E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Prophylaxis against lung transplant rejection Clinical experience suggests that individual tailoring of immunosuppression for patients after lung transplantation could potentially optimize patient outcome. |
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E.1.1.1 | Medical condition in easily understood language |
Prophylaxis against lung transplant rejection |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
High dose immunosuppression containing calcineurin-inhibitors (CNI) is the centerpiece of care after lung-transplantation. Dosing is guided by fixed target levels, established to keep the balance between over-dose causing toxicity and increased risk of infections or under-dose with risk of graft-injury. In a prospective, randomized controlled trial with lung-transplanted patients individual tailoring of immunosuppression by a non-invasive biomarker (Torque-Teno-Virus load in whole blood) will be developed and compared to the standard immunosuppressant dosage. Indicator for toxicity will be the glomerular filtration rate (GFR). |
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E.2.2 | Secondary objectives of the trial |
Not applicable see secondary endpoints below |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. patients 21 to 42 days after primary de novo lung transplantation (bilateral including combined) 2. age ≥ 18 years 3. tacrolimus based immunosuppression 4. written informed consent 5. detectable TTV load at randomization (>2,7 log 10) 6. negative serum pregnancy test in women of childbearing potential. 7. Women of childbearing capacity are required to have a negative serum pregnancy test before treatment and must agree to maintain highly effective methods of contraception by practicing abstinence or by using at least two methods of birth control from the date of consent through the end of the study. If abstinence is not practiced, a combination of hormonal contraceptive (oral, injectable or implants) and a barrier method (condom, diaphragm with a vaginal spermicidal agent) has to be used.
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E.4 | Principal exclusion criteria |
1. patients after unilateral or re-do lung transplantation 2. history or high-risk of obstructive airway complications after lung transplantation 3. respiratory failure (need for oxygen therapy or ventilation at screening after lung transplantation) 4. inability to undergo transbronchial biopsy 5. advanced kidney failure (GFR CKD-EPI <30 ml/min/1.73m2 at inclusion and/or current renal replacement therapy at inclusion or randomization 6. advanced liver cirrhosis (CHILD-Pugh Score C) after lung transplantation 7. fluctuating tacrolimus drug levels (less than 20% in target range after transplantation) 8. patients with symptoms of significant mental illness and with inability to cooperate or communicate with the investigator. 9. unlikeliness to comply with the study requirements 10. HIV positivity 11. evidence of unsolved drug or alcohol addiction 12. breastfeeding women 13. simultaneous participation in other clinical trials if not permitted by the steering committee
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint ΔGFR is defined as the change of the glomerular filtration rate GFR between randomization and 12 months thereafter. GFR will be estimated using the CKD-EPI formula. |
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E.5.2 | Secondary end point(s) |
• GFR (CKD-EPI) at 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization • GFR (Cystatin) at randomization and 12 months after randomization • proportion of patients with biopsy-proven acute cellular rejection (grade A1 or higher) within 12 months after randomization • proportion of patients with an episode of biopsy-proven lymphocytic bronchitis (grade B1R or higher) within 12 months after randomization • proportion of patients with cytomegalovirus (CMV)-infection and number of CMV-disease episodes within 12 months after randomization • proportion of patients with community-acquired respiratory viral infection (CARV) within 12 months after randomization • proportion of patients with fungal and bacterial infections within 12 months after randomization • proportion of patients with any of the above mentioned infections within 12 months after randomization • proportion of patients with unscheduled or emergency hospitalizations within 12 months after randomization • proportion of patients with ICU admissions after randomization • quality of life (EQ-5D visual analog scale) at screening visits and 0, 3, 6, 9 and 12 months after randomization • proportion of patients with new or progressive malignancy within 12 months after randomization • tacrolimus trough levels at screening visits and 0, 3, 6, 9 and 12 months after randomization • daily tacrolimus dose [mg] at screening visits and 0, 3, 6, 9 and 12 months after randomization • proportion of patients with increased/unchanged/decreased (compared to previous visit) target trough levels of tacrolimus at screening visits and 0, 3, 6, 9 and 12 months after randomization • exercise capacity measured by the percent predicted distance achieved in the 6-minute walk test (6-MWT) at randomization and 12 months thereafter • CD4-Lymphocytes counts at 0, 6 and 12 months after randomization • proportion of patients with presence of donor specific antibodies at 0, 6 and 12 months after randomization • FEV1 in % baseline value at screening visits and 0, 3, 6, 9 and 12 months after randomization • incidence of chronic lung allograft dysfunction between randomization and 12 months thereafter • IgG-level at 0, 6 and 12 months after randomization • proportion of patients with rescue immunotherapy (defined by the use of ATG, Rituximab, Alemtuzumab, plasma exchange, immunoadsorption) after randomization • time from randomization to graft loss (defined as re-do transplantation or death)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
timepoints of evaluation see above |
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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 | No |
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 |
Therapeutic Drug Monitoring (TDM) |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 3 |
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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End of the study is defined as “Last Patient Out” and database closure. |
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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 |