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

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ClinicalTrials.gov Identifier: NCT02936505
Recruitment Status : Recruiting
First Posted : October 18, 2016
Last Update Posted : October 23, 2018
Sponsor:
Collaborators:
Oslo University Hospital
Helsinki University Central Hospital
Skane University Hospital
Copenhagen University Hospital, Denmark
Information provided by (Responsible Party):
Göran Dellgren, Vastra Gotaland Region

Brief 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.

Condition or disease Intervention/treatment Phase
Lung Transplantation Allografts Drug: Cyclosporine Drug: Mycophenolate mofetil (MMF) Drug: Rabbit Anti thymocyte globulin Drug: Corticosteroids Drug: Tacrolimus Not Applicable

Detailed 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 242 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 2016
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A:Cyclosporine
Group A: Cyclosporine A, Mycophenolate mofetil (MMF) and corticosteroids according to local practice and approved label.
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.

Drug: 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.


Drug: Rabbit Anti thymocyte globulin
Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).
Other Name: Thymoglobulin®

Drug: 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.

Experimental: Arm B:Tacrolimus
Group B: Tacrolimus (Advagraf), Mycophenolate mofetil (MMF) and corticosteroids.
Drug: 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.


Drug: Rabbit Anti thymocyte globulin
Induction therapy: Thymoglobulin® (Rabbit Anti thymocyte globulin)(1.5 mg/kg given immediately postoperatively).
Other Name: Thymoglobulin®

Drug: 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.

Drug: 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.
Other Name: Advagraf®




Primary Outcome Measures :
  1. Number of patients with incidence of CLAD [ Time Frame: 36 months ]
    The cumulative incidence of CLAD (including both BOS and RAS, as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation.


Secondary Outcome Measures :
  1. Glomerular Filtration Rate [ Time Frame: 3 months ]
    Renal function evaluated by measured glomerular filtration rate

  2. Primary graft dysfunction [ Time Frame: 72 hours ]
    Cumulative incidence of primary graft dysfunction

  3. Composite measure of freedom from AR, CLAD, graft and patient survival [ Time Frame: 12 months ]
    Composite measure of freedom from AR, CLAD, graft survival, and patient survival

  4. Composite measure of freedom from AR, CLAD, graft and patient survival [ Time Frame: 24 months ]
    Composite measure of freedom from AR, CLAD, graft survival, and patient

  5. Composite measure of freedom from AR, CLAD, graft and patient survival [ Time Frame: 36 months ]
    Composite measure of freedom from AR, CLAD, graft survival, and patient

  6. Incidence of primary graft dysfunction [ Time Frame: 72 hours ]
    cumulative incidence of primary graft dysfunction

  7. Patient survival [ Time Frame: 1 year ]
    Patient survival

  8. Patient survival [ Time Frame: 3 year ]
    Patient survival

  9. Cumulative incidence of acute allograft rejection and CLAD [ Time Frame: 6 months ]
    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.

  10. Cumulative incidence of acute allograft rejection and CLAD [ Time Frame: 1 year ]
    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.

  11. Cumulative incidence of acute allograft rejection and CLAD [ Time Frame: 3 year ]
    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.

  12. Cumulative incidence of BOS and RAS [ Time Frame: 6 months ]
    The cumulative incidence of BOS and RAS

  13. Cumulative incidence of BOS and RAS [ Time Frame: 1 year ]
    The cumulative incidence of BOS and RAS

  14. Cumulative incidence of BOS and RAS [ Time Frame: 3 year ]
    The cumulative incidence of BOS and RAS

  15. Development of donor specific antibodies [ Time Frame: 12 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.

  16. Development of donor specific antibodies [ Time Frame: 24 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.

  17. Development of donor specific antibodies [ Time Frame: 36 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.

  18. Renal function mGFR [ Time Frame: 12 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.

  19. Renal function mGFR [ Time Frame: 24 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.

  20. Renal function mGFR [ Time Frame: 36 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.

  21. Renal function cGFR [ Time Frame: 3 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.

  22. Renal function cGFR [ Time Frame: 12 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.

  23. Renal function cGFR [ Time Frame: 24 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.

  24. Renal function cGFR [ Time Frame: 36 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.

  25. Post Transplantation Diabetes Mellitus [ Time Frame: 6 months ]

    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.


  26. Post Transplantation Diabetes Mellitus [ Time Frame: 12 months ]

    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.


  27. Post Transplantation Diabetes Mellitus [ Time Frame: 24 months ]

    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.


  28. Post Transplantation Diabetes Mellitus [ Time Frame: 36 months ]

    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.


  29. Antidiabetic medication [ Time Frame: 6 months ]
    Use of antidiabetic medication

  30. Antidiabetic medication [ Time Frame: 12 months ]
    Use of antidiabetic medication

  31. Antidiabetic medication [ Time Frame: 24 months ]
    Use of antidiabetic medication

  32. Antidiabetic medication [ Time Frame: 36 months ]
    Use of antidiabetic medication

  33. Antihypertensive and lipid lowering drugs [ Time Frame: 12 months ]
    Incidence and number of antihypertensive and lipid lowering drug

  34. Antihypertensive and lipid lowering drugs [ Time Frame: 24 months ]
    Incidence and number of antihypertensive and lipid lowering drug

  35. Antihypertensive and lipid lowering drugs [ Time Frame: 36 months ]
    Incidence and number of antihypertensive and lipid lowering drug

  36. Proteinuria [ Time Frame: 12 months ]
    Development and magnitude of proteinuria

  37. Proteinuria [ Time Frame: 24 months ]
    Development and magnitude of proteinuria

  38. Proteinuria [ Time Frame: 36 months ]
    Development and magnitude of proteinuria

  39. Lipid profile [ Time Frame: 12 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)

  40. Lipid profile [ Time Frame: 24 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)

  41. Lipid profile [ Time Frame: 36 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)

  42. Cytomegalovirus [ Time Frame: 0-36 months ]
    Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).

  43. Malignancy stratified by post-transplant lymphoproliferative disorder (PTLD) and all other cancers. [ Time Frame: 36 months ]
    Cumulative incidence of malignancy stratified by post-transplant lymphoproliferative disorder (PTLD) and all other cancers.

  44. Safety and tolerability [ Time Frame: 0-36 months ]
    Safety and tolerability

  45. Quality of life [ Time Frame: 12 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)

  46. Quality of life [ Time Frame: 24 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)

  47. Quality of life [ Time Frame: 36 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)

  48. Pharmacokinetics [ Time Frame: week 4 ]
    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.

  49. Pharmacokinetics [ Time Frame: 6 months ]
    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.

  50. Immunological equipotency of tacrolimus and cyclosporine A [ Time Frame: 0-36 months ]
    Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro, according to separate protocol.

  51. Occurrence of treatment failures [ Time Frame: 0-36 months ]
    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).

  52. Recovery of right heart function [ Time Frame: 0-36 months ]
    Recovery of right heart function irrespective of diagnosis in patients with pulmonary arterial hypertension (PAH, categories 1-5 according to WHO 1-5).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02936505


Contacts
Layout table for location contacts
Contact: Göran Dellgren, MD, PhD +46 70 4203680 goran.dellgren@vgregion.se
Contact: Gerdt Riise, MD, PhD +46 70 4246062 gerdt.riise@vgregion.se

Locations
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Denmark
Rigshospitalet Recruiting
Copenhagen, Denmark
Contact: Thomas Kromann Lund, MD         
Finland
Helsinki University Hospital Recruiting
Helsinki, Finland
Contact: Peter Raivio, MD         
Norway
Oslo University Hospital Recruiting
Oslo, Norway
Contact: Inga Leukfeldt, MD         
Sweden
Sahlgrenska Univ Hospital Recruiting
Göteborg, Sweden
Contact: Göran Dellgren, MD         
Principal Investigator: Gerdt Riise, MD         
Skåne University Hospital Recruiting
Lund, Sweden
Contact: Johan Svahn, MD, PhD         
Sponsors and Collaborators
Vastra Gotaland Region
Oslo University Hospital
Helsinki University Central Hospital
Skane University Hospital
Copenhagen University Hospital, Denmark
Investigators
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Study Chair: Göran Dellgren, MD, PhD Sahlgrenska Univ Hospital

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Responsible Party: Göran Dellgren, MD, PhD, Vastra Gotaland Region
ClinicalTrials.gov Identifier: NCT02936505     History of Changes
Other Study ID Numbers: Version 6.0
154-16 ( Other Identifier: EC, Gothenburg, Sweden )
2015-004137-27 ( EudraCT Number )
First Posted: October 18, 2016    Key Record Dates
Last Update Posted: October 23, 2018
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Göran Dellgren, Vastra Gotaland Region:
chronic lung allograft dysfunction
cyclosporin
tacrolimus
Bronchiolitis Obliterans Syndrome
Restrictive Allograft Syndrome
CLAD
Additional relevant MeSH terms:
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Cyclosporine
Mycophenolic Acid
Tacrolimus
Cyclosporins
Thymoglobulin
Antilymphocyte Serum
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents