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    Clinical Trial Results:
    A randomized placebo-controlled double blind study to prevent BOS

    Summary
    EudraCT number
    		 2010-022027-30
    Trial protocol
    		 BE  
    Global end of trial date
    11 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2024
    First version publication date
    29 Nov 2024
    Other versions
    Summary report(s)
    		 Study Results

    Trial information

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    Trial identification
    Sponsor protocol code
    VIT001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01212406
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    KU Leuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium, 3000
    Public contact
    Anja Gilissen Clinical Trial Center (CTC) anja.gilissen@uzleuven.be +32 16 342101 , University Hospitals Leuven and KU Leuven, 0032 342101, anja.gilissen@uzleuven.be
    Scientific contact
    Anja Gilissen Clinical Trial Center (CTC) anja.gilissen@uzleuven.be +32 16 342101 , University Hospitals Leuven and KU Leuven, 0032 342101, anja.gilissen@uzleuven.be
    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 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • Prevalence of BOS (grade 1) at 2 and 3 year post-transplant in patietns treated with Vitamin D vs. Placebo
    Protection of trial subjects
    Standard Operating Procedures as per Institution's post-transplant protcol
    Background therapy
    		 Standard immunosuppressive regimen and infectious prophylaxis according to Standard Operating Procedures.
    Evidence for comparator
    		 1,25(OH)2D demonstrates anti-inflammatory effects in the lungs due to local inhibition of NF-κB and mitogen-activated protein kinase (MAPK) activity, thus attenuating secretion of inflammatory cytokines and chemokines, such as interleukin (IL)-1β, IL-6 and IL-8; and influx of inflammatory cells. Next to this, 1,25(OH)2D reduces oxidative stress by inhibiting anti-protease activity and acting on nuclear factor erythroid 2-related factor 2 (Nrf2), a transcriptional regulator of most antioxidant genes (4). 1,25(OH)2D also has anti-infectious properties, by increasing maturation and proliferation of monocytes into macrophages; and transcriptional up-regulation of cathelicidin and defensin-β2 by airway epithelial cells, pulmonary macrophages and neutrophils, which suppress inflammation and are effective in microbial killing, including fungi and Pseudomonas species. 1,25(OH)2D is involved in tissue remodeling, as it demonstrates inhibitory effects on expression of matrix metalloproteinases in airway smooth muscle cells, monocytes and alveolar macrophages, on proliferation and activation of bronchial airway muscle cells and fibroblasts, on extra-cellular matrix deposition by fibroblasts; and on epithelial-mesenchymal transition. Finally, 1,25(OH)2D inhibits proliferation and differentiation of B-cells, suppresses secretion of pro-inflammatory cytokines by CD4+ T-cells, inhibits T-helper (Th)-cells, such as Th1, Th9, Th17 and possibly also Th2, increases development of regulatory T-cells (Treg) and promotes a tolerogenic phenotype of dendritic cells. We therefore investigated the possible immunomodulatory effects of vitamin D in lung transplatation.
    Actual start date of recruitment
    29 Oct 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 87
    Worldwide total number of subjects
    87
    EEA total number of subjects
    87
    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)
    83
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Following written informed consent, patients were randomly assigned to receive either oral vitamin D or placebo using a 1:1 ratio by the University’s Hospital Experimental Pharmacy (http://www.randomization.com). Adult lung transplant recipients able to take oral drugs at hospital discharge following LTx were eligible for inclusion.

    Pre-assignment
    Screening details
    		 See added summary of the published study results

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Study groups were generated through permuted-block randomization using a 1:1 ratio by the University’s Hospital Experimental Pharmacy (http://www.randomization.com). . Both vitamin D and placebo were stored and subsequently delivered by the University’s Hospital Experimental Pharmacy in blinded, sequentially numbered syringes (Exactamed 10 ml 1610 Amber) for oral intake. All participants, nurses and treating physicians were blinded to group assignment during study treatment and later follow-up.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vitamin D
    Arm description
    		 Vitamin D (D-Cure™, cholecalciferol, 100,000 IU, 4 mL, orally, once monthly)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    D-Cure
    Investigational medicinal product code
    Vitamin D
    Other name
    cholecalciferol
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    100,000 IU, 4 mL, orally, once monthly

    Arm title
    		 Placebo
    Arm description
    		 arachide oil (4 mL, orally, once monthly)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    arachide oil
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    4 mL, orally, once monthly

    Number of subjects in period 1
    		Vitamin D Placebo
    Started
    44
    43
    Completed
    36
    34
    Not completed
    8
    9
         Consent withdrawn by subject
    5
    6
         Adverse event, non-fatal
    1
    -
         Lost to follow-up
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall trial
    Reporting group description
    		 -

    Reporting group values
    		 overall trial Total
    Number of subjects
    		 87 87
    Age categorical
    Age of included patients
    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)
    		 83 83
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Gender categorical
    Overall trial
    Units: Subjects
        Female
    		 39 39
        Male
    		 48 48
    Subject analysis sets

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    See added summary of the published study results

    Subject analysis sets values
    		 Overall trial
    Number of subjects
    87
    Age categorical
    Age of included patients
    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)
    83
        From 65-84 years
    4
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Overall trial
    Units: Subjects
        Female
    39
        Male
    48

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 Vitamin D (D-Cure™, cholecalciferol, 100,000 IU, 4 mL, orally, once monthly)

    Reporting group title
    Placebo
    Reporting group description
    		 arachide oil (4 mL, orally, once monthly)

    Subject analysis set title
    Overall trial
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    See added summary of the published study results

    Primary: CLAD

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    End point title
    		 CLAD
    End point description
    See added summary of the published study results
    End point type
    Primary
    End point timeframe
    at 3 years post transplant
    End point values
    		 Vitamin D Placebo
    Number of subjects analysed
    36
    34
    Units: events
        CLAD event
    6
    5
    Statistical analysis title
    		 Primary Endpoint Analysis
    Comparison groups
    Vitamin D v Placebo
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Logrank
    Parameter type
    		 logrank p-value
    Confidence interval
    Notes
    [1] - log-rank analysis showed no statistical difference between both arms
    [2] - log-rank analysis showed no statistical difference between both arms

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the study
    Adverse event reporting additional description
    Nausea leading to IMP discontinuation
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 clincial symptoms
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Overall study
    Reporting group description
    		 nausea leading to discontinuation of IMP

    Serious adverse events
    		 Overall study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 87 (0.00%)
         number of deaths (all causes)
    8
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 87 (1.15%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 87 (1.15%)
         occurrences all number
    1

    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.
    See added summary of the published study results

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28365177
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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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