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    Clinical Trial Results:
    Open label study of isavuconazole in the treatment of patients with invasive Aspergillosis with renal impairment (RI) or of patients with invasive fungal disease (IFD) caused by rare moulds, yeasts or dimorphic fungi.

    Summary
    EudraCT number
    2006-005003-33
    Trial protocol
    GB   BE   HU   CZ   DE   ES  
    Global end of trial date
    05 May 2016

    Results information
    Results version number
    v3(current)
    This version publication date
    22 Apr 2017
    First version publication date
    05 Jun 2015
    Other versions
    v1 (removed from public view) , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    9766-CL-0103
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00634049
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Global Pharma Development, Inc
    Sponsor organisation address
    1 Astellas Way, Northbrook, United States,
    Public contact
    Medical Head ID/IM/TX, Astellas Pharma Global Development, Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Medical Head ID/IM/TX, Astellas Pharma Global Development, 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
    03 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Main objective of the trial was to describe the safety and efficacy of isavuconazole in the treatment of invasive Aspergillosis in patients with renal impairment (RI) or in patients with invasive fungal disease (IFD) caused by rare moulds, yeasts or dimorphic fungi.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    Participants eligible for the study were primarily, but not limited to, those with underlying hematologic malignancies. Treatments for participants underlying disease were not standardized.
    Evidence for comparator
    This study did not have a comparator arm. The choice of a uniform comparator for all patients included in this study was not feasible due to the allowance of patients with IFD caused by many different rare pathogens.
    Actual start date of recruitment
    21 Apr 2008
    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
    Lebanon: 1
    Country: Number of subjects enrolled
    Israel: 21
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Mexico: 8
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 3
    Country: Number of subjects enrolled
    India: 5
    Worldwide total number of subjects
    149
    EEA total number of subjects
    17
    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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    119
    From 65 to 84 years
    29
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Consenting participants with proven,probable or possible invasive Aspergillosis and RI or IFD caused by rare molds, yeasts or dimorphic fungi meeting the inclusion and none of the exclusion criteria were enrolled at multicenter study at 34 centers globally, including centers in the US, European Union, South America, Asia and the Middle East.

    Pre-assignment
    Screening details
    Candidates for screening were male and female participants aged ≥18 years of age,at high risk for developing IFD caused by Aspergillus species,rare molds,yeasts,or other dimorphic fungi.Excluded participants had hepatic dysfunction,chronic aspergillosis, aspergilloma, allergic aspergillosis,advanced HIV or AIDS or were unlikely to survive 30 days.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Isavuconazole
    Arm description
    Isavuconazole (BAL4815) is a broad spectrum triazole. It inhibits sterol 14 α-demethylase, a microsomal P450 enzyme (P45014DM) essential for ergosterol biosynthesis in fungi.
    Arm type
    Experimental

    Investigational medicinal product name
    isavuconazole/CRESEMBA
    Investigational medicinal product code
    BAL8557
    Other name
    isavuconazonium sulfate,(CRESEMBA) as a pro drug of isavuconazole
    Pharmaceutical forms
    Capsule, Injection
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    The IV and oral formulations are 98% bioequivalent and therefore interchangable. A loading regimen of isavuconazole (IV or PO) was used over 2 days, followed by a maintenance regimen from Day 3 to EOT. During Days 1 and 2, three doses of 200 mg isavuconazole were administered every 8 hours for a total of six doses and from Day 3 to End of Treatment (EOT), maintanance dose of 200 mg isavuconazole was administered once daily up to 180 days; with an option for extended treatment under specified criteria.

    Number of subjects in period 1
    Isavuconazole
    Started
    149
    Completed
    146
    Not completed
    3
         Patient never received study drug
    1
         Patient died prior to receiving any study drug
    1
         Screening failure
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isavuconazole
    Reporting group description
    Isavuconazole (BAL4815) is a broad spectrum triazole. It inhibits sterol 14 α-demethylase, a microsomal P450 enzyme (P45014DM) essential for ergosterol biosynthesis in fungi.

