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    Clinical Trial Results:
    A Multicenter, Open-Label, Noncomparative Study to Evaluate the Safety, Tolerability, and Efficacy of Caspofungin Acetate in Children with Documented Candida or Aspergillus Infections

    Summary
    EudraCT number
    		 2014-004911-35
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    31 Jul 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    15 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-0991-043
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00082524
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000010-PIP01-07
    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
    31 Jul 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jul 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this study are to evaluate the safety, tolerability, and efficacy of caspofungin therapy, administered as 50 mg/m^2 intravenous once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1, in pediatric patients (3 months through 17 years of age) with invasive aspergillosis who are refractory to or intolerant of standard therapy or those with invasive or esophageal Candida infections. The primary objective is to report the proportion of pediatric participants treated with caspofungin with one or more drug-related clinical or laboratory adverse experience(s).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. Participants who failed to improve clinically after at least 4 days of caspofungin and in whom the drug had been well-tolerated could receive a dosage increase to 70 mg/m^2 (maximum 70 mg/day) from Day 5 onward. The need to increase the caspofungin dose was at the discretion of the investigator. The higher dose was to be maintained until therapy was discontinued unless toxicity occurred. If drug-related toxicity developed, the dose could be reduced to standard dose (50 mg/m^2).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Apr 2004
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    49
    EEA total number of subjects
    6
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    30
    Adolescents (12-17 years)
    16
    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
    		 Participants were included based on criteria specific to their fungal infection: invasive Aspergillus infections, invasive Candida infections, or esophageal Candida infections. Other inclusion and exclusion criteria applied.

    Pre-assignment
    Screening details
    		 A total of 53 participants were screened and 49 were enrolled in the study.

    Period 1
    Period 1 title
    Treatment and Follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Participants with Invasive Aspergillosis
    Arm description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 28 days and for at least 7 days after resolution of symptoms (maximum of 90 days). Follow-up was up to 28 days after the last infusion of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Caspofungin
    Investigational medicinal product code
    Other name
    CANCIDAS™, MK-0991
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Caspofungin acetate 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 28 days and for at least 7 days after resolution of symptoms (maximum of 90 days). Follow-up was up to 28 days after the last infusion of study drug. Infusion employed a pediatric syringe or ambulatory pump.

    Arm title
    		 Participants with Invasive Candidiasis
    Arm description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days after the last positive culture of Candida from the blood or other normally sterile body site, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Caspofungin
    Investigational medicinal product code
    Other name
    CANCIDAS™, MK-0991
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Caspofungin acetate 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days after the last positive culture of Candida from the blood or other normally sterile body site, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug. Infusion employed a pediatric syringe or ambulatory pump.

    Arm title
    		 Participants with Esophageal Candidiasis
    Arm description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 7 days and for at least 72 hours past resolution of symptoms, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Caspofungin
    Investigational medicinal product code
    Other name
    CANCIDAS™, MK-0991
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Caspofungin acetate 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 7 days and for at least 72 hours past resolution of symptoms, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug. Infusion employed a pediatric syringe or ambulatory pump.

    Number of subjects in period 1
    		Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Started
    10
    38
    1
    Completed therapy
    5 [1]
    23 [2]
    1
    Completed
    6
    36
    1
    Not completed
    4
    2
    0
         Adverse event, serious fatal
    1
    -
    -
         Participant moved
    -
    1
    -
         Adverse event, non-fatal
    3
    -
    -
         Unknown
    -
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who completed study therapy and continued to follow-up.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants who completed study therapy and continued to follow-up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Participants with Invasive Aspergillosis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 28 days and for at least 7 days after resolution of symptoms (maximum of 90 days). Follow-up was up to 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Invasive Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days after the last positive culture of Candida from the blood or other normally sterile body site, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Esophageal Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 7 days and for at least 72 hours past resolution of symptoms, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.

    Reporting group values
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis Total
    Number of subjects
    		 10 38 1 49
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.3 ± 3.9 7.9 ± 5.4 17 ± 0 -
    Gender categorical
    Units: Subjects
        Female
    		 2 16 0 18
        Male
    		 8 22 1 31

    End points

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    End points reporting groups
    Reporting group title
    Participants with Invasive Aspergillosis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 28 days and for at least 7 days after resolution of symptoms (maximum of 90 days). Follow-up was up to 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Invasive Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days after the last positive culture of Candida from the blood or other normally sterile body site, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Esophageal Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 7 days and for at least 72 hours past resolution of symptoms, and a maximum of 28 days. Follow-up was up to 28 days after the last infusion of study drug.

