| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050433 |
| E.1.2 | Term | Prophylaxis against lung transplant rejection |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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| 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 demonstrate that an everolimus-based, quadruple immunosuppressive regimen has superior efficacy compared with a CNI-based triple immunosuppressive regimen on renal function as measured by cGFR according to CKD EPI at 12 months after randomization in lung transplant recipients. |
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the renal function at Months 1, 3, 6, 9 and 12 after randomization measured by CKD EPI , by Cystatin C-based Hoek’s formula, MDRD and Cockcroft-Gault.
• To evaluate the incidence of patients experiencing a decline in GFR of <10, 10-15, 15-20, 20-25 and ≥25 mL/min from pre-Tx, and randomization to Months 6 and 12.
• To evaluate the incidence of, and time to renal replacement at Months 6 and 12 after randomization.
• To evaluate incidence of acute rejection episodes at Months 6 and 12 after randomization.
• To evaluate the incidence of, and time to progression of Bronchiolitis obliterans syndrome (BOS) at Months 6 and 12 after randomization.
• To evaluate incidence of retransplantation at Months 6 and 12 after randomization.
• To evaluate incidence of death at Months 6 and 12 after randomization.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult recipients of de novo cadaveric lung transplants older than 18 years, 3-18 months prior to enrolment
2. Patients with impaired (mild/moderate) renal function, i.e. GFR >50 and <90mL/min measured by CKD EPI prior inclusion, confirmed by two independent measurements
3. Patients able to take oral medication at time of randomization
4. Patients on a CNI-containing triple immunosuppressive regimen at time of randomization
5. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained
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| E.4 | Principal exclusion criteria |
1. Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant
2. Patients with pre-transplant immunosuppressive CNI- or everolimus containing treatment
3. Patients with renal failure or CKD/ESRD who require renal replacement therapy within 7 days prior to randomization or who required renal replacement therapy for clearance for more than 2 weeks prior to transplantation
4. Patients who are recipients of A-B-O incompatible transplant grafts
5. Patients with any known hypersensitivity to everolimus, mycophenolic acid, tacrolimus, cyclosporine A, steroids, other drugs similar to everolimus (e.g., macrolides), or other components of the formulations (e.g. lactose, see also SmPCs)
6. Patients who have received an investigational drug within 30 days prior to randomization
7. Two episodes of acute rejection that required antibody therapy or more than one steroid sensitive episode of acute rejection in the last 3 months prior to randomization. This includes patients who have not completed steroid treatment for acute rejection within 7 days prior to randomization
8. Patients receiving plasmaphoresis or immunomodulatory antibody treatment within 6 months prior to randomization
9. Patients with thrombocytopenia (platelets <100,000/mm³), with an absolute neutrophil count of <1,500/mm³ or leucopenia (leucocytes <3000/mm³), with anemia with Hb < 8g/dl at time of screening
10. Patients with uncontrolled hypercholesterolemia (>330mg/dL; >9mmol/L) or hypertriglyceridemia (>300 mg/dL; >8.5 mmol/L) at time of screening
11. Patients with a creatinine/protein ratio indicating daily urinary protein excretion >1g/24h at time of randomization
12. Patients with history of thrombotic microangiopathies
13. Patients with history of Burkholderia cepacia complex colonisation
14. Patients with BOS ( > grade 1) at time of randomization
15. Patients with history of inability to maintain to CNI target levels in more than 6 of the last 10 measurements according to investigator’s discretion.
16. Patients with symptoms of significant mental illness and with inability to cooperate or communicate with the investigator. Patients who are unlikely to comply with the study requirements, or who are unable to give informed consent
17. Patients with a history of malignancy of any organ system, treated or untreated, during the last five years, whether or not there is evidence of local recurrence or metastases, except squamous or basal cell carcinoma of the skin
18. Patients who are in a intensive care setting in the last 30 days before randomization
19. Patients who are HIV positive or Hepatitis B surface antigen positive or Hepatitis C (PCR+ only) virus positive
20. Patients with clinically significant systemic infection at time of randomization
21. Females who are pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml))
22. The reproductive-developmental toxicity profile of the study drug, the study design, and the study’s target population will guide the schedule for pregnancy tests to be performed throughout the study.
23. Women who are pregnant or breast feeding
24. Patients, who have already been randomized into this study earlier must not be included a second time
25. Evidence of unsolved drug or alcohol addiction
26. Study personnel or first degree relatives of investigator(s) must not be included in the study
27. Participation in another clinical trial.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is to demonstrate superior renal function under the everolimus-based quadruple immunosuppressive regimen as compared to the triple control regimen. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after randomization |
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| E.5.2 | Secondary end point(s) |
• Renal function at Months 1, 3, 6, 9 and 12 measured by cGFR using the CKD-EPI formula, the MDRD formula, and Hoek’s formula
• Incidence of declines in GFR of <10, 10 – <15, 15 – <20, 20 – <25 and ≥25 mL/min from randomization to Months 6 and 12
• Incidence of, and time to renal replacement therapy at Months 6 and 12 after randomization
• Incidence and severity of acute rejections at Months 6 and 12
• Incidence of graft loss and re-transplantation at Months 6 and 12 (time to retransplantation?)
• Incidence of death at Months 6 and 12
• Incidence of Bronchiolitis obliterans syndrome (BOS) at Months 6 and 12 after randomization
• To evaluate the incidence of bacterial, viral and fungal infections.
• Trough levels and adherence to target ranges of cyclosporine A/tacrolimus/everolimus at Months 1, 3, 6, 9 and 12 after randomization
• Quality of life as measured by SF-36 at Months 6 and 12
• Exercise capacity (6MWT) at Months 6 and 12
• Incidence and time to first onset or escalation of therapy for arterial hypertension or diabetes
• To evaluate cholesterol and triglyceride levels at Month 1, 3, 6, 9 and 12 after randomization.
• Safety and tolerability
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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 | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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