    Reporting group values
    Isavuconazole Total
    Number of subjects
    149 149
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    116 116
        From 65-84 years
    29 29
        85 years and over
    1 1
        Not Recorded
    3 3
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.9 ± 16.78 -
    Gender categorical
    Units: Subjects
        Female
    46 46
        Male
    100 100
        Not Recorded
    3 3
    Race
    Race
    Units: Subjects
        White
    108 108
        Black or African American
    10 10
        Asian
    24 24
        Other
    4 4
        Not Recorded
    3 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    22 22
        Not Hispanic or Latino
    124 124
        Not Recorded
    3 3
    Therapy Status
    Intent to Treat Population. (ITT)
    Units: Subjects
        Primary Therapy
    93 93
        Refractory
    38 38
        Intolerant
    12 12
        Missing
    3 3
        Not Recorded
    3 3
    Hematologic malignancy
    Units: Subjects
        Yes
    63 63
        No
    83 83
        Not Recorded
    3 3
    Allogeneic BMT/HSCT
    Units: Subjects
        Yes
    26 26
        No
    120 120
        Not Recorded
    3 3
    Uncontrolled malignancy status
    Units: Subjects
        Yes
    46 46
        No
    100 100
        Not Recorded
    3 3
    Corticosteroid use
    Intent-to-Treat Analysis Set
    Units: Subjects
        Yes
    35 35
        No
    111 111
        Not Recorded
    3 3
    T-cell immunosuppressant use
    Intent-to-Treat Analysis Set
    Units: Subjects
        Yes
    61 61
        No
    48 48
        Missing
    37 37
        Not Recorded
    3 3
    Neutropenic
    Units: Subjects
        Yes
    38 38
        No
    66 66
        Missing
    42 42
        Not Recorded
    3 3
    Subject analysis sets

    Subject analysis set title
    mITT- Aspergillus [Renally Impaired]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Aspergillus - Renally Impaired mITT population consisted of participants who have had proven,probable or possible IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Renal impairment was defined as yes for patients who have a baseline eGFR-MDRD < 60 mL/min/1.73 m^2, no for patients who have a baseline eGFR-MDRD ≥ 60 mL/min/1.73 m^2. Overall there were 24 participants in the mITT-Aspergillus population out of which 20 participants were classified as Renally Impaired (RI).

    Subject analysis set title
    mITT- Aspergillus [Not Renally Impaired]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Aspergillus - Renally Impaired mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Overall there were 24 participants in the mITT-Aspergillus population out of which 4 participants were classified as Not Renally Impaired (NRI).

    Subject analysis set title
    mITT- Mucorales [Primary Therapy]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Primary Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 21 participants receiving isavuconazole as a primary therapy.

    Subject analysis set title
    mITT- Mucorales [Refractory]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Refractory Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis).The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 11 participants whose IFD was refractory to prior AFT.

    Subject analysis set title
    mITT - Mucorales [Intolerant]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Intolerant mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participant had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 5 participants who were intolerant to prior AFT.

    Subject analysis set title
    mITT- Other Filamentous Fungi
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Filamentous Fungi mITT population consisted of 17 participants who have had proven or probable IFD as determined by the DRC caused by other filamentous fungi (4 Fusarium,2 Exophiala,2 Cladosporium,2 Scopulariopsis and 1 each of Acremonium, Alternaria, Curvularia,Exserohilum, Paecilomyces,Pseudallescheria and Scedosporium).

    Subject analysis set title
    mITT- Mould Species
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Mould Species mITT population consisted of 7 participants who have had proven or probable IFD as determined by the DRC caused by mould species.

    Subject analysis set title
    mITT- Dimorphic Fungi
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Dimorphic Fungi mITT population consisted of 29 participants who have had proven or probable IFD as determined by the DRC caused by dimorphic fungi (10 Paracoccidiodes,9 Coccidiodides, 7 Histoplasma, 3 Blastomyces).

    Subject analysis set title
    mITT- Non Candida Yeast
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Non Candida Yeast mITT population consisted of 11 participants who have had proven or probable IFD as determined by the DRC caused by non-Candida yeast (4 Cryptococcus neoformans, 3 Cryptococcus gatii, 2 Cryptococcus NOS and 2 Trichosporon).

    Subject analysis set title
    mITT-Mixed Infections
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Mixed Infections mITT population consisted of 15 participants who have had proven or probable IFD as determined by the DRC caused by mixed infections aspergillosis/mucormycosis.

