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    Summary
    EudraCT Number:2013-001178-20
    Sponsor's Protocol Code Number:IM103-307
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-03-16
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2013-001178-20
    A.3Full title of the trial
    Cardiovascular (CV) risk prediction and CV biomarkers in renal transplant recipients treated with belatacept compared to calcineurin inhibitors (CNI).

    Open randomized 12 month study.
    Cardiovasculair (CV) risico voorspelling en CV biomarkers in nier transplantatie patiënten met Belatacept in vergelijking met calcineurin remmers (CNIs).

    Open gerandomizeerde studie van 12 maanden.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Does conversion to Nulojix reduce the risk of cardiovascular disease in kidney transplant recipients?
    Verlaagd overstappen naar Nulojix het risico op hart- en vaatziekten bij ontvangers van een niertransplantatie?
    A.4.1Sponsor's protocol code numberIM103-307
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUppsale University Hospital, MHT, Department of Nephrology
    B.1.3.4CountrySweden
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBristol-Meyers Squibb International Corporation
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointKlin. Research Interne Geneeskunde
    B.5.3 Address:
    B.5.3.1Street AddressAlbinusdreef 2
    B.5.3.2Town/ cityLeiden
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715262840
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Nulojix
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Meyers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNulojix
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prophylaxis of graft rejection in adults who have received a renal transplant
    E.1.1.1Medical condition in easily understood language
    Prevention of rejection of transplanted kidneys in adults
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10050436
    E.1.2Term Prophylaxis against renal transplant rejection
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to compare cardiovascular(CV) risk estimated by a renal transplant specific CV calculator in renal transplant recipients (RTR) randomized to belatacept or CNI-based immunosuppression.
    E.2.2Secondary objectives of the trial
    •Comparison of individual components of CV risk in RTR randomized to belatacept (BEL) vs. CNI-based immunosuppression – blood pressure, fasting lipids & glucose and eGFR. •Differences in vascular function measured by EndoPAT in CNI treated patients vs. patients switched to BEL. •Changes in biomarkers of ageing in CNI treated patients vs. patients switched to BEL. Incl. peripheral markers (leukocyte telomere length, CDKN2A) and RNA expression profiling in peripheral blood leukocytes. •Changes in biomarkers associated with CV risk factors in CNI treated patients vs. patients switched to BEL measured by Proximity Ligation Assay, ELISA, multicolored FACS analyses (Dutch sites only), SDF Imaging (Dutch sites only) and miRNA measurements. •Analyses of transplant biopsies in a subset of patients (histology, RNA expression) targeting chronic allograft nephropathy in CNI treated patients vs. patients switched to BEL. •Safety analyses – AEs, mortality, rejection episodes and graft losses.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Signed Written Informed Consent
    2. Target Population:
    2.a Renal transplant recipients of living donor or deceased donor kidney transplant.
    2.b Stable renal graft (eGFR > 20 ml/min) with no need for exploratory examination)
    2.c Tacrolimus or CsA (Cyclosporine A) standard treatment since transplantation
    2.d 3 – 60 months post-transplantation at randomization
    3. Age and Sex:
    3.a Men and women, aged 18 to 80 years, both inclusive
    3.b Women of childbearing potential (WOCBP) must be using adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of study drug to minimize the risk of pregnancy. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post- menopausal. Post-menopause is defined as:
    •Amenorrhea that has lasted for 12 consecutive months without another cause, or
    •For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
    Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (e.g. vasectomy) should be considered to be of childbearing potential.
    WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product (belatacept).
    E.4Principal exclusion criteria
    1. Sex and Reproductive Status:
    1.a Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 8 weeks after the last dose of study drug.
    1.b Women who are pregnant or breastfeeding.
    1.c Women with a positive pregnancy test.
    2. Target Disease Exceptions: Subjects who are Epstein-Barr virus IgG negative or have unknown IgG status for EBV.
    3. Medical History and Concurrent Diseases:
    3.a De novo or recurrent underlying renal disease that, in the investigator's opinion, could adversely influence the current allograft
    3.b History of vascular or antibody-mediated rejection in the present transplant
    3.c Ongoing serious infections, as per investigator's opinion
    3.d Signs of post-transplant lymphoproliferative disorder
    3.e History of tuberculosis
    3.f Signs of malignancy. Exceptions are BCC/SCC or non-malignant melanoma
    3.g History of malignancy, unless subject has been considered to have fully recovered from malignancy since >1 year, without any signs of relapse
    3.h Life expectancy < 3 years at the time of randomization
    4. Allergies and Adverse Drug Reactions:
    4.a Hypersensitivity to belatacept
    4.b Previous/ongoing use of rituximab
    5. Other Exclusion Criteria:
    5.a Prisoners, or subjects who are involuntarily incarcerated.
    5.b Subjects who are compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
    E.5 End points
    E.5.1Primary end point(s)
    The primary end-point is the estimated risk of major adverse cardiovascular events (MACE). The natural logarithm of the estimated CV risk for MACE will be calculated as previously described by Soveri et al. (2012) as a linear function of the following variables: age, previous coronary heart disease, smoking, serum creatinine, diabetes mellitus, LDL-cholesterol and number of transplants.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary endpoint will be a comparison of the log of the estimated CV risk between treatment groups (CNI vs. belatacept based immunosuppression) at one year.

    For patients discontinuing the study before one year, the last available estimate of CV risk will be used in the analysis of the ITT population.
    E.5.2Secondary end point(s)
    The secondary end-points are the comparisons between treatments arms for:
    • individual components of CV risk in RTR: blood pressure, fasting lipid profiles, fasting glucose and eGFR.
    • vascular function measured by EndoPAT.
    • biomarkers of ageing (bio-ageing) in RTR: leukocyte telomere length, CDKN2A levels, leukocyte RNA expression profile.
    • biomarkers for CV risk factors in RTR measured by Proximity Ligation Assay, ELISA, multicoloured FACS analyses (Dutch sites only), SDF Imaging (Dutch sites only) and miRNA measurements
    • renal transplant biopsy IFTA scores (Banff criteria)
    • expression of graft fibrosis markers, and other measures of chronic renal transplant markers in kidney biopsies
    • acute rejection
    • allograft losses
    • CV events occurring during the study, i.e.
    o cardiovascular death (due to myocardial infarction (MCI), heart failure or stroke),
    o non fatal MCI
    o non fatal stroke
    o hospitalization due to congestive heart failure
    o hospitalization due to angina pectoris
    o coronary intervention
    • patient survival
    • safety and tolerability
    E.5.2.1Timepoint(s) of evaluation of this end point
    At one year after randomization or for patients discontinuing the study before one year, the last available data will be used in the analysis of the ITT population.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA7
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    At conclusion of study (visit 15) subjects will revert to routine care at the clinic.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-09-13
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