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    Clinical Trial Results:
    Biomarkers Of The Humoral Immune Response After Conversion To Belatacept In Comparison To Conventional Immunosuppressive Therapy In Renal Transplant Patients

    Summary
    EudraCT number
    		 2012-005652-42
    Trial protocol
    		 DE  
    Global end of trial date
    10 Mar 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Nov 2022
    First version publication date
    06 Nov 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IM103-319
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Charité - Universitätsmedizin Berlin
    Sponsor organisation address
    Charitéplatz 1, Berlin, Germany, 10117
    Public contact
    Clinical Trial informations, Charité Universitätsmedizin Berlin, 0049 030614086, klemens.budde@charite.de
    Scientific contact
    Clinical Trial informations, Charité Universitätsmedizin Berlin, 0049 030614086, klemens.budde@charite.de
    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
    11 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine cellular and transcriptional Biomarker candidates of the humoral and cellular immune system that elucidate the effect of Nulojix in preventing DSA formation after conversion in comparison to a CNI- or mTORi-based therapy in renal transplant recipients.
    Protection of trial subjects
    Routine haematology, biochemistry, renal transokabt function, urine analyses and vital signs will becorded according the visit schedule. In addition, physical examination, an electrocardiogram and medical history will be recorded at study entry
    Background therapy
    		 Regulatory T-cells (Tregs) are considered to play a crucial role in maintaining control of immune response following renal transplantation (Tx). So far, only limited data are available from prospective controlled trials on the time course and frequency of Tregs after conversion from either Calcineurin inhibitors (CNIs) or mammalian target of Rapamycin inhibitors (mTORi) to Belatacept, a co-stimulatory blocker of CD80/86. The aim of this study was to evaluate the influence of belatacept on T-cell subsets with focus on Tregs after withdrawal from CNI or mTORi.
    Evidence for comparator
    		 Belatacept, cytotoxic T lymphocyte-associated protein 4 (CTLA-4)-Ig (Nulojix®) is the first clinically relevant co-stimulation blocker, and is a high-affinity chimeric fusion protein that binds to CD80/CD86 on (Antigen-presenting cells) APC . One of the best- characterized costimulatory reactions is between CD28/CTLA-4 on T cells and CD80/CD86 on APC. The interaction between CD28 and CD80/CD86 leads to T-cell activation. Because of its non-renal toxicities, belatacept provides a benefit in preserving renal function by avoiding calcineurin inhibitors and a better cardiovascular risk profile.
    Actual start date of recruitment
    11 Nov 2013
    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: 41
    Worldwide total number of subjects
    41
    EEA total number of subjects
    41
    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)
    32
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at one study centers in Germany, between 2013/11/11 (first patient first visit) and 2016/03/10 (last patient last visit).

    Pre-assignment
    Screening details
    		 Renal transplant recipients, whose received renal allograft at least 3 months were screened. Patients, who have signs of CNI- or mTORi- related toxicity or intolerance were included. One matched control patient was identified and investigated for each renal transplant patient. e.g. gender, comparabel age (+/- 10Y), tranplant. durat. (+/-5Y)

    Period 1
    Period 1 title
    overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    open design of trial with parallel groups

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CNI conversion
    Arm description
    		 Patients on a CNI-based therapy for more than 3 months, who have signs of CNI- related toxicity or intolerance and are converted due to clinical indication to a CNI-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Belatacept
    Investigational medicinal product code
    Other name
    NULOJIX
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 5 mg/kg NULOJIX, administered every 2 weeks for the first 8 weeks, followed by the same dose every 4 weeks thereafter. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Investigational medicinal product name
    Prograf
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 5 mg

    Investigational medicinal product name
    Sandimmun Optoral
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 25 mg, 50 mg, 100 mg

