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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Multi-Center study to Compare the Efficacy and safety of Micafungin Versus Amphotericin B Deoxycholate for the Treatment of Neonatal Candidiasis

    Summary
    EudraCT number
    		 2012-000780-24
    Trial protocol
    		 GR   HU   BG  
    Global end of trial date
    15 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Feb 2016
    First version publication date
    05 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    9463-CL-2303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00815516
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development US
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development US, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development US, Astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The study evaluated how effective and how safe the drug micafungin is when compared to the drug amphotericin B deoxycholate in treating neonates and young infants with certain fungal infections.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, Good Clinical Practice (GCP), ICH (International Committee on Harmonisation) guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. The Independent Ethics Committee (IEC) or Institutional Review Board (IRB) reviewed the ethical, scientific and medical appropriateness of the study before it was conducted. IEC/IRB approval of the protocol, informed consent and subject information and/or advertising, as relevant, was obtained prior to the authorization of drug shipment to a study site. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was reviewed and signed and dated by subject’s guardian or legal representative, the person who administered the informed consent and any other signatories according to local requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Feb 2013
    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
    Brazil: 3
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Colombia: 2
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Philippines: 1
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Ukraine: 2
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    30
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    25
    Infants and toddlers (28 days-23 months)
    5
    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
    		 Infants greater than 48 hours of life through day of life (DOL) 120 with a diagnosis of invasive candidiasis were eligible for this study.

    Pre-assignment
    Screening details
    		 In total, 31 infants were screened and 30 were randomized in a 2:1 ratio to receive micafungin or amphotericin B deoxycholate. Randomization was stratified by estimated gestational age (< 27 weeks, ≥ 27 weeks) and by region (North America/Europe, Latin America / Mexico, other region).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Micafungin
    Arm description
    		 Infants received micafungin at a dose of 10 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Micafungin
    Investigational medicinal product code
    FK463
    Other name
    Mycamine
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion

    Arm title
    		 Amphotericin B
    Arm description
    		 Infants received amphotericin B deoxycholate (CAB) at a dose of 1.0 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amphotericin B deoxycholate
    Investigational medicinal product code
    Other name
    Fungizone, conventional amphotericin B, CAB
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion

    Number of subjects in period 1
    		Micafungin Amphotericin B
    Started
    20
    10
    Completed
    16
    9
    Not completed
    4
    1
         Physician decision
    1
    -
         Death
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Micafungin
    Reporting group description
    		 Infants received micafungin at a dose of 10 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Reporting group title
    Amphotericin B
    Reporting group description
    		 Infants received amphotericin B deoxycholate (CAB) at a dose of 1.0 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Reporting group values
    		 Micafungin Amphotericin B Total
    Number of subjects
    		 20 10 30
    Age categorical
    Units: Subjects
        ≤ 4 weeks
    		 15 10 25
        > 4 weeks to 4 months
    		 5 0 5
    Age Continuous
    Units: days
        arithmetic mean (standard deviation)
    		 30.2 ± 27.99 16.9 ± 5.13 -
    Gender, Male/Female
    Units: participants
        Female
    		 12 4 16
        Male
    		 8 6 14
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 3 6
        Not Hispanic or Latino
    		 4 3 7
        Unknown or Not Reported
    		 13 4 17
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 18 9 27
        Black or African American
    		 0 1 1
        Asian
    		 1 0 1
        Other
    		 1 0 1
    Gestational Age
    Units: Subjects
        < 27 Weeks
    		 3 2 5
        ≥ 27 Weeks
    		 17 8 25
    Region of Enrollment
    Units: Subjects
        North America /Europe
    		 15 9 24
        Latin America /Mexico
    		 4 1 5
        Other
    		 1 0 1
    Fungal Infection Type
    Candidemia: diagnosed if Candida isolated from blood only; Invasive candidiasis: diagnosed if Candida isolated from blood in addition to other body fluids such as cerebrospinal fluid (CSF), peritoneal fluid, or urine.
    Units: Subjects
        Candidemia
    		 12 7 19
        Invasive Candidiasis
    		 8 2 10
        Missing
    		 0 1 1
    Presence of End-Organ Dissemination (EOD)
    End-organ dissemination was assessed using echocardiogram, abdominal ultrasound, including evaluation of the liver, spleen, and kidneys, head ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI), and retinal exam (if clinically feasible). End-organ dissemination was assessed by the independent data review panel (DRP). Missing for the DRP assessment means that no evidence for EOD was documented.
    Units: Subjects
        Yes
    		 7 3 10
        Missing
    		 13 7 20
    Birth Weight
    Units: grams
        arithmetic mean (standard deviation)
    		 1807.3 ± 879.03 2171.4 ± 1008.79 -