    Primary: Percentage of Participants with One or More Drug-related Adverse Experience

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    End point title
    		 Percentage of Participants with One or More Drug-related Adverse Experience [1]
    End point description
    An adverse experience is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor's product, is also an adverse experience. Drug-related adverse experiences were those determined by the investigator to be possibly, probably, or definitely drug related. The All Patients as Treated population included all participants who received at least one dose of caspofungin.
    End point type
    Primary
    End point timeframe
    Up to 14 days after the end of study therapy
    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: No between-group statistical analyses were planned for the study.
    End point values
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Number of subjects analysed
    10
    38
    1
    Units: Percentage of participants
    number (not applicable)
        Clinical Adverse Experiences
    40
    23.7
    0
        Laboratory Adverse Experiences
    20
    39.5
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Discontinued Study Therapy due to a Drug-related Adverse Experience

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    End point title
    		 Percentage of Participants Who Discontinued Study Therapy due to a Drug-related Adverse Experience
    End point description
    An adverse experience is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the sponsor's product, whether or not considered related to the use of the product. Any worsening of a preexisting condition which is temporally associated with the use of the sponsor'd product, is also an adverse experience. Drug-related adverse experiences were those determined by the investigator to be possibly, probably, or definitely drug related. The All Patients as Treated population included all participants who received at least one dose of caspofungin.
    End point type
    Secondary
    End point timeframe
    Up to the last dose of study therapy
    End point values
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Number of subjects analysed
    10
    38
    1
    Units: Percentage of participants
    number (not applicable)
        Clinical Adverse Experiences
    0
    0
    0
        Laboratory Adverse Experiences
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants with One or More Serious Adverse Experiences

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    End point title
    		 Percentage of Participants with One or More Serious Adverse Experiences
    End point description
    A serious adverse experience is any adverse experience that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs an existing inpatient hospitalization, is a congenital anomaly or birth defect, is a cancer, or is an overdose. The All Patients as Treated population included all participants who received at least one dose of caspofungin.
    End point type
    Secondary
    End point timeframe
    Up to 14 days after the end of study therapy.
    End point values
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Number of subjects analysed
    10
    38
    1
    Units: Percentage of participants
    number (not applicable)
        Clinical Adverse Experiences
    50
    7.9
    0
        Laboratory Adverse Experiences
    0
    0
    100
    No statistical analyses for this end point

    Secondary: Percentage of Invasive Aspergillosis Participants with a Favorable Clinical Response

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    End point title
    		 Percentage of Invasive Aspergillosis Participants with a Favorable Clinical Response [2]
    End point description
    Favorable clinical response was defined as clinically significant improvement or resolution of symptoms and radiographic and other relevant investigative (eg, bronchoscopy) abnormalities attributable to Aspergillus infection. The Modified Intent-to-Treat population included participants who received at least 1 full dose of caspofungin therapy and had documented diagnosis of invasive aspergillosis.
    End point type
    Secondary
    End point timeframe
    Last day of study therapy (at least 7 days after resolution of symptoms)
    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: This endpoint analyzes only participants with invasive aspergillosis.
    End point values
    		 Participants with Invasive Aspergillosis
    Number of subjects analysed
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    50 (18.7 to 81.3)
    No statistical analyses for this end point

    Secondary: Percentage of Invasive Candidiasis Participants with a Favorable Overall Response

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    End point title
    		 Percentage of Invasive Candidiasis Participants with a Favorable Overall Response [3]
    End point description
    Favorable overall response was defined as 1) resolution or improvement of most signs and symptoms of the invasive Candida infection and resolution or improvement of all relevant radiographic findings (if previously present), and 2) follow-up cultures from site of infection are negative for Candida or, for infections which would require an invasive procedure for documentation of a follow-up negative culture, no apparent evidence of residual infection from symptoms, physical examination, and appropriate non-invasive studies (laboratory test, imaging, etc). The Modified Intent-to-Treat population included participants who received at least 1 full dose of caspofungin therapy and had documented diagnosis of invasive candidiasis.
    End point type
    Secondary
    End point timeframe
    Last day of study therapy (up to 28 days)
    Notes
    [3] - 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: This endpoint analyzes only participants with invasive candidiasis.
    End point values
    		 Participants with Invasive Candidiasis
    Number of subjects analysed
    37
    Units: Percentage of participants
        number (confidence interval 95%)
    81.1 (64.8 to 92)
    No statistical analyses for this end point

    Secondary: Percentage of Esophageal Candidiasis Participants with Favorable Clinical Response

