiving continuous venovenous hemofiltration (CVVH).
Participant has experienced shock in the prior month or is in shock at the time of Screening.
Participant has severe neutropenia or is severely immunocompromised.
Participant has multiorgan failure.
Participant has a life expectancy of < 30 days due to severity of a concurrent illness.
Participant is a female who has a positive pregnancy test at Screening.
Participant is a female who is breastfeeding.
Participant has received any other investigational medicinal product (IMP) within 30 days.
Participant has any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the participant or the quality of the study data, including acute trauma to the pelvis or urinary tract.
Participant is receiving vasopressor therapy at Screening.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Universitair Ziekenhuis Brussel	Brussels	Belgium	1200
2	Cliniques Universitaires Saint-Luc	Brussels	Belgium
3	Tallinn Childrens Hospital	Tallin	Estonia
4	Tartu Ulikooli Kliinikum - Anestesioloogia ja Intensiivravi Kliinik	Tartu	Estonia
5	JSC "Medical Corporation Evex" " M. Iashvili Batumi Maternal and Child Central Hospital"	Batumi	Georgia
6	JSC "EVEX Medical Corporation"- M Lashvili Childrens Central Hospital	Tbilisi	Georgia
7	Ltd Unimedi Kakheti Childrens New Clinic	Tbilisi	Georgia
8	Heim Pl Orszgos Gyermekgygyszati Intzet	Pilisborosjenő	Hungary
9	Szegedi Tudomnyegyetem	Szegedi Tudomnyegyetem	Hungary
10	Daugavpils regional Hospital	Daugavpils	Latvia
11	Bernu Kliniska Universitates Slimnica Childrens Hospital - Tornakalna	Riga	Latvia
12	Smolensk State Medical University	Smolensk	Russian Federation
13	St. Petersburg State Pediatric Medical University	St. Petersburg	Russian Federation
14	Hospital Germans Trias i Pujol	Barcelona	Spain
15	Hospital Universitario y Politecnico La Fe	Valencia	Spain
16	Siriraj Hospital	Bangkok-noi	Thailand
17	King Chulalongkorn Memorial Hospital, Chulalongkorn University	Bangkok	Thailand
18	PHPT-Chiangrai PrachanuKroh Hospital	Chiang Mai	Thailand
19	Khon Kaen University (KKU) - Faculty of Medicine-Srinagarind Hospital	Khon Kaen	Thailand
20	Dnipropetrovsk Regional Children Clinical Hospital	Kharkiv	Ukraine
21	Regional Children Clinical Hospital	Kharkiv	Ukraine
22	National Childrens Specialized Hospital OHMATDYT of the Ministry of Health of Ukraine	Kiev	Ukraine
23	Higher State Educational Institute of Ukraine Ukrainian Medical Stamatological Academy	Poltava	Ukraine