E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recipients of primary bilateral lung transplant allograft |
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E.1.1.1 | Medical condition in easily understood language |
Recipients of primary bilateral lung transplant allograft |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To study the cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx). |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy between treatment regimes by assessing the difference in mGFR, at 3 months.
The cumulative incidence of PGD at 72 hours.
Patient survival at 1 and 3 year.
The cumulative incidence of AR and CLAD at 6 months, 1 and 3 year.
Number of rejections.
The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months.
Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.
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The cumulative incidence of PTDM at 6, 12, 24 and 36 months after transplantation as defined below;
Cumulative incidence of Post transplant Diabetes Mellitus at 12, 24 and 36 months.
Incidence of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
Development and magnitude of proteinuria at 12, 24 and 36 months.
Lipid profile at 12, 24 and 36 months.
Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
Cumulative incidence of malignancy stratified by PTLD at 36 months.
Safety and tolerability.
Quality of life, at 12, 24 and 36 months.
Define the pharmacokinetics of Tacrolimus in non-CF patients (n=12) and all included CF patients (n=15-20).
Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro.
Occurrence of treatment failures up to or at 36 months.
Recovery of right heart function irrespective of diagnosis in patients with PAH. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy protocol date: 2016-02-15
1. Donor specific antibodies (DSA) and its relation to CLAD and clinical outcome.
2. PTDM – and oral glucose test.
3. Immunological Equipotency of tacrolimus QD and CyA A in vivo and in vitro.
4. Quality of life assessments.
5. CMV and its relation to CLAD
6. CLAD and imaging
7. Pharmacokinetics of Tacrolimus and Advagraf in non-CF and CF patients.
8. Recovery of RV failure in PAH
9. Donor risk factors and its corelation to CLAD and PGD
10. Molecular biomarkers as potential targets for therapeutic strategies after LTx
11. LSort – Lung score and gene activation as biomarker of rejection
12. Waist-to-height (WHtR) as a predictor for CLAD and survival after LTx
13. Cytokines and inflammatory variables in lung transplantation |
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E.3 | Principal inclusion criteria |
1. Male or female lung recipients 18-70 years of age undergoing primary double (including size reduction) lung Transplantation (LTx).
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.
3. Patient that is suitable to receive induction therapy with ATG (Thymoglobulin®).
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E.4 | Principal exclusion criteria |
1. Recipient of multi-organ transplants or previously transplanted organs.
2. Patients with donor greater than 75 years.
3. Donor lung cold ischemic time > 12 hours.
4. Patients who are recipients of ABO incompatible transplants.
5. Patients with platelet count < 50,000/mm3 at the evaluation before transplantation.
6. 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-transplant.
7. Patients with hypersensitivity to, or other reasons to not be able to take the immunosuppressive drugs used in the study.
8. Patients who previously have been treated with anti-thymocyte globuline preparations (e.g. ATG-Fresenius®, Thymoglobulin®).
9. Patient unable to participate in the study for the full 36-month period.
10. Patients with any past (within the past 3-5 years) or present malignancy (other than excised basal cell carcinoma).
11. Females capable of becoming pregnant must have a negative pregnancy test prior to randomization and are recomended 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.
12. Patients who are unlikely to comply with the study requirements.
13. Patients, and/or those receiving organs from donors, who are positive for HIV, Hepatitis B surface antigen or Hepatitis C virus.
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E.5 End points |
E.5.1 | Primary end point(s) |
Cumulative incidence of Chronic Lung Allograft Dysfunction (CLAD) (including both Bronchioloitis Obliterans Syndrome (BOS) and Restrictive Allograft Syndrome (RAS), as defined by the ISHLT-criteria, Appendix II) at 36 months after lung transplantation (LTx). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 3 years of treatment with study drug. |
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E.5.2 | Secondary end point(s) |
1. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance at 3 months.
2. The cumulative incidence of primary graft dysfunction (PGD) at 72 hours.
3. Patient survival at 1 and 3 year.
4. The cumulative incidence of acute allograft rejection (AR) and CLAD at 6 months, 1 and 3 year.
5. Determined by clinical criteria, computed tomography (CT) and trans bronchial lung biopsy with broncho-alveolar lavage (BAL).
6. Number of rejections (cellular and antibody mediated), stratified by biopsy and non-biopsy verified rejections.
7. The cumulative incidence of BOS and RAS at 6 months, 1 and 3 year.
8. The composite measure of freedom from AR, CLAD, graft survival, and patient survival at 12, 24 and 36 months after transplantation. The diagnosis of AR will be based on either clinical signs or histological biopsy confirmation using the ISHLT Working Classification of Lung Transplant Pathology.
9. Development of donor specific antibodies (DSA) at 12, 24 and 36 months, according to specific protocol.
10. Renal function evaluated by measured glomerular filtration rate (mGFR), by Iohexol or Cr-EDTA clearance, at 12, 24 and 36 months.
11. Renal function evaluated by calculated glomerular filtration rate (cGFR), by three different formulas, at 3, 12, 24 and 36 months.
12. The cumulative incidence of Post Transplantation Diabetes Mellitus (PTDM) at 6, 12, 24 and 36 months after transplantation as defined below;
o 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).
13. Use of antidiabetic medication at 6, 12, 24 and 36 months.
14. Incidence and number of antihypertensive and lipid lowering drugs at 12, 24 and 36 months.
15. Development and magnitude of proteinuria at 12, 24 and 36 months.
16. Lipid profile at 12, 24 and 36 months.
17. Incidence of Cytomegalovirus (CMV) that required treatment (CMV-infection and CMV syndrome).
18. Cumulative incidence of malignancy stratified by PTLD and all other at 36 months.
19. Safety and tolerability.
20. Quality of life, assessed by EQ5D and St Georges Respiratory Questionnaire (SGRQ), both self-administered, at 12, 24 and 36 months.
21. 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.
22. Immunological equipotency of tacrolimus once daily (OD) and cyclosporine A twice daily (BiD) in vivo and in vitro, according to separate protocol.
23. 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).
24. Recovery of right heart function irrespective of diagnosis in patients with pulmonary arterial hypertension (PAH, categories 1-5 according to WHO 1-5). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |