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    Clinical Trial Results:
    A randomized open-label trial to evaluate the cardiovascular risk in stable renal allograft recipients on a ciclosporin A (CsA) based regimen monitored either by residual expression of nuclear factor of activated T-cells (NFAT) – regulated genes or CsA trough levels

    Summary
    EudraCT number
    		 2011-003547-21
    Trial protocol
    		 DE  
    Global end of trial date
    31 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 May 2022
    First version publication date
    21 May 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RCHD–CsA1004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Renal Center Heidelberg
    Sponsor organisation address
    Im Neuenheimer Feld 162, Heidelberg, Germany, 69120
    Public contact
    Clinical Trials Information, Renal Clinic Heidelberg (Nephrology Unit, University Hospital Heidelberg), +49 622191120, info@nierenzentrum-heidelberg.com
    Scientific contact
    Clinical Trials Information, Renal Clinic Heidelberg (Nephrology Unit, University Hospital Heidelberg), +49 622191120, info@nierenzentrum-heidelberg.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
    31 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The comparison of a CsA-based immunosuppression either monitored by CsA trough levels or NFAT-regulated gene expression concerning the cardiovascular risk
    Protection of trial subjects
    Assess renal allograft function Assess Quality of Life assessed by the ESRD SCLTM questionnaire and SF12 questionaire
    Background therapy
    		 triple drug immunosuppressive therapy consisting of mycophenolate and steroids in addition to ciclosporin A
    Evidence for comparator
    		 Standard Therapy: Ciclosporin A adapted to Ciclosporin A trough levels (comparator). Ciclosporin A is an approved drug and used in clinical practice since more than 30 years. Using Ciclosporin A trough levels is the standard procedure for monitoring and adaption of Ciclosporin A dosages.
    Actual start date of recruitment
    15 Aug 2012
    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
    Germany: 55
    Worldwide total number of subjects
    55
    EEA total number of subjects
    55
    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)
    44
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients of the renal transplant outpatient clinic at the Renal Center Heidelberg (Department of Nephrology University Hospital Heidelberg) suitable to participate in the study were asked to participate and enrolled consecutively.

    Pre-assignment
    Screening details
    		 Inclusion criteria specified that patients were to be 18 years or older, have received a renal allograft from a deceased or living donor at least 6 months before study entry, and have stable renal allograft function, receiving Ciclosporin A and mycophenolate. Key exclusion criteria included history of biopsy-proven acute rejection.

    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    All patients were blinded to treatment procedures (not knowing the method of Ciclosporin A monitoring and adaption).

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm A
    Arm description
    		 CsA adapted to standard C0 levels (80-150µg/L)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ciclosporin A
    Investigational medicinal product code
    Other name
    Sandimmun ostoral
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    adapted to Ciclosporin A trough level (80-150 ug/L)

    Arm title
    		 Arm B
    Arm description
    		 CsA adapted to residual NFAT-regulated gene expression (15 –30%) if CsA C0 ≥ 30 µg/L
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciclosporin A
    Investigational medicinal product code
    Other name
    Sandimmun ostoral
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    adapted to NFAT-regulated gene expression (15-30%) with Ciclosporin A trough level >30 ug/L.

    Number of subjects in period 1
    		Arm A Arm B
    Started
    27
    28
    Completed
    27
    26
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 CsA adapted to standard C0 levels (80-150µg/L)

    Reporting group title
    Arm B
    Reporting group description
    		 CsA adapted to residual NFAT-regulated gene expression (15 –30%) if CsA C0 ≥ 30 µg/L

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 27 28
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.1 ± 14.0 50.9 ± 12.3 -
    Gender categorical
    Units: Subjects
        Female
    		 13 6 19
        Male
    		 14 22 36

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 CsA adapted to standard C0 levels (80-150µg/L)

    Reporting group title
    Arm B
    Reporting group description
    		 CsA adapted to residual NFAT-regulated gene expression (15 –30%) if CsA C0 ≥ 30 µg/L

    Primary: change in pulse wave velocity from baseline to month 6

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    End point title
    		 change in pulse wave velocity from baseline to month 6
    End point description
    change of PWV from baseline to month 6
    End point type
    Primary
    End point timeframe
    6 months
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    27
    26
    Units: m/s
        arithmetic mean (standard deviation)
    0.4 ± 1.4
    -1.7 ± 2.0
    Statistical analysis title
    		 primary end point
    Statistical analysis description
    The null hypothesis was that the change in PWV between baseline and month 6 was the same in both treatment arms. The primary analysis was performed on the intention-to-treat population. Analysis of covariance (ANCOVA) was applied, with treatment, age, baseline PWV and eGFR as covariates.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    6 months (baseline to month 6)
    Adverse event reporting additional description
    all adverse events occurring from baseline to month 6 were collected
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Standard monitoring by Ciclosporin A trough level (comparator, standard)

    Reporting group title
    Arm B
    Reporting group description
    		 Ciclosporin A adapted by NFAT-regulated gene expression (experimental group)

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 27 (25.93%)
    9 / 26 (34.62%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Infection
         subjects affected / exposed
    4 / 27 (14.81%)
    6 / 26 (23.08%)
         occurrences causally related to treatment / all
    1 / 5
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 27 (59.26%)
    15 / 26 (57.69%)
    General disorders and administration site conditions
    infection
         subjects affected / exposed
    11 / 27 (40.74%)
    8 / 26 (30.77%)
         occurrences all number
    20
    13
    calcineurin inhibitor related
         subjects affected / exposed
    16 / 27 (59.26%)
    7 / 26 (26.92%)
         occurrences all number
    30
    12

    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 limitations and caveats
    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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