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    Clinical Trial Results:
    A multicenter, open-label, single-arm, multiple-dose study to evaluate the safety, pharmacokinetics, and efficacy of ceftobiprole medocaril in term and pre-term neonates and infants up to 3 months of age with late-onset sepsis

    Summary
    EudraCT number
    		 2022-001837-35
    Trial protocol
    		 LT   LV   SK   PL   Outside EU/EEA   EE   BG   DE  
    Global end of trial date
    18 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jul 2025
    First version publication date
    02 Jul 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BPR-PIP-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05856227
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: 64.407
    Sponsors
    Sponsor organisation name
    Basilea Pharmaceutica International Ltd, Allschwil
    Sponsor organisation address
    Hegenheimermattweg 167b, Allschwil, Switzerland, 4123
    Public contact
    Study director, Basilea Pharmaceutica International Ltd, Allschwil, +41 616061111, medical.information@basilea.com
    Scientific contact
    Study director, Basilea Pharmaceutica International Ltd, Allschwil, +41 616061111, medical.information@basilea.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000205-PIP02-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Dec 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterise the safety profile of ceftobiprole in term and pre-term neonates and infants up to 3 months of age with LOS.
    Protection of trial subjects
    The study was conducted according to the ethical principles that have their origins in the World Medical Association Declaration of Helsinki, the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP), and applicable national and local laws and regulations for the conduct of clinical research and the protection of personal data. If conflicts between local laws and regulations arose, more stringent requirements were adopted.
    Background therapy
    		 The investigational medicinal product, ceftobiprole may have been combined with locally-provided ampicillin and/or an aminoglycoside based on the Investigator’s judgment.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    06 Aug 2023
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    9
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    6
    Newborns (0-27 days)
    2
    Infants and toddlers (28 days-23 months)
    1
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment began in August 2023. The study included pediatric patients from Europe and the USA.

    Pre-assignment
    Screening 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.

    Period 1
    Period 1 title
    Overall Trial (ITT/Safety population) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pre-term Neonates
    Arm description
    		 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.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftobiprole medocaril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study treatment consisted of IV ceftobiprole medocaril for 3 – 10 days, which could be extended to 14 days if considered clinically necessary by the Investigator. Ceftobiprole was administered as a 2-hour IV infusion, with the dose adjusted according to gestational and post-natal ages. To limit infusion volume for the pre-term and term neonates, the ceftobiprole medocaril infusion was administered at a concentration of 4 mg/mL.

    Arm title
    		 Term Neonates
    Arm description
    		 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
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceftobiprole medocaril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study treatment consisted of IV ceftobiprole medocaril for 3 – 10 days, which could be extended to 14 days if considered clinically necessary by the Investigator. Ceftobiprole was administered as a 2-hour IV infusion, with the dose adjusted according to gestational and post-natal ages. To limit infusion volume for the pre-term and term neonates, the ceftobiprole medocaril infusion was administered at a concentration of 4 mg/mL.

    Number of subjects in period 1
    		Pre-term Neonates Term Neonates
    Started
    6
    3
    Completed
    4
    2
    Not completed
    2
    1
         Adverse event, non-fatal
    -
    1
         Due to Investigator absence
    1
    -
         Cerebrospinal fluid test positive for S. aureus
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pre-term Neonates
    Reporting group description
    		 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.

    Reporting group title
    Term Neonates
    Reporting group description
    		 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

    Reporting group values
    		 Pre-term Neonates Term Neonates Total
    Number of subjects
    		 6 3 9
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 6 0 6
        Newborns (0-27 days)
    		 0 2 2
        Infants and toddlers (28 days-23 months)
    		 0 1 1
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 19.2 ( 11.05 ) 26.7 ( 4.51 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 4
        Male
    		 3 2 5
    Race
    Units: Subjects
        White
    		 5 3 8
        Unknown or Not Reported
    		 1 0 1
    Gestational age
    Units: Weeks
        arithmetic mean (standard deviation)
    		 28.5 ( 4.68 ) 39.0 ( 1.73 ) -
    Baseline weight
    Units: gram(s)
        arithmetic mean (standard deviation)
    		 1429.2 ( 777.49 ) 3156.7 ( 1094.36 ) -

    End points

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    End points reporting groups
    Reporting group title
    Pre-term Neonates
    Reporting group description
    		 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.

