A controlled randomized, open-label, multi-centre study evaluating if an immunosuppressive protocol, based on ATG-induction, once daily tacrolimus-dose (Advagraf®), mycophenolate mofetil and corticosteroid reduces the incidence of chronic lung allograft dysfunction (CLAD) after lung transplantation, in comparison with a standard cyclosporin-based protocol.
Study purpose: To evaluate whether the use of a once-daily tacrolimus-dose regimen (Advagraf®), based on anti-thymocyte globulin (Thymoglobulin®) induction, mycophenolate mofetil (MMF) and corticosteroids, reduces the cumulative incidence of CLAD after de novo lung transplantation at 36 months, in comparison with a twice-daily cyclosporin-based protocol, otherwise identical between groups.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
249
Cyclosporin A (Sandimmun Neoral® or similar): * Cyclosporin A given orally pretransplant in the dose of 2-3 mg/kg. * Continued postop day 1 in the dose of 3mg/kgx2, according to local practice and blood concentration: 0-3 months 250-300; 3-6 months 200-250; 6-12 months 150-200; \>12 months 100-150 ng/ml. Cyclosporine A will be administered twice daily.
MMF target dose: 2000 mg/day (1gx2): o Controlled by a single Area Under the Curve (AUC) measurement day 90 with a target AUC between 40 and 60 mg.h/L and corrected accordingly.
Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).
Rigshospitalet
Copenhagen, Denmark
Helsinki University Hospital
Helsinki, Finland
Oslo University Hospital
Oslo, Norway
Sahlgrenska Univ Hospital
Gothenburg, Sweden
Skåne University Hospital
Number of patients with incidence of CLAD
The cumulative incidence of CLAD (including both BOS and RAS, as defined in the Appendix II) after lung transplantation.
Time frame: 36 months is primary outcome
Number of patients with incidence of CLAD
The cumulative incidence of CLAD (including both BOS and RAS, as defined by the Appendix II) at 48 months after lung transplantation.
Time frame: 48 months is outcome for the continuation study
Number of patients with incidence of CLAD
The cumulative incidence of CLAD (including both BOS and RAS, as defined by the Appendix II) at 60 months after lung transplantation.
Time frame: 60 months is outcome for continuation study
Number of patients with incidence of CLAD
The cumulative incidence of CLAD (including both BOS and RAS, as defined by the Appendix II) at 72 months after lung transplantation.
Time frame: 72 months is outcome for continuation study
Glomerular Filtration Rate
Renal function evaluated by measured glomerular filtration rate
Time frame: 3 months
Primary graft dysfunction
Cumulative incidence of primary graft dysfunction
Time frame: 72 hours
Composite measure of freedom from AR, CLAD, graft and patient survival
Composite measure of freedom from first event of AR, CLAD, graft survival, and patient survival
Time frame: 12 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Corticosteroids: * Day 0 (day of lung transplantation); 500+500mg methylprednisolone iv. before reperfusion, i.e. restoration of blood flow into the transplanted allograft. * From day 1: Initiated at 0.2 mg/kg/day; tapered to 0.1 mg/kg 3-6 months; less than 0,1 mg/kg \> 6 months.
* Tacrolimus should be given orally pretransplant in the dose of 0.1 mg/kg. * Continued postop day 1 according to local practice and blood concentration: 0-3 months 10-14, 3-6 months 8-12, 6-12 months 8-10, \>12 months 6-8 ng/ml. Tacrolimus will be administered once daily.
Lund, Sweden
Composite measure of freedom from AR, CLAD, graft and patient survival
Composite measure of freedom from first event of AR, CLAD, graft survival, and patient
Time frame: 24 months
Composite measure of freedom from AR, CLAD, graft and patient survival
Composite measure of freedom from first event of AR, CLAD, graft survival, and patient
Time frame: 36 months
Incidence of primary graft dysfunction
cumulative incidence of primary graft dysfunction
Time frame: 72 hours
Patient survival
Patient survival
Time frame: 1 year
Patient survival
Patient survival
Time frame: 3 year
Cumulative incidence of acute allograft rejection and CLAD
The cumulative incidence of acute allograft rejection (AR) and CLAD. - Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL). - Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
Time frame: 6 months
Cumulative incidence of acute allograft rejection and CLAD
The cumulative incidence of acute allograft rejection (AR) and CLAD. - Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL). - Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
Time frame: 1 year
Cumulative incidence of acute allograft rejection and CLAD
The cumulative incidence of acute allograft rejection (AR) and CLAD. - Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL). - Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
Time frame: 3 year
Cumulative incidence of BOS and RAS
The cumulative incidence of BOS and RAS
Time frame: 6 months
Cumulative incidence of BOS and RAS
The cumulative incidence of BOS and RAS
Time frame: 1 year
Cumulative incidence of BOS and RAS
The cumulative incidence of BOS and RAS
Time frame: 3 year
Development of donor specific antibodies
Development of donor specific antibodies (DSA) according to specific protocol.
Time frame: 12 months
Development of donor specific antibodies
Development of donor specific antibodies (DSA) according to specific protocol.
Time frame: 24 months
Development of donor specific antibodies
Development of donor specific antibodies (DSA) according to specific protocol.