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 3mg, 5mg

    Arm title
    		 mTORi conversion
    Arm description
    		 Patients on a mTORi-based therapy for more than 3 months, who have signs ofmTORi related toxicity or intolerance and are converted due to clinical indication to a mTORi-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Belatacep
    Investigational medicinal product code
    Other name
    NULOJIX
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A dose of 5 mg/kg NULOJIX, administered every 2 weeks for the first 8 weeks, followed by the same dose every 4 weeks thereafter. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Investigational medicinal product name
    Certican
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg

    Arm title
    		 CNI control
    Arm description
    		 matched-control patients who remain on their current immunosuppression regimen.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Prograf
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 5 mg

    Investigational medicinal product name
    Sandimmun Optoral
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 25 mg, 50 mg, 100 mg

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, 3mg, 5mg

    Arm title
    		 mTORi control
    Arm description
    		 matched-control patients who remain on their current immunosuppression regimen.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Certican
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg

    Number of subjects in period 1
    		CNI conversion mTORi conversion CNI control mTORi control
    Started
    11
    11
    10
    9
    Completed
    10
    9
    9
    9
    Not completed
    1
    2
    1
    0
         Adverse event, serious fatal
    -
    1
    -
    -
         Consent withdrawn by subject
    -
    1
    -
    -
         Adverse event, non-fatal
    1
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CNI conversion
    Reporting group description
    		 Patients on a CNI-based therapy for more than 3 months, who have signs of CNI- related toxicity or intolerance and are converted due to clinical indication to a CNI-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Reporting group title
    mTORi conversion
    Reporting group description
    		 Patients on a mTORi-based therapy for more than 3 months, who have signs ofmTORi related toxicity or intolerance and are converted due to clinical indication to a mTORi-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Reporting group title
    CNI control
    Reporting group description
    		 matched-control patients who remain on their current immunosuppression regimen.

    Reporting group title
    mTORi control
    Reporting group description
    		 matched-control patients who remain on their current immunosuppression regimen.

    Reporting group values
    		 CNI conversion mTORi conversion CNI control mTORi control Total
    Number of subjects
    		 11 11 10 9 41
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 9 8 8 7 32
        From 65-84 years
    		 2 3 2 2 9
        85 years and over
    		 0 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 1 5 1 5 12
        Male
    		 10 6 9 4 29
    underlying disease
    Units: Subjects
        Chronic Glomerulonephritis
    		 3 2 5 3 13
        Diabetes-Adult type
    		 2 1 0 0 3
        Polycystic
    		 3 2 1 1 7
        Hypertensive Nephropathy
    		 0 0 1 0 1
        Hemolytic Uremic Syndrome
    		 0 1 0 0 1
        Pyelonephritis
    		 0 1 0 0 1
        IgA Nephropathy
    		 0 1 1 0 2
        Reflux Nephropathy
    		 0 1 0 1 2
        Alport Syndrome
    		 0 0 1 0 1
        Interstitial Nephritis
    		 0 0 0 1 1
        Immune Complex Nephritis
    		 0 0 0 1 1
        Other
    		 3 2 1 2 8
    Age at conservation
    Units: years
        arithmetic mean (standard deviation)
    		 53.83 ± 13.14 55.49 ± 13.88 50.79 ± 12.84 57.58 ± 14.06 -
    Time after transplant
    Units: years
        arithmetic mean (standard deviation)
    		 6.53 ± 5.75 10.15 ± 4.06 7.82 ± 5.07 10.33 ± 4.69 -
    Creatinine
    Units: mg/dl
        arithmetic mean (standard deviation)
    		 2.68 ± 0.75 1.68 ± 0.48 1.99 ± 0.35 1.11 ± 0.29 -
    Proteinuria
    Units: mg/l
        arithmetic mean (standard deviation)
    		 155.5 ± 104.6 268.9 ± 280.2 193.0 ± 180.1 118.2 ± 57.7 -

