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

Lung Transplantation Clinical Trial

— ScanCLAD  

Official title:

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

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
• 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
• 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

Related Conditions & MeSH terms

• Allografts
• Lung Transplantation

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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