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    Summary
    EudraCT Number:2015-004137-27
    Sponsor's Protocol Code Number:ScanCLAD_1.0(formerVersion_0.1)
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-06-10
    Trial 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 ConcernedDenmark - DHMA
    A.2EudraCT number2015-004137-27
    A.3Full title of the trial
    A Scandinavian controlled, randomized, open-label, and multi-centre study evaluating if once-daily tacrolimus or twice-daily cyclosporin, reduces the 3-year incidence of chronic lung allograft dysfunction after lung transplantation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical study in Scandinavian wherein a once-daily immunosuppresive drug reduces the 3-year incidence of rejection after lung transplantationor, compared with twice-daily drug.
    A.3.2Name or abbreviated title of the trial where available
    ScanCLAD
    A.4.1Sponsor's protocol code numberScanCLAD_1.0(formerVersion_0.1)
    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 SponsorTransplantationscntrum, Sahlgrenska Universitetssjukhuset
    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 supportAstellas Pharma Europe LTD
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGothia Forum
    B.5.2Functional name of contact pointDennis Lindholm
    B.5.3 Address:
    B.5.3.1Street AddressSahlgrenska Universitetssjukhuset, Gröna stråket 12
    B.5.3.2Town/ cityGöteborg
    B.5.3.3Post code413 45
    B.5.3.4CountrySweden
    B.5.4Telephone number+46700823610
    B.5.6E-maildennis.lindholm@vgregion.se
    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 Advagraf (tacrolimus)
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe L.V.
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTACROLIMUS
    D.3.9.1CAS number 104987-11-3
    D.3.9.4EV Substance CodeSUB10797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number0.5 to 5
    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.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.2.1.1.1Trade name Sandimmun Neoral (cyklosporine A)
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Sverige AB
    D.2.1.2Country which granted the Marketing AuthorisationSweden
    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 Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCiclosporin
    D.3.9.3Other descriptive nameCICLOSPORIN A
    D.3.9.4EV Substance CodeSUB129839
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 100
    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
    Recipients of primary bilateral lung transplant allograft
    E.1.1.1Medical condition in easily understood language
    Recipients of primary bilateral lung transplant allograft
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10050433
    E.1.2Term Prophylaxis against lung 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
    To study the cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx).
    E.2.2Secondary objectives of the trial
    To compare the efficacy between treatment regimes by assessing the difference in mGFR, at 3 months.
    The cumulative incidence of PGD at 72 hours.
    Patient survival at 1 and 3 year.
    The cumulative incidence of AR and CLAD at 6 months, 1 and 3 year.
    Number of rejections.
    The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
    The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months.
    Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.
    The cumulative incidence of PTDM at 6, 12, 24 and 36 months after transplantation as defined below;
    Cumulative incidence of Post transplant Diabetes Mellitus at 12, 24 and 36 months.
    Incidence of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
    Development and magnitude of proteinuria at 12, 24 and 36 months.
    Lipid profile at 12, 24 and 36 months.
    Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
    Cumulative incidence of malignancy stratified by PTLD at 36 months.
    Safety and tolerability.
    Quality of life, at 12, 24 and 36 months.
    Define the pharmacokinetics of Tacrolimus in non-CF patients (n=12) and all included CF patients (n=15-20).
    Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro.
    Occurrence of treatment failures up to or at 36 months.
    Recovery of right heart function irrespective of diagnosis in patients with PAH.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Substudy protocol date: 2016-02-15
    1. Donor specific antibodies (DSA) and its relation to CLAD and clinical outcome.
    2. PTDM – and oral glucose test.
    3. Immunological Equipotency of tacrolimus QD and CyA A in vivo and in vitro.
    4. Quality of life assessments.
    5. CMV and its relation to CLAD
    6. CLAD and imaging
    7. Pharmacokinetics of Tacrolimus and Advagraf in non-CF and CF patients.
    8. Recovery of RV failure in PAH
    9. Donor risk factors and its corelation to CLAD and PGD
    10. Molecular biomarkers as potential targets for therapeutic strategies after LTx
    11. LSort – Lung score and gene activation as biomarker of rejection
    12. Waist-to-height (WHtR) as a predictor for CLAD and survival after LTx
    13. Cytokines and inflammatory variables in lung transplantation
    E.3Principal inclusion criteria
    1. Male or female lung recipients 18-70 years of age undergoing primary double (including size reduction) lung Transplantation (LTx).