    End points

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    End points reporting groups
    Reporting group title
    CNI conversion
    Reporting group description
    		 Patients on a CNI-based therapy for more than 3 months, who have signs of CNI- related toxicity or intolerance and are converted due to clinical indication to a CNI-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Reporting group title
    mTORi conversion
    Reporting group description
    		 Patients on a mTORi-based therapy for more than 3 months, who have signs ofmTORi related toxicity or intolerance and are converted due to clinical indication to a mTORi-free immunosuppression with Belatacept. Patients received belatacept 5 mg/kg on baseline (day 0), week 2 (day 14), week 4 (day 28), week 6 (day 42), and week 8 (day 56), and then every 4 weeks thereafter until completion of the trial. In addition, immunosuppressive co-medication of steroids and Mycophenolate was continued unchanged in all study patients.

    Reporting group title
    CNI control
    Reporting group description
    		 matched-control patients who remain on their current immunosuppression regimen.

    Reporting group title
    mTORi control
    Reporting group description
    		 matched-control patients who remain on their current immunosuppression regimen.

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Comparison between baseline and monthly changes

    Primary: Change of plasma cell levels

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    End point title
    		 Change of plasma cell levels
    End point description
    We analysed CD4+ T cell frequency and absolute numbers by TBNK Kit (BD Bioscience). We found no significant changes in CD4+ T cell frequency after CNI (Figure 4A) or mTORi (Figure 4B) conversion to belatacept compared to BL at M1 (CNI: p=0.799, mTORi: p=0.646), M3 (CNI: p=0.477, mTORi: p=0.859), M6 (CNI: p=0.333, mTORi: p=0.678) and compared to the matched- CNI or mTORi control group. No differences were observed after conversion to belatacept at M3 (p=0.314) and M6 (p=0.859) comparing to pre-conversion or matched CNI control. The CD4+ absolute numbers were not significantly different after conversion to belatacept from mTORi-treated (Figure 4D) at M1, 3, 6 compared to pre-conversion and the matched mTORi controls
    End point type
    Primary
    End point timeframe
    from baseline to 6 months
    End point values
    		 CNI conversion mTORi conversion CNI control mTORi control Baseline
    Number of subjects analysed
    11
    11
    10
    9
    10
    Units: µl
    arithmetic mean (standard deviation)
        1 months
    577.42 ± 260.61
    0 ± 0
    0 ± 0
    0 ± 0
    740.11 ± 319.87
    Attachments
    		 Frequency and absolute numbers of CD4+ T cells
    Statistical analysis title
    		 Change of the plasma cells levels
    Comparison groups
    CNI conversion v Baseline
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: change of biomarkers of the humoral and cellular immune system: T-Helper (Th1 and Th2

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    End point title
    		 change of biomarkers of the humoral and cellular immune system: T-Helper (Th1 and Th2
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 CNI conversion mTORi conversion CNI control mTORi control
    Number of subjects analysed
    11
    11
    10
    9
    Units: Cell/µl
    arithmetic mean (full range (min-max))
        Baseline
    70 (17 to 105)
    50 (25 to 58)
    264 (228 to 723)
    236 (137 to 519)
        Month 12
    25 (10 to 88)
    29 (15 to 31)
    299 (200 to 529)
    153 (61 to 241)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    overall trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    CNI_control-group
    Reporting group description
    		 CNI_control patients were matched by identical baseline immunosuppression, age (+/- 10 years), gender, renal function (+/- 1.5mg/dl creatinine) and time post-transplant (+/- 10 years) Controls were investigated at 3 time points over a 6-month period with a careful documentation of clinical follow-up.

    Reporting group title
    CNI-to-belatacept
    Reporting group description
    		 Renal transplantation patients were converted because of clinical reasons in context of CNI-related toxicity or intolerance with a clinical indication of conversion to CNI-free therapy with belatacept.