    Subject analysis sets values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects
    20
    4
    21
    11
    5
    17
    7
    29
    11
    15
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    13
    3
    17
    10
    5
    15
    4
    24
    7
    13
        From 65-84 years
    6
    1
    4
    1
    0
    2
    3
    5
    4
    2
        85 years and over
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Not Recorded
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ± 20.65
    41.5 ± 25.72
    51.7 ± 14.72
    46.4 ± 16.55
    39.6 ± 15.22
    47.5 ± 14.26
    58.6 ± 18.27
    45.7 ± 14.79
    52.5 ± 17.25
    49.8 ± 16.68
    Gender categorical
    Units: Subjects
        Female
    8
    1
    4
    3
    0
    7
    2
    7
    5
    7
        Male
    12
    3
    17
    8
    5
    10
    5
    22
    6
    8
        Not Recorded
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Race
    Race
    Units: Subjects
        White
    17
    4
    12
    10
    3
    13
    5
    20
    6
    12
        Black or African American
    0
    0
    1
    1
    2
    1
    1
    2
    1
    1
        Asian
    3
    0
    8
    0
    0
    3
    1
    4
    3
    2
        Other
    0
    0
    0
    0
    0
    0
    0
    3
    1
    0
        Not Recorded
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    1
    0
    1
    0
    0
    1
    0
    17
    2
    0
        Not Hispanic or Latino
    19
    4
    20
    11
    5
    16
    7
    12
    9
    15
        Not Recorded
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Therapy Status
    Intent to Treat Population. (ITT)
    Units: Subjects
        Primary Therapy
        Refractory
        Intolerant
        Missing
        Not Recorded
    Hematologic malignancy
    Units: Subjects
        Yes
    11
    3
    11
    7
    4
        No
    9
    1
    10
    4
    1
        Not Recorded
    0
    0
    0
    0
    0
    Allogeneic BMT/HSCT
    Units: Subjects
        Yes
    7
    2
    4
    4
    5
        No
    13
    2
    17
    7
    0
        Not Recorded
    0
    0
    0
    0
    0
    Uncontrolled malignancy status
    Units: Subjects
        Yes
    5
    2
    11
    6
    1
        No
    15
    2
    10
    5
    4
        Not Recorded
    0
    0
    0
    0
    0
    Corticosteroid use
    Intent-to-Treat Analysis Set
    Units: Subjects
        Yes
    12
    1
    5
    3
    2
        No
    8
    3
    16
    8
    3
        Not Recorded
    0
    0
    0
    0
    0
    T-cell immunosuppressant use
    Intent-to-Treat Analysis Set
    Units: Subjects
        Yes
    15
    3
    7
    6
    5
        No
    5
    1
    14
    5
    0
        Missing
    0
    0
    0
    0
    0
        Not Recorded
    0
    0
    0
    0
    0
    Neutropenic
    Units: Subjects
        Yes
    5
    3
    4
    5
    1
        No
    15
    1
    17
    6
    4
        Missing
    0
    0
    0
    0
    0
        Not Recorded
    0
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Isavuconazole
    Reporting group description
    Isavuconazole (BAL4815) is a broad spectrum triazole. It inhibits sterol 14 α-demethylase, a microsomal P450 enzyme (P45014DM) essential for ergosterol biosynthesis in fungi.

    Subject analysis set title
    mITT- Aspergillus [Renally Impaired]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Aspergillus - Renally Impaired mITT population consisted of participants who have had proven,probable or possible IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Renal impairment was defined as yes for patients who have a baseline eGFR-MDRD < 60 mL/min/1.73 m^2, no for patients who have a baseline eGFR-MDRD ≥ 60 mL/min/1.73 m^2. Overall there were 24 participants in the mITT-Aspergillus population out of which 20 participants were classified as Renally Impaired (RI).

    Subject analysis set title
    mITT- Aspergillus [Not Renally Impaired]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Aspergillus - Renally Impaired mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Classification by the DRC was based on the type of pathogen which was found to be the cause of participants IFD. The Aspergillus-mITT population was presented by renal status, renally impaired and not renally impaired. Overall there were 24 participants in the mITT-Aspergillus population out of which 4 participants were classified as Not Renally Impaired (NRI).

