Clinical Study Evaluating Two Treatment Protocols for Immunosuppressive Drugs. Looking at 3-year Incidence of CLAD.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lung Transplantation, Allografts

Intervention / Treatment
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* Drug: Cyclosporine
* Drug: Mycophenolate mofetil (MMF)
* Drug: Rabbit Anti thymocyte globulin
* Drug: Corticosteroids
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female lung recipients 18-70 years of age undergoing primary double (including size reduction) lung transplantation. 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. Exclusion Criteria Recipients of multiorgan transplant, and or previously transplanted with any organ, including previous lung transplantation. Patients with hypersensitivity to, or other reasons to not be able to take the immunosuppressive drugs used in the study. Donor lung cold ischemic time > 12 hours. Patients who previously have been treated with anti-thymocyte globulin preparations (e.g. ATG-Fresenius®, Thymoglobulin®). Patients who are recipients of ABO-incompatible transplants. Patients with platelet count < 50,000/mm3 at the evaluation before transplantation. Patients who are unlikely to comply with the study requirements. Patients, and/or those receiving organs from donors, who are positive for HIV, Hepatitis B surface antigen or Hepatitis C virus. Patients with donor greater than 75 years. 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. Patient unable to participate in the study for the full 36-month period Patients with any past (within the past 3-5 years) or present malignancy (other than excised basal cell carcinoma). Females capable of becoming pregnant must have a negative pregnancy test prior to randomization. Females are recommended to practice a medically approved method of birth control for the duration of the study and a period of 8 weeks following discontinuation of study medication, even where there has been a history of infertility

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A:Cyclosporine<br>Group A: Cyclosporine A, Mycophenolate mofetil (MMF) and corticosteroids according to local practice and approved label. | Drug: Cyclosporine<br>* 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.<br>* Other names: Sandimmun Neural;Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: Cellcept;Drug: Rabbit Anti thymocyte globulin<br>* Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).<br>* Other names: Thymoglobulin®;Drug: Corticosteroids<br>* 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.<br>* Other names: Methylprednisolon;|
| Experimental: Arm B:Tacrolimus<br>Group B: Tacrolimus (Advagraf), Mycophenolate mofetil (MMF) and corticosteroids. | Drug: Mycophenolate mofetil (MMF)<br>* 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.<br>* Other names: Cellcept;Drug: Rabbit Anti thymocyte globulin<br>* Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).<br>* Other names: Thymoglobulin®;Drug: Corticosteroids<br>* 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.<br>* Other names: Methylprednisolon;Drug: Tacrolimus<br>* 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.<br>* Other names: Advagraf®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 72 months is outcome for continuation study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular Filtration Rate | Renal function evaluated by measured glomerular filtration rate | 3 months | 
| Primary graft dysfunction | Cumulative incidence of primary graft dysfunction | 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 | 12 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 | 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 | 36 months | 
| Incidence of primary graft dysfunction | cumulative incidence of primary graft dysfunction | 72 hours | 
| Patient survival | Patient survival | 1 year | 
| Patient survival | Patient survival | 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. | 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. | 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. | 3 year | 
| Cumulative incidence of BOS and RAS | The cumulative incidence of BOS and RAS | 6 months | 
| Cumulative incidence of BOS and RAS | The cumulative incidence of BOS and RAS | 1 year | 
| Cumulative incidence of BOS and RAS | The cumulative incidence of BOS and RAS | 3 year | 
| Development of donor specific antibodies | Development of donor specific antibodies (DSA) according to specific protocol. | 12 months | 
| Development of donor specific antibodies | Development of donor specific antibodies (DSA) according to specific protocol. | 24 months | 
| Development of donor specific antibodies | Development of donor specific antibodies (DSA) according to specific protocol. | 36 months | 
| Renal function mGFR | Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance. | 12 months | 
| Renal function mGFR | Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance. | 24 months | 
| Renal function mGFR | Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance. | 36 months | 
| Renal function cGFR | Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas. | 3 months | 
| Renal function cGFR | Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas. | 12 months | 
| Renal function cGFR | Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas. | 24 months | 
| Renal function cGFR | Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas. | 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. | 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. | 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. | 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. | 36 months | 
| Antidiabetic medication | Use of antidiabetic medication | 6 months | 
| Antidiabetic medication | Use of antidiabetic medication | 12 months | 
| Antidiabetic medication | Use of antidiabetic medication | 24 months | 
| Antidiabetic medication | Use of antidiabetic medication | 36 months | 
| Antihypertensive and lipid lowering drugs | Incidence and number of antihypertensive and lipid lowering drug | 12 months | 
| Antihypertensive and lipid lowering drugs | Incidence and number of antihypertensive and lipid lowering drug | 24 months | 
| Antihypertensive and lipid lowering drugs | Incidence and number of antihypertensive and lipid lowering drug | 36 months | 
| Proteinuria | Development and magnitude of proteinuria | 12 months | 
| Proteinuria | Development and magnitude of proteinuria | 24 months | 
| Proteinuria | Development and magnitude of proteinuria | 36 months | 
| Lipid profile | Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c) | 12 months | 
| Lipid profile | Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c) | 24 months | 
| Lipid profile | Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c) | 36 months | 
| Cytomegalovirus | Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome). | 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. | 36 months | 
| Safety and tolerability | Safety and tolerability | 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) | 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. | 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). | 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. | 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). | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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). | 0-36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic lung allograft dysfunction, cyclosporin, tacrolimus, Bronchiolitis Obliterans Syndrome, Restrictive Allograft Syndrome, CLAD, immunization, renal function, survival