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    Clinical Trial Results:
    Pharmacokinetic study with a loading dose of clofazimine in adult patients with nontuberculous mycobacterial disease

    Summary
    EudraCT number
    		 2021-002062-40
    Trial protocol
    		 NL  
    Global end of trial date
    31 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Sep 2024
    First version publication date
    14 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UMCN-AKF-21.04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05294146
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud university medical center
    Sponsor organisation address
    Geert grooteplein Zuid 10, Nijmegen, Netherlands, 6525GA
    Public contact
    Rob Aarnouste, Radboud university medical center, +31 243617744, rob.aarnoutse@radboudumc.nl
    Scientific contact
    Rob Aarnouste, Radboud university medical center, +31 243617744, rob.aarnoutse@radboudumc.nl
    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
    08 Aug 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overarching aim of this study is to contribute to dose optimization of CFZ in the treatment of NTM diseases. The primary objective of this study is to describe the PK of CFZ, after 4 weeks of treatment with a loading dose regimen of 300 mg once daily, in adult patients with NTM disease.
    Protection of trial subjects
    Written informed consent is to be obtained from all subjects prior to any trial procedures being performed. Investigators may discuss the availability of the trial and the opportunity for entry with a potential patient without first obtaining consent. The patients are informed about the study by a letter (PIF) before their first appointment and will be seen by a physician. The investigators have both ethical and legal responsibility to ensure that each patient being considered for inclusion in this trial is given a full explanation of the protocol. This shall be documented on a written Informed Consent Form that shall be approved by the same METC responsible for approval of this protocol. The principal investigator or other study doctor asks for participation. Informed consent is given at least 24 hours later. In case the medical doctor of the participant is also the investigator, it will be emphasized to the participant that participation in this study is strictly voluntary and that the decision on whether or not to participate will by no means influence the clinical care they will receive. Also, as described in the PIF, participants have the possibility to ask questions to an independent expert. The investigator must assure that patients’ anonymity will be strictly maintained and that their identities are protected from unauthorized parties. Only an identification code (i.e., not names) should be recorded on any form submitted to the IEC. The investigator must keep a screening log showing codes, for all patients screened and for all patients enrolled in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 2021
    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
    Netherlands: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    6
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients will be included at the Radboudumc center of expertise for mycobacterial diseases. Patients from all over the country are referred to the Radboudumc. Informed consent will be obtained at the Radboudumc. We will include all adult patients with NTM disease who are eligible for treatment with CFZ.

    Pre-assignment
    Screening details
    		 In order to be eligible to participate in this study, a subject must meet all of the following criteria: - The participant is diagnosed with pulmonary or extrapulmonary NTM disease and is eligible for treatment with CFZ - The participant is at least 18 years of age

    Period 1
    Period 1 title
    CFZ dosing (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    not applicable

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 CFZ loading dose
    Arm description
    		 300mg CFZ daily for 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    clofazimine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    daily use of 3 tablets of 100mg for 28 days, followed by the 100mg daily dose for 14 weeks

    Arm title
    		 CFZ standard dose
    Arm description
    		 100mg CFZ daily for 14 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    clofazimine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    daily use of 3 tablets of 100mg for 28 days, followed by the 100mg daily dose for 14 weeks

    Number of subjects in period 1
    		CFZ loading dose CFZ standard dose
    Started
    12
    12
    Completed
    12
    8
    Not completed
    0
    4
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    -
    1
         clinical deterioration
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CFZ dosing
    Reporting group description
    		 -

    Reporting group values
    		 CFZ dosing Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 69 (39 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    CFZ loading dose
    Reporting group description
    		 300mg CFZ daily for 28 days

    Reporting group title
    CFZ standard dose
    Reporting group description
    		 100mg CFZ daily for 14 weeks

    Primary: Cmax

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    End point title
    		 Cmax
    End point description
    End point type
    Primary
    End point timeframe
    Day 28 and 4 months
    End point values
    		 CFZ loading dose CFZ standard dose
    Number of subjects analysed
    12
    8
    Units: mg/L
        geometric mean (confidence interval 95%)
    0.87 (0.69 to 1.11)
    0.96 (0.71 to 1.2)
    Statistical analysis title
    		 descriptive
    Comparison groups
    CFZ loading dose v CFZ standard dose
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 confidence interval
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.11

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    entire trial
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 none
    Dictionary version
    1
    Reporting groups
    Reporting group title
    all subjects
    Reporting group description
    		 -

    Serious adverse events
    		 all subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 12 (50.00%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    nausea and vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pulmonary hemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    COPD
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal and urinary disorders
    tubulo-interstitial nephritis
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Influenza A
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    weight loss, dyspnea
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 all subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Investigations
    Elektrolyte imbalance
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    10
    Hypoalbuminaemia
         subjects affected / exposed
    6 / 12 (50.00%)
         occurrences all number
    8
    Cardiac disorders
    QTc prolongation
         subjects affected / exposed
    9 / 12 (75.00%)
         occurrences all number
    9
    Ear and labyrinth disorders
    Ototoxicity
         subjects affected / exposed
    12 / 12 (100.00%)
         occurrences all number
    12
    Gastrointestinal disorders
    GI complaints
         subjects affected / exposed
    11 / 12 (91.67%)
         occurrences all number
    28
    Skin and subcutaneous tissue disorders
    skin-related
         subjects affected / exposed
    10 / 12 (83.33%)
         occurrences all number
    20

    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.
    no formal statistical test was done, in the statistical analysis section we reported the GM of Cmax and 95%CI of Cmax after the load dose.
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    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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