    Subject analysis set title
    mITT- Mucorales [Primary Therapy]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Primary Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 21 participants receiving isavuconazole as a primary therapy.

    Subject analysis set title
    mITT- Mucorales [Refractory]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Refractory Therapy mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participants had proven and 5 participants had probable invasive mucormycosis).The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 11 participants whose IFD was refractory to prior AFT.

    Subject analysis set title
    mITT - Mucorales [Intolerant]
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Mucorales – Intolerant mITT population consisted of participants who have had proven or probable IFD as determined by the DRC. Based on the DRC assessment 37 participants were assessed to have proven or probable Mucorales infection (32 participant had proven and 5 participants had probable invasive mucormycosis). The DRC also categorized each patient by therapy status; these groups were primary therapy, refractory and intolerant. There were 5 participants who were intolerant to prior AFT.

    Subject analysis set title
    mITT- Other Filamentous Fungi
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Filamentous Fungi mITT population consisted of 17 participants who have had proven or probable IFD as determined by the DRC caused by other filamentous fungi (4 Fusarium,2 Exophiala,2 Cladosporium,2 Scopulariopsis and 1 each of Acremonium, Alternaria, Curvularia,Exserohilum, Paecilomyces,Pseudallescheria and Scedosporium).

    Subject analysis set title
    mITT- Mould Species
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Mould Species mITT population consisted of 7 participants who have had proven or probable IFD as determined by the DRC caused by mould species.

    Subject analysis set title
    mITT- Dimorphic Fungi
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Dimorphic Fungi mITT population consisted of 29 participants who have had proven or probable IFD as determined by the DRC caused by dimorphic fungi (10 Paracoccidiodes,9 Coccidiodides, 7 Histoplasma, 3 Blastomyces).

    Subject analysis set title
    mITT- Non Candida Yeast
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Non Candida Yeast mITT population consisted of 11 participants who have had proven or probable IFD as determined by the DRC caused by non-Candida yeast (4 Cryptococcus neoformans, 3 Cryptococcus gatii, 2 Cryptococcus NOS and 2 Trichosporon).

    Subject analysis set title
    mITT-Mixed Infections
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Other Mixed Infections mITT population consisted of 15 participants who have had proven or probable IFD as determined by the DRC caused by mixed infections aspergillosis/mucormycosis.

    Primary: Crude success rate of overall outcome of treatment evaluated by the Data Review Committee (DRC) Day 42, Day 84 and EOT (mITT)

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    End point title
    Crude success rate of overall outcome of treatment evaluated by the Data Review Committee (DRC) Day 42, Day 84 and EOT (mITT) [1]
    End point description
    The DRC assessed overall response based on individual clinical, mycological and radiological response assessments. Participants with a complete or partial response were considered a success.
    End point type
    Primary
    End point timeframe
    Day 42, Day 84 and End of Treatment [EOT]
    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 statistical inferences were made due to the non-comparative study design. However, study outcomes were tabulated by renal status and baseline organism to provide context to historic literature.
    End point values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects analysed
    20
    4
    21
    11
    5
    17
    7
    29
    11
    15
    Units: Percent
    number (not applicable)
        Day 42 [Success]
    25
    50
    14.3
    9.1
    0
    47.1
    28.6
    41.4
    36.4
    13.3
        Day 84 [Success]
    30
    25
    9.5
    36.4
    20
    41.2
    28.6
    44.8
    36.4
    13.3
        End of Treatment [EOT Success]
    30
    66.7
    31.6
    36.4
    20
    64.7
    28.6
    64.3
    72.7
    14.3
    No statistical analyses for this end point

    Secondary: All-Cause Crude Mortality Through Day 42 and Day 84 (ITT)

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    End point title
    All-Cause Crude Mortality Through Day 42 and Day 84 (ITT)
    End point description
    All-cause Mortality was assessed through Day 42 and Day 84 and summarized for ITT population.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment (EOT [Day 180]).
    End point values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects analysed
    20
    4
    21
    4
    5
    17
    7
    29
    11
    15
    Units: Percent
    number (not applicable)
        All-cause Mortality Through Day 42
    15
    0
    33.3
    45.5
    40
    11.8
    0
    6.9
    9.1
    20
        All-cause Mortality Through Day 84
    25
    25
    42.9
    45.5
    40
    17.6
    14.3
    6.9
    9.1
    33.3
    No statistical analyses for this end point