    End points

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    End points reporting groups
    Reporting group title
    Micafungin
    Reporting group description
    		 Infants received micafungin at a dose of 10 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Reporting group title
    Amphotericin B
    Reporting group description
    		 Infants received amphotericin B deoxycholate (CAB) at a dose of 1.0 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Primary: Fungal-free survival

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    End point title
    		 Fungal-free survival [1]
    End point description
    Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive at one week following the last dose of study drug with a mycological response of eradication and no requirement for alternative systemic antifungal therapy for continued treatment. Eradication was defined as culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 hours apart, or for Candida meningitis and/or candiduria, 1 negative culture. This endpoint was analyzed using the full analysis set (all randomized infants who were administered any amount of study drug).
    End point type
    Primary
    End point timeframe
    One week after the last dose of study drug (maximum of 49 days)
    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: Since this study was terminated early, the total number of evaluable subjects was far below the fully powered sample size. For this circumstance, the statistical inference based on the planned hypothesis was not applicable and not performed.
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    20
    10
    Units: percentage of participants
        number (confidence interval 95%)
    60 (36.1 to 80.9)
    70 (34.8 to 93.3)
    No statistical analyses for this end point

    Secondary: Time to mycological clearance of invasive candidiasis

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    End point title
    		 Time to mycological clearance of invasive candidiasis
    End point description
    Time to mycological clearance of invasive candidiasis is defined as the time from first dose to the day of mycological eradication for baseline invasive candidiasis infection. Eradication was defined as a culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 hours apart, or for for Candida meningitis and/or candiduria, 1 negative culture. Infants without eradication during the treatment period and who survived were censored at one day after the end of treatment. Infants without eradication who died before completing the treatment period or were lost to follow-up during the treatment were censored at their death or last contact day. "99999" indicates data could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after the last dose of study drug (maximum of 72 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    20
    10
    Units: days
        median (confidence interval 95%)
    6 (3 to 99999)
    3 (0 to 9)
    No statistical analyses for this end point

    Secondary: Fungal-free survival at end of study drug therapy in infants with end-organ dissemination

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    End point title
    		 Fungal-free survival at end of study drug therapy in infants with end-organ dissemination
    End point description
    Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive at the end of study drug therapy with a mycological response of eradication based upon the DRP assessment and no requirement for alternative systemic antifungal therapy for continued treatment. This endpoint was analyzed for participants in the full analysis set with end-organ dissemination.
    End point type
    Secondary
    End point timeframe
    The end of study drug therapy (maximum of 42 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    7
    3
    Units: percentage of participants
        number (confidence interval 95%)
    42.9 (9.9 to 81.6)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Fungal-free survival one week after last dose of study drug in infants with end-organ dissemination

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    End point title
    		 Fungal-free survival one week after last dose of study drug in infants with end-organ dissemination
    End point description
    Fungal-free survival was assessed by an independent data review panel (DRP). Fungal-free survival is defined as the percentage of participants alive one week after last dose of study drug with a mycological response of eradication based upon the DRP assessment and no requirement for alternative systemic antifungal therapy for continued treatment. This endpoint was analyzed for participants in the full analysis set with end-organ dissemination.
    End point type
    Secondary
    End point timeframe
    One week after the last dose of study drug (maximum of 49 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    7
    3
    Units: percentage of participants
        number (confidence interval 95%)
    42.9 (9.9 to 81.6)
    33.3 (0.8 to 90.6)
    No statistical analyses for this end point

    Secondary: Percentage of participants with emergent fungal infections

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    End point title
    		 Percentage of participants with emergent fungal infections
    End point description
    An emergent fungal infection is defined as ● An invasive fungal infection which is detected at any time during the study that is a non-Candida organism, or ● An invasive fungal infection which is detected during the treatment or post-treatment period with a Candida species identified other than those detected at Baseline. If this occurred within 96 hours of the first dose of study drug, the infection was considered part of the final diagnosis of enrolling infection and not an emergent infection. "99999" indicates values that could not be estimated.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after the last dose of study drug (maximum of 72 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    20
    10
    Units: percentage of participants
        number (confidence interval 95%)
    5 (0.1 to 24.9)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of participants with recurrent fungal infections

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    End point title
    		 Percentage of participants with recurrent fungal infections
    End point description
    A recurrent infection is defined as a systemic fungal infection in an infant with eradication at the end of study drug therapy, who developed positive blood cultures or a mycologically confirmed deep-seated Candida infection, with the same species as the enrolling infection. This endpoint was analyzed for participants in the full analysis set with eradication at the end of study drug therapy. "99999" indicates values that could not be estimated.
    End point type
    Secondary
    End point timeframe
    Up to 30 days after the last dose of study drug (maximum of 72 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    11
    8
    Units: percentage of participants
        number (confidence interval 95%)
    0 (-99999 to 99999)
    12.5 (0.3 to 52.7)
    No statistical analyses for this end point