    2. Patient willing and capable of giving written informed consent for study participation and anticipated to be able to participate in the study for 36 months.
    E.4Principal exclusion criteria
    1. Recipients of multiorgan transplant, and or previously transplanted with any organ, including previous lung transplantation.
    2. Patients with hypersensitivity to, or other reasons to not be able to take the immunosuppressive drugs used in the study.
    3. Donor lung cold ischemic time > 12 hours.
    4. Patients who previously have been treated with anti-thymocyte globuline preparations (e.g. ATG-Fresenius®, Thymoglobulin®).
    5. Patients who are recipients of ABO-incompatible transplants.
    6. Patients with platelet count < 50,000/mm3 at the evaluation before transplantation.
    7. Patients who are unlikely to comply with the study requirements.
    8. Patients, and/or those receiving organs from donors, who are positive for HIV, Hepatitis B surface antigen or Hepatitis C virus.
    9. Patients with donor greater than 75 years.
    10. Patient who have received an unlicensed drug or therapy within one month prior to study entry or if such therapy is to be instituted post-transplantation.
    11. Patient unable to participate in the study for the full 36-month period
    12. Patients with any past (within the past 3-5 years) or present malignancy (other than excised basal cell carcinoma).
    13. Females capable of becoming pregnant must have a negative pregnancy test prior to randomization.
    E.5 End points
    E.5.1Primary end point(s)
    Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx).
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 3 years of treatment with study drug.
    E.5.2Secondary end point(s)
    1. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance at 3 months.
    2. The cumulative incidence of primary graft dysfunction (PGD) at 72 hours.
    3. Patient survival at 1 and 3 year.
    4. The cumulative incidence of acute allograft rejection (AR) and CLAD at 6 months, 1 and 3 year.
    5. Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL).
    6. Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
    7. The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
    8. The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months after transplantation. The diagnosis of AR will be based on either clinical signs or histological biopsy confirmation using the ISHLT Working Classification of Lung Transplant Pathology.
    9. Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
    10. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
    11. Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.
    12. The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) at 6, 12, 24 and 36 months after transplantation as defined below;
    o Cumulative incidence of:
     ≥2 Fasting Plasma Glucose (FPG) ≥7,0 mmol/L ≥ 30 consecutive days apart.
     Oral hypoglycaemic treatment ≥30 consecutive days.
     Insulin ≥30 consecutive days.
     HgbA1c ≥6.5% (according to American Diabetes Association – ADA)
     Symptoms of Diabetes and Random Plasma Glucose (RPG) ≥ 11.1 mmol/L.
     2-hour Plasma Glucose (2-hPG) ≥ 11.1 mmol/L during an oral glucose tolerance test (OGTT).
    13. Use of antidiabetic medication at 6, 12, 24 and 36 months.
    14. Incidence and number of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
    15. Development and magnitude of proteinuria at 12, 24 and 36 months.
    16. Lipid profile at 12, 24 and 36 months.
    17. Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
    18. Cumulative incidence of malignancy stratified by PTLD and all other at 36 months.
    19. Safety and tolerability.
    20. Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ), both self-administered, at 12, 24 and 36 months.
    21. Define the pharmacokinetics of Tacrolimus in non-CF patients (n=12) and all included CF patients (n=15-20) undergoing primary lung transplantation (LTx) treated with an Advagraf® based-immunosuppression.
    22. Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro, according to separate protocol.
    23. Occurrence of treatment failures up to or at 36 months; defined as a composite endpoint of graft loss, death, loss to follow up or discontinuation due to lack of efficacy or toxicity (at least one condition must be present).
    24. Recovery of right heart function irrespective of diagnosis in patients with pulmonary arterial hypertension (PAH, categories 1-5 according to WHO 1-5).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Se above (E.5.2)
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence Yes
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    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 Yes
    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 years5
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    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: 222
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 242
    F.4.2.2In the whole clinical trial 242
    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)
    Since lifelong CNI treatment after lung transplantation is needed investigators will discuss following treatment with the patient in quesion.
    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 Decision2016-08-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-24
    P. End of Trial
    P.End of Trial StatusOngoing
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