Neonatal Sepsis
Conditions
Keywords
Late-onset sepsis, Neonates, Infants
Brief summary
This study evaluated the safety, pharmacokinetics and efficacy of ceftobiprole in term and pre-term newborn babies and infants up to 3 months of age with late-onset sepsis (LOS). Ceftobiprole is an antibiotic which belongs to a group of medicines called 'cephalosporin antibiotics'. It is approved for its use to treat adults and children with pneumonia in many European and non-European countries.
Detailed description
This was a multicenter, open-label, single-arm, multiple-dose study of intravenous (IV) ceftobiprole medocaril (prodrug of the active moiety ceftobiprole). It could be combined with ampicillin and/or an aminoglycoside based on the Investigator's judgement according to manufacturer's instructions and/or local standard of care. Following screening, ceftobiprole was administered as a 2-hour infusion at a dose of 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, depending on age and weight. The target treatment duration was 3-10 days, which could be extended to 14 days if considered clinically necessary by the Investigator.
Interventions
Ceftobiprole medocaril: 7.5 mg/kg every 12 hours to 15 mg/kg every 8 hours, administered IV as a 2-hour infusion.
Sponsors
Basilea Pharmaceutica
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Days to 3 Months
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Informed consent from parent(s) or other legally acceptable representative (LAR) to participate in the study * Male or female, with a gestational age of ≥ 24 weeks and a post-natal age ranging from ≥ 3 days to ≤ 3 months * Diagnosis of documented or presumed bacterial LOS requiring administration of systemic antibiotic treatment * Sufficient vascular access to receive study drug and to allow blood sampling at a site separate from the study drug infusion line Key
Exclusion criteria
* Refractory septic shock not responding to 60 minutes of vasopressor treatment within 48 hours before enrollment * Proven ventilator-associated pneumonia * Proven central nervous system infection (e.g., meningitis, brain abscess) * Proven osteomyelitis, infective endocarditis, or necrotizing enterocolitis * Impaired renal function or known significant renal disease, as evidenced by an estimated glomerular filtration rate (using the Schwartz formula or other applicable formula) calculated to be less than 2/3 of normal for the applicable age group, OR urinary output \< 0.5 mL/kg/h (measured over at least 8 hours), OR requirement for dialysis * Progressively fatal underlying disease, or life expectancy \< 30 days * Use of systemic antibacterial therapy for longer than 72 hours within 7 days before start of study medication * Participation in another clinical study with an investigational product within 30 days of enrollment in the current study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events (AEs) | Up to 5-7 weeks | Number of patients with AEs, serious adverse events (SAEs), AEs leading to discontinuations and AEs of special interest |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | On treatment Day 3 prior to and 2, 4, and 8 hours after the start of the first ceftobiprole infusion of the day | Observed pharmacokinetic parameter Cmax of ceftobiprole (the active moiety), its pro-drug ceftobiprole medocaril and the open-ring metabolite in term and pre-term neonates with post-natal age up to 3 months |
| Number of Patients With a Clinical Response | Up to 28 days | Clinical cure rate at the end of treatment (EOT) at day 3-14 and test of cure (TOC) at 7-14 days after last ceftobiprole dose visits in the Intent-to-Treat (ITT) population |
| Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Up to 28 days | Improved signs and symptoms of LOS (including fever, hypothermia, abnormal heart rate, signs of impaired circulation, petechial rash or sclerema neonatorum, respiratory distress, gastrointestinal distress, irritability, lethargy and/or muscular or arterial hypotonia) assessed at Day 3, EOT, and TOC visits (ITT) populations. |
| Number of Patients With a Microbiological Response | Up to 28 days | Microbiological eradication or presumed eradication rate at the EOT and TOC visits. |
Countries
Bulgaria, Estonia, Germany, Latvia, Lithuania, Poland, Slovakia, United States
Participant flow
Recruitment details
Treatment was administered in hospital setting
Pre-assignment details
A total of 11 patients were screened for enrollment in this study, two of whom failed the screening process. Nine patients (six pre-term neonates and three term neonates) were enrolled and assigned to the study treatment
Participants by arm
| Arm | Count |
|---|---|
| Pre-term Neonates Pediatric patients (gestational age ≥ 24 to 36 weeks), with post-natal age ranging from ≥ 3 days to ≤ 3 months.