    Secondary: Time to positive clinical response

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    End point title
    		 Time to positive clinical response
    End point description
    Time to a positive clinical response is defined as the time from the first dose to the day during the treatment period that a positive clinical response (defined as a complete response or partial response) is observed for the first time, assessed by the Investigator. Complete Response is defined as the resolution of all attributable signs related to fungal infection, if present at baseline and Partial Response is defined as improvement in attributable signs related to the fungal infection, if present at baseline. Infants without positive responses and who survived were censored at one day post the end of treatment. Infants without positive responses who died before completing the treatment period, or were lost to follow-up during the treatment were censored at their death or last contact day. This endpoint was analyzed in full analysis set participants with clinical signs and symptoms related to the fungal Infection at Baseline.
    End point type
    Secondary
    End point timeframe
    From first dose up to 30 days after the last dose of study drug (maximum of 72 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    18
    10
    Units: days
        median (confidence interval 95%)
    8 (7 to 15)
    11 (7 to 14)
    No statistical analyses for this end point

    Secondary: Clinical response at the end of study drug therapy

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    End point title
    		 Clinical response at the end of study drug therapy
    End point description
    Clinical response assessments were based on the following definitions and assessed by the DRP: ● Complete Response: Resolution of all attributable signs related to fungal infection, if present at baseline. ● Partial Response: Improvement in attributable signs related to the fungal infection, if present at baseline. ● Stabilization: Minor improvement or no change in attributable signs related to the fungal infection, if present at baseline, and infant continued on therapy without deterioration. ● Progression: Deterioration in attributable signs related to the fungal infection, if present at baseline; or if death occurred presumably related to a fungal infection. This endpoint was analyzed in full analysis set participants with clinical signs and symptoms related to the fungal Infection at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and end of study drug therapy (maximum of 42 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    18
    10
    Units: percentage of participants
    number (not applicable)
        Complete
    55.6
    70
        Partial
    5.6
    0
        Stable
    5.6
    10
        Progression
    16.7
    20
        Missing
    16.7
    0
    No statistical analyses for this end point

    Secondary: Clinical response one week after last dose of study drug

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    End point title
    		 Clinical response one week after last dose of study drug
    End point description
    Clinical response assessments were based on the following definitions and assessed by the DRP: • Complete Response: Resolution of all attributable signs related to fungal infection, if present at baseline. • Partial Response: Improvement in attributable signs related to the fungal infection, if present at baseline. • Stabilization: Minor improvement or no change in attributable signs related to the fungal infection, if present at baseline, and infant continued on therapy without deterioration. • Progression: Deterioration in attributable signs related to the fungal infection, if present at baseline; or if death occurred presumably related to a fungal infection. This endpoint was analyzed in full analysis set participants with clinical signs and symptoms related to the fungal Infection at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline and one week after the last dose of study drug (maximum of 49 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    18
    10
    Units: percentage of participants
    number (not applicable)
        Complete
    55.6
    70
        Partial
    5.6
    0
        Stable
    5.6
    10
        Progression
    5.6
    20
        Missing
    27.8
    0
    No statistical analyses for this end point

    Secondary: Mycological response at end of study drug therapy

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    End point title
    		 Mycological response at end of study drug therapy
    End point description
    Mycological response assessments were based on the following definitions and assessed by the DRP: ● Eradication: Culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 h apart; for Candida meningitis and/or candiduria, 1 negative culture. ● Persistence: Continued isolation or histological documentation from a normally sterile site.
    End point type
    Secondary
    End point timeframe
    End of study drug therapy (maximum of 42 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    20
    10
    Units: percentage of participants
    number (not applicable)
        Eradication
    55
    80
        Persistence
    10
    20
        Not Assessed
    35
    0
    No statistical analyses for this end point

    Secondary: Mycological response one week after last dose of study drug

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    End point title
    		 Mycological response one week after last dose of study drug
    End point description
    Mycological response assessments were based on the following definitions and assessed by the DRP: • Eradication: Culture or histologically documented absence of the infecting Candida species from all positive normally sterile sites during therapy, documented by 2 negative samples, drawn at least 24 h apart; for Candida meningitis and/or candiduria, 1 negative culture. • Persistence: Continued isolation or histological documentation from a normally sterile site.
    End point type
    Secondary
    End point timeframe
    One week after the last dose of study drug (maximum of 49 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    20
    10
    Units: percentage of participants
    number (not applicable)
        Continuing Eradication/Eradication
    55
    80
        Persistence
    10
    20
        Not Assessed
    35
    0
    No statistical analyses for this end point

