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Clinical Trial Details — Status: Active, not recruiting

Administrative data

NCT number NCT02936505
Other study ID # Version 8.0
Secondary ID 154-162015-00413
Status Active, not recruiting
Phase N/A
First received
Last updated
Start date October 12, 2016
Est. completion date October 30, 2026

Study information

Verified date April 2023
Source Vastra Gotaland Region
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


Description:

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.


Recruitment information / eligibility

Status Active, not recruiting
Enrollment 249
Est. completion date October 30, 2026
Est. primary completion date October 30, 2025
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility Inclusion Criteria 1. Male or female lung recipients 18-70 years of age undergoing primary double (including size reduction) lung transplantation. 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. 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 globulin 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. 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Cyclosporine
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.
Mycophenolate mofetil (MMF)
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.
Rabbit Anti thymocyte globulin
Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).
Corticosteroids
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
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.

Locations

Country Name City State
Denmark Rigshospitalet Copenhagen
Finland Helsinki University Hospital Helsinki
Norway Oslo University Hospital Oslo
Sweden Sahlgrenska Univ Hospital Göteborg
Sweden Skåne University Hospital Lund

Sponsors (5)

Lead Sponsor Collaborator
Vastra Gotaland Region Copenhagen University Hospital, Denmark, Helsinki University Central Hospital, Oslo University Hospital, Skane University Hospital

Countries where clinical trial is conducted

Denmark,  Finland,  Norway,  Sweden, 

References & Publications (1)

Dellgren G, Lund TK, Raivio P, Leuckfeld I, Svahn J, Magnusson J, Riise GC. Design and Rationale of a Scandinavian Multicenter Randomized Study Evaluating if Once-Daily Tacrolimus Versus Twice-Daily Cyclosporine Reduces the 3-year Incidence of Chronic Lung Allograft Dysfunction After Lung Transplantation (ScanCLAD Study). Adv Ther. 2020 Mar;37(3):1260-1275. doi: 10.1007/s12325-020-01224-1. Epub 2020 Jan 28. — View Citation

Outcome

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