Patients were treated with ceftobiprole 7.5 mg/kg or 10 mg/kg (bodyweight \< 4 kg) infused over 2 hours and administered every 12 hours.
Ceftobiprole may have been combined with locally-provided ampicillin and/or an aminoglycoside based on the Investigator's judgment. | 6 |
| Term Neonates Pediatric patients (gestational age ≥ 37 weeks), with post-natal age ranging from ≥ 3 days to ≤ 3 months.
Patients were treated with ceftobiprole 10 mg/kg (bodyweight \< 4 kg) or 15mg/kg (bodyweight ≥ 4 kg) infused over 2 hours and administered every 12 hours.
Ceftobiprole may have been combined with locally-provided ampicillin and/or an aminoglycoside based on the Investigator's judgment | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Cerebrospinal fluid test positive for S. aureus | 1 | 0 |
| Overall Study | Due to Investigator absence | 1 | 0 |
Baseline characteristics
| Characteristic | Pre-term Neonates | Term Neonates | Total |
|---|---|---|---|
| Age, Continuous | 19.2 Days STANDARD_DEVIATION 11.05 | 26.7 Days STANDARD_DEVIATION 4.51 | 21.7 Days STANDARD_DEVIATION 9.77 |
| Baseline weight | 1429.2 gram STANDARD_DEVIATION 777.49 | 3156.7 gram STANDARD_DEVIATION 1094.36 | 2005.0 gram STANDARD_DEVIATION 1193.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 3 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gestational age | 28.5 Weeks STANDARD_DEVIATION 4.68 | 39.0 Weeks STANDARD_DEVIATION 1.73 | 32.0 Weeks STANDARD_DEVIATION 6.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 3 Participants | 8 Participants |
| Region of Enrollment Bulgaria | 2 participants | 1 participants | 3 participants |
| Region of Enrollment Estonia | 2 participants | 0 participants | 2 participants |
| Region of Enrollment Lithuania | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Poland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 2 participants | 0 participants | 2 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 3 |
| other Total, other adverse events | 3 / 6 | 3 / 3 |
| serious Total, serious adverse events | 1 / 6 | 1 / 3 |
Outcome results
Primary
Number of Patients With Adverse Events (AEs)
Number of patients with AEs, serious adverse events (SAEs), AEs leading to discontinuations and AEs of special interest
Time frame: Up to 5-7 weeks
Population: The safety population consists of all enrolled patients who received at least one dose of ceftobiprole
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | Any AE | 3 Participants |
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | Study-drug-related AE | 0 Participants |
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | SAE | 1 Participants |
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | Study-drug-related SAE | 0 Participants |
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | AE leading to treatment discontinuation | 0 Participants |
| Pre-term Neonates | Number of Patients With Adverse Events (AEs) | AE of special interest | 1 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | AE leading to treatment discontinuation | 1 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | Any AE | 3 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | Study-drug-related SAE | 0 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | Study-drug-related AE | 0 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | AE of special interest | 1 Participants |
| Term Neonates | Number of Patients With Adverse Events (AEs) | SAE | 1 Participants |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite
Observed pharmacokinetic parameter Cmax of ceftobiprole (the active moiety), its pro-drug ceftobiprole medocaril and the open-ring metabolite in term and pre-term neonates with post-natal age up to 3 months
Time frame: On treatment Day 3 prior to and 2, 4, and 8 hours after the start of the first ceftobiprole infusion of the day
Population: Pharmacokinetics (PK) population All patients who received at least one dose of ceftobiprole and had at least one sample of plasma concentration measurement obtained by the appropriate methodology.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pre-term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Ceftobiprole | 17.2 μg/mL |
| Pre-term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Ceftobiprole medocaril | 0.585 μg/mL |
| Pre-term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Open-ring metabolite | 1.18 μg/mL |
| Term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Ceftobiprole | 28.4 μg/mL |
| Term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Ceftobiprole medocaril | 0.552 μg/mL |
| Term Neonates | Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite | Open-ring metabolite | 1.68 μg/mL |
Secondary
Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS)
Improved signs and symptoms of LOS (including fever, hypothermia, abnormal heart rate, signs of impaired circulation, petechial rash or sclerema neonatorum, respiratory distress, gastrointestinal distress, irritability, lethargy and/or muscular or arterial hypotonia) assessed at Day 3, EOT, and TOC visits (ITT) populations.