    Secondary: Follow-up status for infants with end-organ assessments

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    End point title
    		 Follow-up status for infants with end-organ assessments
    End point description
    End-organ dissemination was assessed through abdominal ultrasound and/or computed tomography (CT), echocardiogram, head imaging and retinal exam. Each specific finding, documented by 1 of these techniques, was evaluated as follows: ● Improvement: Improvement in size, number or density of identified lesions. Complete response was not expected but may have been documented. ● Stabilization: Minor improvement or no change in size, number or density of identified lesions. ● Worsening: Increase in size or number of identified lesions. This endpoint was analyzed in full analysis set participants with end-organ assessments.
    End point type
    Secondary
    End point timeframe
    Baseline and 30 days after the last dose of study drug (maximum of 72 days)
    End point values
    		 Micafungin Amphotericin B
    Number of subjects analysed
    7
    3
    Units: percentage of participants
    number (not applicable)
        Improved
    57.1
    33.3
        Stable
    14.3
    0
        Worsened
    14.3
    66.7
        Not Assessed
    14.3
    0
    No statistical analyses for this end point

    Secondary: Plasma Micafungin Concentration

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    End point title
    		 Plasma Micafungin Concentration [2]
    End point description
    This endpoint was analyzed in the pharmacokinetics (PK) analysis set, including those infants who received any amount of study drug, have at least one study drug concentration, and have dosing and blood collection date and time data sufficient for inclusion in a population pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    15 minutes post intravenous infusion (IV), 4-8 hours post IV and 15-24 hours post IV
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK analyses were performed in the micafungin treatment group only.
    End point values
    		 Micafungin
    Number of subjects analysed
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Within 15 Minutes Post IV
    25130.5 ± 13964.3
        4-8 Hours Post IV
    23751.7 ± 9547.7
        15-24 Hours Post IV
    14118.3 ± 12396
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 72 hours after the last dose; mean duration of study drug exposure among micafungin-treated patients was 18.6 days and 15.5 days for Amphotericin B-treated patients.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Amphotericin B
    Reporting group description
    		 Infants received amphotericin B deoxycholate (CAB) at a dose of 1.0 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Reporting group title
    Micafungin
    Reporting group description
    		 Infants received micafungin at a dose of 10 mg/kg per day by intravenous infusion for a minimum of 21 days to a maximum of 28 days for infants without end-organ dissemination or for a maximum of 42 days for infants with end-organ dissemination.

    Serious adverse events
    		 Amphotericin B Micafungin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    12 / 20 (60.00%)
         number of deaths (all causes)
    0
    2
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 20 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (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 perforation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Obstructive airways disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis neonatal
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Amphotericin B Micafungin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 10 (70.00%)
    14 / 20 (70.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    2
    Hypothermia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Infusion site rash
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Galactorrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypercapnia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Antithrombin III decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Bacteria blood identified
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood bilirubin abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Oxygen consumption increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Serum ferritin increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Medical device complication
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 20 (25.00%)
         occurrences all number
    2
    5
    Thrombocytopenia
         subjects affected / exposed
    3 / 10 (30.00%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Neutropenia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Eosinophilia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Anaemia neonatal
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    Leukocytosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Dermatitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Osteopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Staphylococcal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    3
    Endocarditis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Neonatal infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypochloraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2013
    - Add clarifying language for a negative or positive culture and a time window of ± 3 h to the treatment period collection of every 48 h. - Time windows added to Schedule of Assessments. - Include a new criterion prohibiting participation in another interventional study while on treatment. - Provide clarity around qualifying specimens from an indwelling catheter. - Clarify that there are limited amount of antifungal therapies approved in the introduction. - Provide further clarifying details on non-GLP studies. - Replace ‘subject’ with ‘infant’ under discontinuation criteria and include clarification of the end of study visit (ESV) procedure window. - Update study drug handling. - Provide clarity on dilution requirements, flushing technique, clarification on color of coverings and consistency in instructions on the administration of micafungin and of CAB. - Add details for unblinded personnel on maintaining blind for study drug materials. -Provide guidance during treatment for removal and replacement of existing central lines. - Ensure the collection of all antifungal treatment provided. - Added the volume of blood to be drawn for blood culture. - Clarify pharmacoeconomic data collection on length of stay. - Update to definition of adverse events. - Definition of infusion related reaction is provided with guidance on what is to be documented around the reaction. - Additional information on AEs specific to the comparator. - Include revisions regarding notification of SAEs in the study, investigators responsibility for IRB/IEC notification and information on CIOMS in a blinded study. - Addition of protocol deviation information and definition. - Addition of definition of End of Study. - Informed consent requirements are updated. - Added clarification of requirements if there is new or important information. - Additional information provided regarding sponsor insurance for study subjects. - Updated clinical study report signatory.

    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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