    Secondary: Crude success rate of clinical response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)

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    End point title
    Crude success rate of clinical response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)
    End point description
    The DRC evaluated clinical response to treatment for patients at day 42, day 84 and EOT. The list of possible clinical responses to treatment as assessed by the DRC is as follows; Success [Resolution of all attributable clinical symptoms and physical findings and Partial resolution of attributable clinical symptoms and physical findings], Failure [No resolution of any attributable clinical symptoms and physical findings and/or worsening and Not done or missing] and Not applicable [No attributable signs and symptoms present at baseline and no symptoms attributable to IFD developed post baseline]. Each type of clinical response to treatment evaluated by the DRC at day 42, day 84 and EOT were summarized.
    End point type
    Secondary
    End point timeframe
    Day 42, Day 84 and EOT
    End point values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects analysed
    20
    4
    21
    11
    5
    17
    7
    29
    11
    15
    Units: percent
    number (not applicable)
        Day 42 [Success]
    55
    75
    50
    33.3
    50
    78.6
    71.4
    85.2
    77.8
    50
        Day 42 [Failure]
    45
    25
    50
    66.7
    50
    21.4
    28.6
    14.8
    22.2
    50
        Day 84 [Success]
    45
    25
    40
    22.2
    50
    76.9
    50
    88.9
    77.8
    50
        Day 84 [Failure]
    55
    75
    60
    77.8
    50
    23.1
    50
    11.1
    22.2
    50
        EOT [Success]
    55
    66.7
    55.6
    22.2
    50
    81.3
    85.7
    82.1
    70
    38.5
        EOT [Failure]
    45
    33.3
    44.4
    77.8
    50
    18.8
    14.3
    17.9
    30
    61.5
    No statistical analyses for this end point

    Secondary: Crude success rate of mycological response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)

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    End point title
    Crude success rate of mycological response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)
    End point description
    The DRC evaluated mycological response to treatment for patients at day 42, day 84 and EOT. The list of possible mycological responses to treatment is as follows, Success [Eradication and Presumed eradication], Failure [Persistence, Presumed persistence and Not done or missing] and Not applicable [No mycological evidence available at baseline]. Each type of mycological response to treatment evaluated by the DRC at day 42, day 84 and EOT was summarized.
    End point type
    Secondary
    End point timeframe
    Day 42, Day 84 and End of Treatment (EOT).
    End point values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects analysed
    20
    4
    21
    11
    5
    17
    7
    29
    11
    15
    Units: percent
    number (not applicable)
        Day 42 [Success]
    30
    50
    4.8
    0
    0
    29.4
    28.6
    27.6
    45.5
    13.3
        Day 42 [Failure]
    70
    50
    95.2
    100
    100
    70.6
    71.4
    72.4
    54.5
    86.7
        Day 84 [Success]
    35
    25
    9.5
    27.3
    40
    35.3
    28.6
    27.6
    45.5
    13.3
        Day 84 [Failure]
    65
    75
    90.5
    72.7
    60
    64.7
    71.4
    72.4
    54.5
    86.7
        EOT [Success]
    35
    66.7
    31.6
    36.4
    40
    70.6
    28.6
    53.6
    81.8
    14.3
        EOT [Failure]
    65
    33.3
    68.4
    63.6
    60
    29.4
    71.4
    46.4
    18.2
    85.7
    No statistical analyses for this end point

    Secondary: Crude success rate of radiological response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)

