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
Conditions
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.
Interventions
DRUGCefiderocol
Administered intravenously over 3 hours
DRUGStandard 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.
Sponsors
Shionogi
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Months to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Single Dose Phase: Maximum Observed Plasma Concentration (Cmax) of Cefiderocol | Up to 8 hours postdose | — |
| Single-Dose Phase: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 up to Day 28 | An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs reported after the initial dose of study drug. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. |
| Multiple-Dose Phase: Number of Participants With TEAEs | Day 1 up to Day 42 | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. SAEs included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as AEs reported after the initial dose of study drug. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. |
| Single Dose Phase: Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to Infinity (AUCinf) of Cefiderocol | Up to 8 hours postdose | — |
| Single Dose Phase: Apparent Terminal Elimination Half-life (t1/2) of Cefiderocol | Up to 8 hours postdose | — |
| Multiple Dose Phase: Cmax of Cefiderocol | Up to 8 hours postdose | — |
| Multiple Dose Phase: Area Under the Plasma Concentration Time Curve Extrapolated From Time 0 to the Last Measurable Concentration (AUC0-t) of Cefiderocol | Up to 8 hours postdose | — |
| Multiple Dose Phase: t1/2 of Cefiderocol | Up to 8 hours postdose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multiple-Dose Phase: Number of Participants With a Clinical Outcome, as Assessed by the Investigator | End of treatment (EOT; up to Day 14), post-treatment (7 days after EOT [up to Day 21]), and end of study (EOS; 28 days after last dose [up to Day 42]) | The clinical outcomes were clinical cure, clinical failure, and indeterminate. Clinical Cure: Resolution or substantial improvement of baseline signs and symptoms. Participants with bacteremia must have had eradication of bacteremia caused by the Gram-negative pathogen. Clinical Failure: No apparent response to therapy; persistence or worsening of baseline signs and/or symptoms, reappearance of signs and/or symptoms; development of new signs and/or symptoms requiring antibiotic therapy other than, or in addition to, study treatment therapy; or death due to pneumonia/complicated intra-abdominal infection (cIAI) or complicated urinary tract infections (cUTI) or bloodstream infection (BSI)/sepsis. Indeterminate: Lost to follow-up such that a determination of clinical cure/failure could not be made. |
| Multiple-Dose Phase: Number of Participants With a Microbiological Outcome, as Assessed by the Investigator | EOT (up to Day 14), post-treatment (7 days after EOT [up to Day 21]), and EOS (28 days after last dose [up to Day 42]) | Microbiological outcomes were eradication, persistence, and indeterminate. For hospital-acquired pneumonia (HAP)/ventilator-acquired pneumonia (VAP)/cIAI and BSI/sepsis- Eradication: Absence of baseline Gram-negative pathogen from an appropriate clinical specimen; Persistence: Continued presence of baseline Gram-negative pathogen from an appropriate clinical specimen; Indeterminate: No culture obtained from an appropriate clinical specimen or additional antibiotic therapy for the treatment of current infection including missed sampling. For cUTI- Eradication: A urine culture showed baseline Gram-negative uropathogen found at entry at ≥10\^5 colony forming units (CFU)/milliliters (mL) was reduced to \<10\^3 CFU/mL; Persistence: A urine culture showed that the baseline Gram-negative uropathogen found at entry at ≥10\^5 CFU/mL remained at ≥10\^3 CFU/mL; Indeterminate: No urine culture obtained or additional antibiotic therapy for the treatment of current infection including missed sampling. |
Countries
Belgium, Estonia, Georgia, Hungary, Latvia, Russia, Spain, Thailand, Ukraine
Contacts
STUDY_DIRECTORShionogi Clinical Trials Administrator Clinical Support Help Line
Shionogi
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 12 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 43 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 11 | 0 / 6 |
| other Total, other adverse events | 0 / 6 | 1 / 6 | 3 / 6 | 1 / 6 | 2 / 12 | 1 / 11 | 3 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 12 | 0 / 11 | 1 / 6 |
Outcome results
None listed