    Reporting group title
    mTORi_control group
    Reporting group description
    		 mTORi_control patients were matched by identical baseline immunosuppression, age (+/- 10 years), gender, renal function (+/- 1.5mg/dl creatinine) and time post-transplant (+/- 10 years) Controls were investigated at 3 time points over a 6-month period with a careful documentation of clinical follow-up.

    Reporting group title
    mTORi-to-belatacept
    Reporting group description
    		 Renal transplantation patients were converted because of clinical reasons in context of mTORi-related toxicity or intolerance with a clinical indication of conversion to mTORi-free therapy with belatacept.

    Serious adverse events
    		 CNI_control-group CNI-to-belatacept mTORi_control group mTORi-to-belatacept
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 11 (27.27%)
    6 / 10 (60.00%)
    6 / 9 (66.67%)
    8 / 10 (80.00%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoma of kidney
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    middle hand bone fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fracture wrist. Re
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Claudicatio re
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PAVK (periphere Arterien.. Ateriosklerose)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronay ateriosklerosos
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    edema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    3 / 9 (33.33%)
    5 / 10 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aneurysma spurium (re femoral)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    myocardinfarct and death
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    syncope
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    virale panureitis, left
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastroenteritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bloody stool
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    erysipel
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute renal failure
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    akute TX failure
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    detcorntion of graft function
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    blockade brachialis re.
    Additional description: (suspicion)
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia (atypical)
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastrointestinal infect
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    VHF
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    UTI
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlegmone Dig II (re hand)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    acute gout attack
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 CNI_control-group CNI-to-belatacept mTORi_control group mTORi-to-belatacept
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    10 / 10 (100.00%)
    6 / 9 (66.67%)
    10 / 10 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamos cellcarcinom in situ
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    arterial hypertension (Worsening)
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Edema
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 10 (50.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    7
    0
    0
    Surgical and medical procedures
    Verrucas on foot
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    common cold
         subjects affected / exposed
    4 / 11 (36.36%)
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    3 / 10 (30.00%)
         occurrences all number
    4
    3
    2
    3
    cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    night sweat
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Reproductive system and breast disorders
    swelling of testicle (left) Hoden
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    1
    0
    3
    respiartory infection, upper airway
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    0
    2
    Investigations
    Vit D deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    GGT increase
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    lack of Vit B1
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    PSA increasing (suspected)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    thrombopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    weight increase
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    wound (footpad)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Cardiac disorders
    VHF
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    lumbago
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    hyperuricemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    hypocalcemia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    1 / 9 (11.11%)
    2 / 10 (20.00%)
         occurrences all number
    0
    2
    1
    2
    PAVK
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    2
    Ear and labyrinth disorders
    sudden deafness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    tinitus, left
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    conjunctivitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    hyosphagma eye left
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    cataract
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoe
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    2
    0
    0
    abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    bloody stool
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    stomach pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    excanthem
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    exzision nävus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Itching
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    pyoderma face skin
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    acne dermatitis (worsening)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    acne pustulara
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Alopezia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    hair loss
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    aggravation proteinuria
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    back pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    heel spurs
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    neck pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    aphthae, Oral blood blister
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    0
    1
    bursitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    2
    denditis left underleg
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    herpes infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    2
    0
    1
    Herpes lapiales
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 10 (20.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Laryngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Polyposis nasi
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    sinusitis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    suspicion of tendonitis left
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    swollen/pain ankle
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    UTI
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 10 (20.00%)
    2 / 9 (22.22%)
    2 / 10 (20.00%)
         occurrences all number
    1
    3
    2
    3
    oral trush
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    sore throat
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    swollen left forearm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    tooth disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperkalimie
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    metabolic acidose
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    azidosis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    hypophosphatemia
    Additional description: (<0.5 mmol/l)
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 9 (11.11%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    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.
    -limited data available in the literature to date -data would have to be validated with higher numbers of patients (for power calculation) -extention with analyses of cytokine production or proliferation capacity of different cell types
    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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