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    End point title
    Crude success rate of radiological response to treatment evaluated by the Data Review Committee (DRC) at Day 42, 84 and EOT (mITT)
    End point description
    Radiological responses to treatment as assessed by the DRC at different time points are as follows, Day 42-Success [Improvement of at least 25% from baseline for invasive aspergillosis and other filamentous mold infections],Failure [No postbaseline radiology available]; Day 84-Success [Improvement of at least 50% from baseline for invasive aspergillosis and other filamentous mold infections], Failure [No postbaseline radiology available for patient with baseline evidence of radiologic disease]; EOT-Success [Improvement of at least 25% from baseline if EOT occurs prior to day 42 and at least 50% improvement from baseline if EOT occurs after day 42 for invasive aspergillosis and other filamentous mold infections], Failure [No postbasline radiology available].
    End point type
    Secondary
    End point timeframe
    Day 42, Day 84 and EOT
    End point values
    mITT- Aspergillus [Renally Impaired] mITT- Aspergillus [Not Renally Impaired] mITT- Mucorales [Primary Therapy] mITT- Mucorales [Refractory] mITT - Mucorales [Intolerant] mITT- Other Filamentous Fungi mITT- Mould Species mITT- Dimorphic Fungi mITT- Non Candida Yeast mITT-Mixed Infections
    Number of subjects analysed
    20
    4
    21
    11
    5
    17
    7
    29
    11
    15
    Units: percent
    number (not applicable)
        Day 42 [Success]
    30
    25
    0
    10
    0
    25
    16.7
    21.4
    0
    7.1
        Day 42 [Failure]
    70
    75
    100
    90
    100
    75
    83.3
    78.6
    100
    92.9
        Day 84 [Success]
    20
    25
    4.8
    20
    20
    6.3
    0
    28.6
    10
    14.3
        Day 84 [Failure]
    80
    75
    95.2
    80
    80
    93.8
    100
    71.4
    90
    85.7
        EOT [Success]
    15
    66.7
    16.7
    20
    20
    50
    0
    33.3
    10
    7.7
        EOT [Failure]
    85
    33.3
    83.3
    80
    80
    50
    100
    66.7
    90
    92.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients were assessed for the occurrence of AEs on an ongoing basis during the course of the study and up to follow-up visit 1 (28 days after the last administration of study drug).
    Adverse event reporting additional description
    All adverse events analysis was completed on Safety Analysis Set (SAF) population. Adverse events reported are Treatment Emergent Adverse Events (TEAEs). A treatment- emergent adverse event is any adverse event that starts after the first administration of study medication until 28 days after the last dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Not Renally Impaired
    Reporting group description
    -