Time frame: Up to 28 days
Population: The ITT population consists of all enrolled patients who received at least one dose of ceftobiprole.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Not done | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Worsened | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Improved | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Not done | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Resolved | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Resolved | 2 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Worsened | 0 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Improved | 2 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Improved | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Unchanged | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Unchanged | 3 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Worsened | 1 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Unchanged | 2 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Not done | 0 Participants |
| Pre-term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Resolved | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Not done | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Resolved | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Improved | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Unchanged | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Worsened | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | Day 3 | Not done | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Resolved | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Improved | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Unchanged | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Worsened | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | EOT | Not done | 1 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Resolved | 2 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Improved | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Unchanged | 0 Participants |
| Term Neonates | Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS) | TOC | Worsened | 1 Participants |
Secondary
Number of Patients With a Clinical Response
Clinical cure rate at the end of treatment (EOT) at day 3-14 and test of cure (TOC) at 7-14 days after last ceftobiprole dose visits in the Intent-to-Treat (ITT) population
Time frame: Up to 28 days
Population: The ITT population consists of all enrolled patients who received at least one dose of ceftobiprole.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pre-term Neonates | Number of Patients With a Clinical Response | EoT | Cure | 4 Participants |
| Pre-term Neonates | Number of Patients With a Clinical Response | EoT | Failure | 0 Participants |
| Pre-term Neonates | Number of Patients With a Clinical Response | EoT | Unevaluable | 2 Participants |
| Pre-term Neonates | Number of Patients With a Clinical Response | TOC | Cure | 4 Participants |
| Pre-term Neonates | Number of Patients With a Clinical Response | TOC | Failure | 0 Participants |
| Pre-term Neonates | Number of Patients With a Clinical Response | TOC | Unevaluable | 2 Participants |
| Term Neonates | Number of Patients With a Clinical Response | TOC | Failure | 1 Participants |
| Term Neonates | Number of Patients With a Clinical Response | EoT | Cure | 2 Participants |
| Term Neonates | Number of Patients With a Clinical Response | TOC | Cure | 2 Participants |
| Term Neonates | Number of Patients With a Clinical Response | EoT | Failure | 1 Participants |
| Term Neonates | Number of Patients With a Clinical Response | TOC | Unevaluable | 0 Participants |
| Term Neonates | Number of Patients With a Clinical Response | EoT | Unevaluable | 0 Participants |
Secondary
Number of Patients With a Microbiological Response
Microbiological eradication or presumed eradication rate at the EOT and TOC visits.
Time frame: Up to 28 days
Population: The microbiological Intent-to-treat (mITT) population consists of all patients in the ITT population with a causative pathogen identified at baseline.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Pre-term Neonates | Number of Patients With a Microbiological Response | EOT | Persistence | 0 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | EOT | Eradication | 4 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | EOT | Presumed eradication | 0 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | EOT | Unevaluable | 2 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | TOC | Eradication | 4 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | TOC | Presumed eradication | 0 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | TOC | Persistence | 0 Participants |
| Pre-term Neonates | Number of Patients With a Microbiological Response | TOC | Unevaluable | 2 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | TOC | Unevaluable | 0 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | EOT | Persistence | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | TOC | Eradication | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | EOT | Eradication | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | TOC | Persistence | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | EOT | Presumed eradication | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | TOC | Presumed eradication | 1 Participants |
| Term Neonates | Number of Patients With a Microbiological Response | EOT | Unevaluable | 0 Participants |