Time frame: 36 months
Renal function mGFR
Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
Time frame: 12 months
Renal function mGFR
Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
Time frame: 24 months
Renal function mGFR
Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
Time frame: 36 months
Renal function cGFR
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
Time frame: 3 months
Renal function cGFR
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
Time frame: 12 months
Renal function cGFR
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
Time frame: 24 months
Renal function cGFR
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
Time frame: 36 months
Post Transplantation Diabetes Mellitus
The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) after transplantation as defined below. 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). Baseline OGTT will be performed pre-transplant.
Time frame: 6 months
Post Transplantation Diabetes Mellitus
The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) after transplantation as defined below. 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). Baseline OGTT will be performed pre-transplant.
Time frame: 12 months
Post Transplantation Diabetes Mellitus
The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) after transplantation as defined below. 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). Baseline OGTT will be performed pre-transplant.
Time frame: 24 months
Post Transplantation Diabetes Mellitus
The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) after transplantation as defined below -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). Baseline OGTT will be performed pre-transplant.
Time frame: 36 months
Antidiabetic medication
Use of antidiabetic medication
Time frame: 6 months
Antidiabetic medication
Use of antidiabetic medication
Time frame: 12 months
Antidiabetic medication
Use of antidiabetic medication
Time frame: 24 months
Antidiabetic medication
Use of antidiabetic medication
Time frame: 36 months
Antihypertensive and lipid lowering drugs
Incidence and number of antihypertensive and lipid lowering drug
Time frame: 12 months
Antihypertensive and lipid lowering drugs
Incidence and number of antihypertensive and lipid lowering drug
Time frame: 24 months
Antihypertensive and lipid lowering drugs
Incidence and number of antihypertensive and lipid lowering drug
Time frame: 36 months
Proteinuria
Development and magnitude of proteinuria
Time frame: 12 months
Proteinuria
Development and magnitude of proteinuria
Time frame: 24 months
Proteinuria
Development and magnitude of proteinuria
Time frame: 36 months
Lipid profile
Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
Time frame: 12 months
Lipid profile
Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
Time frame: 24 months
Lipid profile
Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
Time frame: 36 months
Cytomegalovirus
Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
Time frame: 0-36 months
Malignancy stratified by post-transplant lymphoproliferative disorder (PTLD) and all other cancers.
Cumulative incidence of malignancy stratified by post-transplant lymphoproliferative disorder (PTLD) and all other cancers.
Time frame: 36 months
Safety and tolerability
Safety and tolerability
Time frame: 0-36 months
Quality of life assessed by EQ5D Questionnaire
Quality of life, the relative difference over time will be investigated after LTx, where 5 questions are raised and answer is between 11111 (no problems) and 33333 (extreme problems in all dimensions)
Time frame: 12 months
Quality of life assessed by St Georges Respiratory Questionnaire (SGRQ)
Quality of life, the relative difference over time will be investigated after LTx. The SGRQ total score ranges from 0 to 100 where 100 indicates the worst quality of life.
Time frame: 12 months
Quality of life, assessed by EQ5D Questionnaire
Quality of life, the relative difference over time will be investigated after LTx, where 5 questions are raised and answer is between 11111 (no problems) and 33333 (extreme problems in all dimensions).
Time frame: 24 months
Quality of life, assessed by St Georges Respiratory Questionnaire (SGRQ)
Quality of life, the relative difference over time will be investigated after LTx. The SGRQ total score ranges from 0 to 100 where 100 indicates the worst quality of life.
Time frame: 24 months
Quality of life, assessed by EQ5D Questionnaire (SGRQ)
Quality of life, the relative difference over time will be investigated after LTx, where 5 questions are raised and answer is between 11111 (no problems) and 33333 (extreme problems in all dimensions).
Time frame: 36 months
Quality of life, assessed by St Georges Respiratory Questionnaire (SGRQ)
Quality of life, the relative difference over time will be investigated after LTx. The SGRQ total score ranges from 0 to 100 where 100 indicates the worst quality of life.
Time frame: 36 months
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 0h after administration, 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 1h after administration 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 2h after administration 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 3h after administration 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 4h after administration 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 6h after administration 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics (from whole blood concentrations from at 8h after administration and 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics (from whole blood concentrations from at 10h after administration and 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics (from whole blood concentrations at 12h after administration and 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 23h after administration and 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics from whole blood concentrations at 24h after administration and 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.
Time frame: week 4
Pharmacokinetics, of the Tacrolimus drug in patients in the CF sub group population
Define the pharmacokinetics as an AUC construction, 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.
Time frame: week 4
Pharmacokinetics of the Tacrolimus drug in patients in the CF sub group
Define the pharmacokinetics as an AUC construction, 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.
Time frame: 6 months
Immunological equipotency of tacrolimus and cyclosporine A
Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro, according to separate protocol.
Time frame: 0-36 months
Occurrence of treatment failures
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).
Time frame: 0-36 months
Recovery of right heart function
Recovery of right heart function irrespective of diagnosis in patients with pulmonary arterial hypertension (PAH, categories 1-5 according to WHO 1-5).
Time frame: 0-36 months