    Reporting group title
    Renally Impaired
    Reporting group description
    -

    Serious adverse events
    Not Renally Impaired Renally Impaired
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 87 (52.87%)
    43 / 59 (72.88%)
         number of deaths (all causes)
    23
    24
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Arteritis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myeloid leukaemia recurrent
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Leukaemia recurrent
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Immune system disorders
    Acute graft versus host disease
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft versus host disease
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung transplant rejection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multi-organ failure
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Electromechanical dissociation
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 87 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypercapnia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 87 (1.15%)
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sinus disorder
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 87 (3.45%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 87 (4.60%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 87 (1.15%)
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiolitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 87 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillosis
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    BK virus infection
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchiectasis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus enteritis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 87 (1.15%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mucormycosis
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 87 (6.90%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 87 (2.30%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia blastomyces
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia fungal
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia primary atypical
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pseudomonal sepsis
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 87 (1.15%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    0 / 87 (0.00%)
    6 / 59 (10.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    1 / 4
    Sinusitis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis fungal
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 87 (1.15%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    0 / 87 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Zygomycosis
         subjects affected / exposed
    2 / 87 (2.30%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Not Renally Impaired Renally Impaired
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 87 (78.16%)
    54 / 59 (91.53%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 59 (5.08%)
         occurrences all number
    5
    3
    Hypotension
         subjects affected / exposed
    5 / 87 (5.75%)
    5 / 59 (8.47%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 87 (8.05%)
    1 / 59 (1.69%)
         occurrences all number
    8
    1
    Chills
         subjects affected / exposed
    3 / 87 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    3
    8
    Fatigue
         subjects affected / exposed
    2 / 87 (2.30%)
    4 / 59 (6.78%)
         occurrences all number
    2
    5
    Oedema peripheral
         subjects affected / exposed
    8 / 87 (9.20%)
    8 / 59 (13.56%)
         occurrences all number
    8
    11
    Pain
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 59 (5.08%)
         occurrences all number
    3
    4
    Pyrexia
         subjects affected / exposed
    15 / 87 (17.24%)
    9 / 59 (15.25%)
         occurrences all number
    27
    14
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 87 (2.30%)
    7 / 59 (11.86%)
         occurrences all number
    2
    9
    Insomnia
         subjects affected / exposed
    8 / 87 (9.20%)
    5 / 59 (8.47%)
         occurrences all number
    9
    8
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 59 (5.08%)
         occurrences all number
    2
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 87 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    6
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 87 (1.15%)
    4 / 59 (6.78%)
         occurrences all number
    2
    4
    Sinus tachycardia
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Tachycardia
         subjects affected / exposed
    4 / 87 (4.60%)
    4 / 59 (6.78%)
         occurrences all number
    5
    4
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    2 / 87 (2.30%)
    4 / 59 (6.78%)
         occurrences all number
    2
    4
    Neutropenia
         subjects affected / exposed
    2 / 87 (2.30%)
    6 / 59 (10.17%)
         occurrences all number
    2
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 87 (13.79%)
    3 / 59 (5.08%)
         occurrences all number
    14
    3
    Dyspnoea
         subjects affected / exposed
    7 / 87 (8.05%)
    6 / 59 (10.17%)
         occurrences all number
    7
    6
    Epistaxis
         subjects affected / exposed
    5 / 87 (5.75%)
    2 / 59 (3.39%)
         occurrences all number
    6
    2
    Haemoptysis
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 87 (2.30%)
    4 / 59 (6.78%)
         occurrences all number
    3
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 59 (5.08%)
         occurrences all number
    5
    3
    Headache
         subjects affected / exposed
    14 / 87 (16.09%)
    11 / 59 (18.64%)
         occurrences all number
    19
    13
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 87 (4.60%)
    7 / 59 (11.86%)
         occurrences all number
    4
    8
    Abdominal pain upper
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 59 (1.69%)
         occurrences all number
    5
    2
    Constipation
         subjects affected / exposed
    10 / 87 (11.49%)
    5 / 59 (8.47%)
         occurrences all number
    11
    5
    Diarrhoea
         subjects affected / exposed
    10 / 87 (11.49%)
    16 / 59 (27.12%)
         occurrences all number
    11
    22
    Haematochezia
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Nausea
         subjects affected / exposed
    14 / 87 (16.09%)
    19 / 59 (32.20%)
         occurrences all number
    19
    23
    Stomatitis
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    17 / 87 (19.54%)
    16 / 59 (27.12%)
         occurrences all number
    26
    24
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Renal impairment
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    7 / 87 (8.05%)
    2 / 59 (3.39%)
         occurrences all number
    7
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 87 (9.20%)
    6 / 59 (10.17%)
         occurrences all number
    8
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 87 (5.75%)
    3 / 59 (5.08%)
         occurrences all number
    5
    4
    Myalgia
         subjects affected / exposed
    2 / 87 (2.30%)
    3 / 59 (5.08%)
         occurrences all number
    2
    4
    Pain in extremity
         subjects affected / exposed
    3 / 87 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 87 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    7
    4
    Hyperglycaemia
         subjects affected / exposed
    4 / 87 (4.60%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    Hyperkalaemia
         subjects affected / exposed
    4 / 87 (4.60%)
    7 / 59 (11.86%)
         occurrences all number
    5
    8
    Hypernatraemia
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    3 / 87 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    3
    3
    Hypokalaemia
         subjects affected / exposed
    6 / 87 (6.90%)
    6 / 59 (10.17%)
         occurrences all number
    8
    6
    Hypophosphataemia
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Hypomagnesaemia
         subjects affected / exposed
    7 / 87 (8.05%)
    2 / 59 (3.39%)
         occurrences all number
    7
    2
    Infections and infestations
    Clostridial infection
         subjects affected / exposed
    0 / 87 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 87 (1.15%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Herpes zoster
         subjects affected / exposed
    5 / 87 (5.75%)
    1 / 59 (1.69%)
         occurrences all number
    7
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 87 (6.90%)
    5 / 59 (8.47%)
         occurrences all number
    7
    6
    Urinary tract infection
         subjects affected / exposed
    2 / 87 (2.30%)
    7 / 59 (11.86%)
         occurrences all number
    2
    7

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2007
    Amendment 1 issued on October 16, 2007, clarified the type of participants to be enrolled, including changes requested by Regulatory Authorities. Clarifications were made to the duration of study drug, clinical and mycological responses, and to the timing of evaluations for secondary efficacy variables including the addition that survival status should be assessed for all participants, including those discontinued prior to day 42 or day 84 due to an unsuccessful outcome. The ceiling for total bilirubin, aspartate transaminase (AST) and alanine transaminase (ALT) abnormalities were decreased per regulatory advice. The estimated number of centers that participated in the study was adjusted from 200 to 150.
    27 May 2010
    Amendment 2 issued on May 27, 2010, identified the change in the study sponsorship from Basilea to Astellas. The project physician, biostatistician and clinical pharmacologist were also changed. Isavuconazole dosing and the fasting requirement for oral isavuconazole administration were amended. The prohibited concomitant drugs were updated. The European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of IFD were changed from 2002 to the revised 2008 criteria.
    17 Nov 2010
    Amendment 3 issued on November 17, 2010, amended maximum duration of therapy from 84 days up to 180 days and the timing of the first study drug maintenance dose was also amended. The primary and secondary analysis and efficacy variables were amended to specify that outcome criteria were assessed by the DRC and Investigator and to add additional time points for analysis. The exploratory analysis variables were amended to specify pharmacokinetic analysis and the addition of analysis of serum galactomannan (GM) as a biomarker for treatment of invasive aspergillosis. The inclusion and exclusion criteria were also amended and clarified. The criterion for withdrawing participants with possible IFD was removed, and prohibited and cautionary drugs and drug-drug interactions (DDIs) were updated. Various study procedures in the Schedule of Assessments were amended, clarified and added. Bronchoalveolar lavage (BAL) galactomannan (GM) was clarified as mycological criteria for enrollment of participants with invasive aspergillosis. The Protocol was amended to classify these participants as possible versus probable cases of IFD. Additional follow-up criteria for enrollment of these participants were also added. The CLCr calculation was amended to standardize reporting; ideal rather than actual BW was used in the calculation. The laboratory tests albumin, p-amylase and lipase were also added, and an improvement of < 25% was included in radiological response criteria.
    11 Jun 2012
    Amendment 5 issued on June 11, 2012, amended and clarified the efficacy variables and analysis sets and modified the entry criteria. Entry criteria changes included allowance of enrollment of participants on dialysis and of participants with proven or probable invasive mucormycosis who required primary therapy, and exclusion of participants who were enrolled in previous isavuconazole trials. Sirolimus and tyrosine kinase inhibitors were added as medications to use with caution, and clarification was added that statins could be discontinued at time of first dose. Various study procedures were amended, clarified and added to the Schedule of Assessments. The laboratory tests hematocrit and blood, urea and nitrogen test (BUN) were added.
    06 Feb 2013
    Amendment 6.1 issued on February 06, 2013, added inclusion criterion 7, stating that participants were not to participate in any other clinical trial within 30 days prior to first administration of study drug. Exclusion criterion 12 was revised to remove the exception that allowed concurrent participation in open-label protocols; limited the enrollment to participants that had proven or probable IFD caused by rare molds, yeasts or dimorphic fungi and participants who had proven or probable invasive zycomycosis who required primary treatment; relabeled inclusion criterion 5 as inclusion criterion 6; and clarified that no waivers to inclusion or exclusion criteria were permitted. The total sample size was increased from 100 participants to 150 participants to allow enrollment of specified subsets of participants requiring primary therapy. As the sample size was increased and the inclusion of participants with specific infections was limited, the sections of the Protocol that were no longer relevant to participants to be enrolled under this amendment were identified, and exclusion criterion 15 was removed to allow the inclusion of participants with invasive aspergillosis. A section entitled End of Trial in All Participating Countries was added to the Protocol, to define the end of trial for this Protocol and allow for consistency throughout participating countries. The Protocol was also updated to indicate that preliminary data suggested isavuconazole may shorten the QT interval.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Jan 2009
    Enrollment in the clinical study was suspended in January 2009 pending further characterization of newly identified impurities. After successful completion of the studies, regulatory notifications, and transfer of Sponsorship from Basilea to Astellas, resumption of enrollment occurred in April 2011 for the 9766-CL-0103/WSA-CS-003 study (hereafter referred to as 9766-CL-0103).
    01 Apr 2011

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Primary limitation is the non-comparative design. Conduct of a large randomized controlled study in these rare diseases was not considered feasible. The results provide evidence that CRESEMBA is effective for the treatment for mucormycosis.
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