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    End point title
    		 Percentage of Esophageal Candidiasis Participants with Favorable Clinical Response [4]
    End point description
    Favorable clinical response was defined as 1) resolution, or reduction of endoscopic lesions by at least one stepwise grade (or no endoscopy performed), and 2) resolution or improvement of esophageal signs / symptoms from the baseline findings. The Modified Intent-to-Treat population included participants who received at least 1 full dose of caspofungin therapy and had documented diagnosis of esophageal candidiasis.
    End point type
    Secondary
    End point timeframe
    Last day of study therapy (up to 28 days)
    Notes
    [4] - 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: This endpoint analyzes only participants with esophageal candidiasis.
    End point values
    		 Participants with Esophageal Candidiasis
    Number of subjects analysed
    1
    Units: Percentage of participants
        number (not applicable)
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 14 days after the end of study therapy
    Adverse event reporting additional description
    Although a participant may have had two or more clinical adverse events, the participant is counted only once within a category. The same participant may appear in different categories.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Participants with Invasive Aspergillosis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 28 days and for at least 7 days after resolution of symptoms. Follow-up was for 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Invasive Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days after the last positive culture of Candida from the blood or other normally sterile body site, and a maximum of 28 days. Follow-up was for 28 days after the last infusion of study drug.

    Reporting group title
    Participants with Esophageal Candidiasis
    Reporting group description
    		 Participants received caspofungin 50 mg/m^2 in a 1-hour intravenous infusion once daily (maximum 70 mg/day) following a loading dose of 70 mg/m^2 (maximum 70 mg/day) on Day 1. Duration of therapy was for a minimum of 14 days and for at least 72 hours past resolution of symptoms, and a maximum of 28 days. Follow-up was for 28 days after the last infusion of study drug.

    Serious adverse events
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 38 (7.89%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    5
    0
    0
         number of deaths resulting from adverse events
    Investigations
    C-reactive protein increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 38 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic embolus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Zygomycosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Participants with Invasive Aspergillosis Participants with Invasive Candidiasis Participants with Esophageal Candidiasis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 10 (90.00%)
    33 / 38 (86.84%)
    0 / 1 (0.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    5 / 38 (13.16%)
    0 / 1 (0.00%)
         occurrences all number
    0
    5
    0
    Hypotension
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    0
    Phlebitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Chills
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Crepitations
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    5 / 38 (13.16%)
    0 / 1 (0.00%)
         occurrences all number
    3
    7
    0
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Pleurisy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Rales
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory distress
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Tachypnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    6 / 38 (15.79%)
    0 / 1 (0.00%)
         occurrences all number
    17
    7
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 10 (20.00%)
    9 / 38 (23.68%)
    0 / 1 (0.00%)
         occurrences all number
    17
    9
    0
    Bacteria urine identified
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Band neutrophil count increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    Bilirubin conjugated increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    4
    3
    0
    Blood bicarbonate increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    4 / 10 (40.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    0
    Blood calcium decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    Blood chloride increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    Blood magnesium decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    Blood phosphorus decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    Blood potassium decreased
         subjects affected / exposed
    4 / 10 (40.00%)
    8 / 38 (21.05%)
    0 / 1 (0.00%)
         occurrences all number
    8
    10
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Blood sodium increased
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    0
    Blood urea increased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    Blood uric acid decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Breath sounds abnormal
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    5
    7
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 38 (10.53%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    1
    6
    0
    Platelet count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    4
    0
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Injury, poisoning and procedural complications
    Feeding tube complication
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Hypotonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 38 (7.89%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    0
    Lip dry
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Nausea
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    3
    2
    0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis bullous
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Ecchymosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    2
    2
    0
    Pruritus
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Rash
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Rash papular
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    0
    Skin nodule
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 38 (2.63%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Cytomegalovirus infection
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    Fungal sepsis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 38 (5.26%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Anorexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Fluid retention
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    Magnesium deficiency
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 38 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Mar 2006
    Protocol Amendment MK-0991-043-01 included the following changes: 1) personnel contact information was updated to reflect current telephone numbers, fax numbers, email addresses, and mailing addresses, 2) the Background section was shortened to provide only new and the most relevant information. The reader is referred to the Product Package Insert and the Confidential Investigator’s Brochure (CIB) for detailed background information, 3) the included age range was expanded from patients aged 2 to 17 years to patients aged 3 months to 17 years and a rationale for this change was added, 4) instructions for collection of blood samples for pharmacokinetic (PK) analysis were modified. Five-point PK sampling on Day 4 is required for all patients aged 3 months to <24 months while for patients aged 24 months to 17 years only a subset of sites will perform 5-point sampling on Day 4., 5) the wording under Section I. E. 2. 3 Infusion of Caspofungin has been updated, 6) the estimated overall duration of the study was increased to 36 months and an interim report is now planned, 7) the List of References was updated, 8) several appendices were restructured to clarify the procedures for processing and shipping of fungal isolates and PK samples. “Recommended Volume” has been replaced with “Maximum Volume” in APPENDIX 7, 9) minor typographical errors were corrected. Additional wording changes were made for clarity but these did not alter the intent of the content of the original protocol.

    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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