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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

Tracking Information
First Submitted Date  ICMJE October 15, 2016
First Posted Date  ICMJE October 18, 2016
Last Update Posted Date October 23, 2018
Actual Study Start Date  ICMJE October 2016
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02936505 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2016)
  • Glomerular Filtration Rate [ Time Frame: 3 months ]
    Renal function evaluated by measured glomerular filtration rate
  • Primary graft dysfunction [ Time Frame: 72 hours ]
    Cumulative incidence of primary graft dysfunction
  • 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
  • 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
  • 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
  • Incidence of primary graft dysfunction [ Time Frame: 72 hours ]
    cumulative incidence of primary graft dysfunction
  • Patient survival [ Time Frame: 1 year ]
    Patient survival
  • Patient survival [ Time Frame: 3 year ]
    Patient survival
  • 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.
  • 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.
  • 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.
  • Cumulative incidence of BOS and RAS [ Time Frame: 6 months ]
    The cumulative incidence of BOS and RAS
  • Cumulative incidence of BOS and RAS [ Time Frame: 1 year ]
    The cumulative incidence of BOS and RAS
  • Cumulative incidence of BOS and RAS [ Time Frame: 3 year ]
    The cumulative incidence of BOS and RAS
  • Development of donor specific antibodies [ Time Frame: 12 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.
  • Development of donor specific antibodies [ Time Frame: 24 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.
  • Development of donor specific antibodies [ Time Frame: 36 months ]
    Development of donor specific antibodies (DSA) according to specific protocol.
  • Renal function mGFR [ Time Frame: 12 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
  • Renal function mGFR [ Time Frame: 24 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
  • Renal function mGFR [ Time Frame: 36 months ]
    Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance.
  • Renal function cGFR [ Time Frame: 3 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
  • Renal function cGFR [ Time Frame: 12 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
  • Renal function cGFR [ Time Frame: 24 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
  • Renal function cGFR [ Time Frame: 36 months ]
    Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different Formulas.
  • 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.
  • 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.
  • 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.
  • 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.
  • Antidiabetic medication [ Time Frame: 6 months ]
    Use of antidiabetic medication
  • Antidiabetic medication [ Time Frame: 12 months ]
    Use of antidiabetic medication
  • Antidiabetic medication [ Time Frame: 24 months ]
    Use of antidiabetic medication
  • Antidiabetic medication [ Time Frame: 36 months ]
    Use of antidiabetic medication
  • Antihypertensive and lipid lowering drugs [ Time Frame: 12 months ]
    Incidence and number of antihypertensive and lipid lowering drug
  • Antihypertensive and lipid lowering drugs [ Time Frame: 24 months ]
    Incidence and number of antihypertensive and lipid lowering drug
  • Antihypertensive and lipid lowering drugs [ Time Frame: 36 months ]
    Incidence and number of antihypertensive and lipid lowering drug
  • Proteinuria [ Time Frame: 12 months ]
    Development and magnitude of proteinuria
  • Proteinuria [ Time Frame: 24 months ]
    Development and magnitude of proteinuria
  • Proteinuria [ Time Frame: 36 months ]
    Development and magnitude of proteinuria
  • Lipid profile [ Time Frame: 12 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
  • Lipid profile [ Time Frame: 24 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
  • Lipid profile [ Time Frame: 36 months ]
    Lipid profile (Total cholesterol, LDL-cholesterol, HDL-cholesterol, Triglycerides, TSH, T4, HbA1c)
  • Cytomegalovirus [ Time Frame: 0-36 months ]
    Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
  • 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.
  • Safety and tolerability [ Time Frame: 0-36 months ]
    Safety and tolerability
  • Quality of life [ Time Frame: 12 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)
  • Quality of life [ Time Frame: 24 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)
  • Quality of life [ Time Frame: 36 months ]
    Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ)
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Study Evaluating Two Treatment Protocols for Immunosuppressive Drugs. Looking at 3-year Incidence of CLAD.
Official Title  ICMJE 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
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lung Transplantation
  • Allografts
Intervention  ICMJE
  • 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.
  • 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®
Study Arms  ICMJE
  • Active Comparator: Arm A:Cyclosporine
    Group A: Cyclosporine A, Mycophenolate mofetil (MMF) and corticosteroids according to local practice and approved label.
    Interventions:
    • Drug: Cyclosporine
    • Drug: Mycophenolate mofetil (MMF)
    • Drug: Rabbit Anti thymocyte globulin
    • Drug: Corticosteroids
  • Experimental: Arm B:Tacrolimus
    Group B: Tacrolimus (Advagraf), Mycophenolate mofetil (MMF) and corticosteroids.
    Interventions:
    • Drug: Mycophenolate mofetil (MMF)
    • Drug: Rabbit Anti thymocyte globulin
    • Drug: Corticosteroids
    • Drug: Tacrolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 17, 2016)
242
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2023
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Göran Dellgren, MD, PhD +46 70 4203680 goran.dellgren@vgregion.se
Contact: Gerdt Riise, MD, PhD +46 70 4246062 gerdt.riise@vgregion.se
Listed Location Countries  ICMJE Denmark,   Finland,   Norway,   Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02936505
Other Study ID Numbers  ICMJE Version 6.0
154-16 ( Other Identifier: EC, Gothenburg, Sweden )
2015-004137-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Göran Dellgren, Vastra Gotaland Region
Study Sponsor  ICMJE Vastra Gotaland Region
Collaborators  ICMJE
  • Oslo University Hospital
  • Helsinki University Central Hospital
  • Skane University Hospital
  • Copenhagen University Hospital, Denmark
Investigators  ICMJE
Study Chair: Göran Dellgren, MD, PhD Sahlgrenska Univ Hospital
PRS Account Vastra Gotaland Region
Verification Date November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP