Clinical trial NCT04335539: A Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of Cefiderocol in Hospitalized Pediatric Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: Shionogi Inc.
Sponsor class: INDUSTRY
First posted: 2020-04-06
Enrollment: 54
Sex: ALL
Minimum age (years): 3
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Eligibility criteria: Inclusion Criteria:

1. Participant's parent(s) or legally authorized representative (LAR) provides written informed consent in accordance with regional and country-specific laws and regulations.
2. 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).
3. 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.
4. 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.
5. 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:

1. 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).
2. Multiple-dose only: Participant has an infection caused only by a confirmed Gram-positive pathogen.
3. 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).
4. Participant has cystic fibrosis.
5. 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.
6. Participant has end-stage renal disease (ESRD), is on hemodialysis (HD), or receiving continuous venovenous hemofiltration (CVVH).
7. Participant has experienced shock in the prior month or is in shock at the time of Screening.
8. Participant has severe neutropenia or is severely immunocompromised.
9. Participant has multiorgan failure.
10. Participant has a life expectancy of \< 30 days due to severity of a concurrent illness.
11. Participant is a female who has a positive pregnancy test at Screening.
12. Participant is a female who is breastfeeding.
13. Participant has received any other investigational medicinal product (IMP) within 30 days.
14. 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.
15. Participant is receiving vasopressor therapy at Screening.

Primary outcomes:
measure: Number of Participants with Adverse Events in the Single Dose Phase
timeFrame: 28 days
measure: Maximum Observed Plasma Concentration (Cmax) of Cefiderocol in the Single Dose Phase
timeFrame: 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.
measure: Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to Infinity (AUCinf) of Cefiderocol in the Single Dose Phase
timeFrame: 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.
measure: Apparent Terminal Elimination Half-life of Cefiderocol in the Single Dose Phase
timeFrame: 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.
measure: Number of Participants with Adverse Events in the Multiple Dose Phase
timeFrame: Up to 28 days after last dose (33 to 42 days depending on treatment duration)
measure: Maximum Observed Plasma Concentration (Cmax) of Cefiderocol in the Multiple Dose Phase
timeFrame: 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.
measure: Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to Infinity (AUCinf) of Cefiderocol in the Multiple Dose Phase
timeFrame: 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.
measure: Apparent Terminal Elimination Half-life of Cefiderocol in the Multiple Dose Phase
timeFrame: 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 outcomes:
measure: Percentage of Participants with a Clinical Response in the Multiple Dose Phase
timeFrame: At 7 and 28 days after the end of treatment
measure: Percentage of Participants with a Microbiological Response Per Pathogen in the Multiple Dose Phase
timeFrame: At 7 and 28 days after the end of treatment
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Tallin
country: Estonia
facility: Tallinn Childrens Hospital
city: Tartu
country: Estonia
facility: Tartu Ulikooli Kliinikum - Anestesioloogia ja Intensiivravi Kliinik
city: Batumi
country: Georgia
facility: JSC "Medical Corporation Evex" " M. Iashvili Batumi Maternal and Child Central Hospital"
city: Tbilisi
country: Georgia
facility: JSC "EVEX Medical Corporation"- M Lashvili Childrens Central Hospital
city: Tbilisi
country: Georgia
facility: Ltd Unimedi Kakheti Childrens New Clinic
city: Pilisborosjenő
country: Hungary
facility: Heim Pl Orszgos Gyermekgygyszati Intzet
city: Szegedi Tudomnyegyetem
country: Hungary
facility: Szegedi Tudomnyegyetem
city: Daugavpils
country: Latvia
facility: Daugavpils regional Hospital
city: Riga
country: Latvia
facility: Bernu Kliniska Universitates Slimnica Childrens Hospital - Tornakalna
city: Smolensk
country: Russian Federation
facility: Smolensk State Medical University
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Pediatric Medical University
city: Barcelona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Valencia
country: Spain
facility: Hospital Universitario y Politecnico La Fe
city: Bangkok-noi
country: Thailand
facility: Siriraj Hospital
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital, Chulalongkorn University
city: Chiang Mai
country: Thailand
facility: PHPT-Chiangrai PrachanuKroh Hospital
city: Khon Kaen
country: Thailand
facility: Khon Kaen University (KKU) - Faculty of Medicine-Srinagarind Hospital
city: Kharkiv
country: Ukraine
facility: Dnipropetrovsk Regional Children Clinical Hospital
city: Kharkiv
country: Ukraine
facility: Regional Children Clinical Hospital
city: Kiev
country: Ukraine
facility: National Childrens Specialized Hospital OHMATDYT of the Ministry of Health of Ukraine
city: Poltava
country: Ukraine
facility: Higher State Educational Institute of Ukraine Ukrainian Medical Stamatological Academy
Study officials:
affiliation: Shionogi
name: Shionogi Clinical Trials Administrator Clinical Support Help Line
role: STUDY_DIRECTOR
References: