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    Clinical Trial Results:
    Open label study of the efficacy and safety of isavuconazole for the treatment of Chronic Pulmonary Aspergillosis

    Summary
    EudraCT number
    		 2016-003921-40
    Trial protocol
    		 GB  
    Global end of trial date
    22 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2020
    First version publication date
    09 Feb 2020
    Other versions
    Summary report(s)
    		 2016IF002 statement

    Trial information

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    Trial identification
    Sponsor protocol code
    2016IF002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 REC reference: 17/NW/0298
    Sponsors
    Sponsor organisation name
    Manchester University NHS Foundation Trust
    Sponsor organisation address
    29 Grafton Street, Manchester, United Kingdom, M13 9WU
    Public contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 161276 4125, research.sponsor@mft.nhs.uk
    Scientific contact
    Dr Lynne Webster, Manchester University NHS Foundation Trust, +44 161276 4125, research.sponsor@mft.nhs.uk
    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
    22 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Isavuconazole is an antifungal agent that was recently approved for the treatment of invasive aspergillosis on the basis of non-inferior outcomes compared to the standard of care, voriconazole. Isavuconazole is associated with a lower incidence of side effects than current standard treatment with antifungal drugs. There are no data on the use of isavuconazole in chronic pulmonary aspergillosis (CPA). The trial hypothesis is that isavuconazole will be at least as effective and safe as current available therapy for CPA. The primary objective of the study is to assess the efficacy and safety of isavuconazole in the treatment of CPA.
    Protection of trial subjects
    The most common treatment-related adverse reactions are elevated liver chemistry (7.9%). These changes are not related to liver failure and rarely requires stopping of treatment. Monitoring of liver enzymes during treatment will be considered during study scheduled visits. Isavuconazole has a moderate effect on the ability of patients to drive and use machines. Patients will be advised to avoid driving or operating machinery if symptoms of confusional state, somnolence, fainting and/or dizziness are experienced. Patients on treatment will be seen in the clinic at regular intervals to check for the signs and symptoms of adverse reactions. Patients will be provided with supportive care to reduce the burden of the side effects. Female patients of childbearing age are advised to use effective methods of contraception to prevent pregnancy. Patients are screened for pregnancy at regular intervals during the scheduled visits. In case of overdose, there is no specific treatment but patients will be treated with supportive care and appropriate medical support will be provided . As a preventative measure and to check compliance, the patient diary and number of capsules taken and returned will be checked during each visit to ensure overdose has not occured and also to check if the patient is receiving adequate level of treatment.
    Background therapy
    		 None.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Jan 1900
    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
    United Kingdom: 99999
    Worldwide total number of subjects
    99999
    EEA total number of subjects
    99999
    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)
    99999
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Potential participants will be identified through screening of the patients referred to the National Aspergillosis Centre by their local GP or consultant with suspected diagnosis of CPA. Potential participants who are deemed to be eligible or meeting the inclusion criteria will be provided with a participant information sheet.

    Pre-assignment
    Screening details
    		 Inclusion criteria: 1. Willing to give informed consent 2. Male or female aged 18 years plus 3. Diagnosed with CPA with azoles treatment indicated 4. Participants must not have received antifungals for treatment of CPA in the last 6 months and not for longer than 3 months 5. Sexually active females must agree to effective contraception

    Period 1
    Period 1 title
    Isavuconazole (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open label study with no active comparator or placebo so no blinding was to take place.

    Arms
    Arm title
    		 Isavuconazole treatment
    Arm description
    		 Eligible patients will be treated with isavuconazole (200mg) three times daily for 6 doses, followed by 200mg once daily. Patients will attend scheduled visits at 1, 2, 4, 6, 9, , 12, 16, 20, 24, 30, 36, 44 and 52 weeks of treatment and followed up for 6 months with two scheduled visits at 12 and 24 week after the end of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cresemba 100 mg hard capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Eligible patients will be treated with isavuconazole (200mg) three times daily for 6 doses, followed by 200mg once daily. Patients will attend scheduled visits at 1, 2, 4, 6, 9, , 12, 16, 20, 24, 30, 36, 44 and 52 weeks of treatment and followed up for 6 months with two scheduled visits at 12 and 24 week after the end of treatment.

    Number of subjects in period 1
    		Isavuconazole treatment
    Started
    99999
    Completed
    99999

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Isavuconazole treatment
    Reporting group description
    		 Eligible patients will be treated with isavuconazole (200mg) three times daily for 6 doses, followed by 200mg once daily. Patients will attend scheduled visits at 1, 2, 4, 6, 9, , 12, 16, 20, 24, 30, 36, 44 and 52 weeks of treatment and followed up for 6 months with two scheduled visits at 12 and 24 week after the end of treatment.

    Primary: Monitoring of clinical and biochemical evidence of toxicity throughout treatment period

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    End point title
    		 Monitoring of clinical and biochemical evidence of toxicity throughout treatment period [1]
    End point description
    End point type
    Primary
    End point timeframe
    Within treatment period
    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: This trial was terminated prior to opening at the trust.
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Primary: Clinical and radiological evidence of response to treatment after 12 months of therapy , as assessed by response on chest CT scan and clinical response (assessed using the SGRQ) and classified as improvement, stability and deterioration

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    End point title
    		 Clinical and radiological evidence of response to treatment after 12 months of therapy , as assessed by response on chest CT scan and clinical response (assessed using the SGRQ) and classified as improvement, stability and deterioration [2]
    End point description
    End point type
    Primary
    End point timeframe
    After 12 months of treatment
    Notes
    [2] - 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: This trial was terminated prior to opening at the trust.
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Serological response (improvement in Aspergillus IgG by 20% or to <40mg/L after 6 and 12 months of treatment)

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    End point title
    		 Serological response (improvement in Aspergillus IgG by 20% or to <40mg/L after 6 and 12 months of treatment)
    End point description
    End point type
    Secondary
    End point timeframe
    After 6 and 12 months of treatment
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Discontinuation of study drug before 12 months

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    End point title
    		 Discontinuation of study drug before 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    Before 12 months
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Symptomatic improvement (any 2 key symptoms other than weight gain)

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    End point title
    		 Symptomatic improvement (any 2 key symptoms other than weight gain)
    End point description
    End point type
    Secondary
    End point timeframe
    After follow up complete
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Proportion of patients showing improvement in SGRQ by >8 points at 6 and 12 months

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    End point title
    		 Proportion of patients showing improvement in SGRQ by >8 points at 6 and 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    At 6 and 12 months
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Proportion of patients showing deterioration SGRQ by >4 points at 6 and 12 months

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    End point title
    		 Proportion of patients showing deterioration SGRQ by >4 points at 6 and 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    At 6 and 12 months
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Weight gain or loss of >3Kg at 6 and 12 months

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    End point title
    		 Weight gain or loss of >3Kg at 6 and 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    At 6 and 12 months
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Recurrence 6 months after therapy discontinuation, assessed by deterioration in SGRQ by ≥8 points.

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    End point title
    		 Recurrence 6 months after therapy discontinuation, assessed by deterioration in SGRQ by ≥8 points.
    End point description
    End point type
    Secondary
    End point timeframe
    After 6 months of treatment
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: Positive respiratory culture for Aspergillus fumigatus with emergence of isavuconazole resistance

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    End point title
    		 Positive respiratory culture for Aspergillus fumigatus with emergence of isavuconazole resistance
    End point description
    End point type
    Secondary
    End point timeframe
    After follow up end
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Secondary: PK analysis of Isavuconazole in patients on treatment

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    End point title
    		 PK analysis of Isavuconazole in patients on treatment
    End point description
    End point type
    Secondary
    End point timeframe
    After follow up completion
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Other pre-specified: Inflammatory markers during treatment; C Reactive Protein and Plasma Viscosity

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    End point title
    		 Inflammatory markers during treatment; C Reactive Protein and Plasma Viscosity
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Exploratory endpoint. After follow up complete.
    End point values
    		 Isavuconazole treatment
    Number of subjects analysed
    99999
    Units: 99999
    99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All SAEs that occur between day 1 of treatment and 30 days post the last trial treatment dose administration (or after this date if the site investigator considers the event to be related to the trial treatment) must be submitted to the Sponsor.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Isavuconazole treatment
    Reporting group description
    		 Eligible patients will be treated with isavuconazole (200mg) three times daily for 6 doses, followed by 200mg once daily.

    Serious adverse events
    		 Isavuconazole treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 99999 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Isavuconazole treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 99999 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: This trial was terminated prior to opening at the trust. As such, no adverse events occurred.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This trial was cancelled as the company supplying the Investigational Medicinal Product (IMP) was brought out by another company who did not want to continue with the trial concept. No R&D confirmation of capacity and capability was given or contract
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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