    Reporting group title
    Term Neonates
    Reporting group description
    		 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

    Primary: Number of Patients With Adverse Events (AEs)

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    End point title
    		 Number of Patients With Adverse Events (AEs) [1]
    End point description
    Number of patients with AEs, serious adverse events (SAEs), AEs leading to discontinuations and AEs of special interest
    End point type
    Primary
    End point timeframe
    Up to 5–7 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Pre-term Neonates Term Neonates
    Number of subjects analysed
    6
    3
    Units: Count of Participants
    number (not applicable)
        Any AE
    3
    3
        Study-drug-related AE
    0
    0
        SAE
    1
    1
        Study-drug-related SAE
    0
    0
        AE leading to treatment discontinuation
    0
    1
        AE of special interest
    1
    1
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Ceftobiprole, Ceftobiprole Medocaril, and Open-ring Metabolite
    End point description
    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
    End point type
    Secondary
    End point timeframe
    On treatment Day 3 prior to and 2, 4, and 8 hours after the start of the first ceftobiprole infusion of the day.
    End point values
    		 Pre-term Neonates Term Neonates
    Number of subjects analysed
    6
    3
    Units: μg/mL
    median (full range (min-max))
        Ceftobiprole
    17.2 (11.0 to 22.6)
    28.4 (19.1 to 33.8)
        Ceftobiprole medocaril
    0.585 (0.276 to 5.70)
    0.552 (0.376 to 2.59)
        Open-ring metabolite
    1.18 (0.624 to 1.69)
    1.68 (0.998 to 2.06)
    No statistical analyses for this end point

    Secondary: Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS)

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    End point title
    		 Number of Participants With Improved Signs and Symptoms of Late Onset Sepsis (LOS)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    At the Day 3 and up to 5-7 weeks
    End point values
    		 Pre-term Neonates Term Neonates
    Number of subjects analysed
    6
    3
    Units: Number of Patients
    number (not applicable)
        Day 3 Resolved
    1
    1
        Day 3 Improved
    1
    0
        Day 3 Unchanged
    3
    1
        Day 3 Worsened
    0
    1
        Day 3 Not done
    1
    0
        EoT Resolved
    1
    1
        EoT Improved
    1
    0
        EoT unchanged
    2
    1
        EoT Worsened
    1
    0
        EoT Not done
    1
    1
        TOC Resolved
    2
    2
        TOC Improved
    2
    0
        TOC unchanged
    1
    0
        TOC Worsened
    1
    1
        TOC Not done
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Patients With a Clinical Response

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    End point title
    		 Number of Patients With a Clinical Response
    End point description
    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
    End point type
    Secondary
    End point timeframe
    5-7 weeks
    End point values
    		 Pre-term Neonates Term Neonates
    Number of subjects analysed
    6
    3
    Units: Number of Participants
    number (not applicable)
        EOT Cure
    4
    2
        EoT Failure
    0
    1
        EoT Unevaluable
    2
    0
        TOC Cure
    4
    2
        TOC Failure
    0
    1
        TOC Unevaluable
    2
    0
    No statistical analyses for this end point

    Secondary: Number of Patients With a Microbiological Response

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    End point title
    		 Number of Patients With a Microbiological Response
    End point description
    Microbiological eradication or presumed eradication rate at the EOT and TOC visits.
    End point type
    Secondary
    End point timeframe
    5-7 weeks
    End point values
    		 Pre-term Neonates Term Neonates
    Number of subjects analysed
    6
    3
    Units: Number of Participants
    number (not applicable)
        EOT Eradication
    4
    1
        EOT Presumed eradication
    0
    1
        EOT Persistence
    0
    1
        EOT Unevaluable
    2
    0
        TOC Eradication
    4
    1
        TOC Presumed eradication
    0
    1
        TOC Persistence
    0
    1
        TOC Unevaluable
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study medication up to LFU visit.
    Adverse event reporting additional description
    Treatment-emergent adverse events and serious adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Term Neonates
    Reporting group description
    		 Term neonates

    Reporting group title
    Pre-term neonates
    Reporting group description
    		 Pre-term neonates

    Serious adverse events
    		 Term Neonates Pre-term neonates
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Enterobacter sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Term Neonates Pre-term neonates
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    3 / 6 (50.00%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Vena cava thrombosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Intraventricular haemorrhage neonatal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Thrombocytosis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    4
    Withdrawal syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary dysplasia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Endocrine disorders
    Adrenal haemorrhage
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Sepsis neonatal
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2024
    The number of term and pre-term neonates was reduced from at least 15 to at least 8 patients, comprising at least two term neonates, and at least six pre-term neonates less than < 37 weeks gestational age.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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