Viral Load Guided Immunosuppression After Lung Transplantation

Study Overview
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Brief Summary
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The VIGILung study is an open-label, randomized, multicenter trial in lung transplant recipients to investigate the safety and efficacy of personalized immunosuppression guided by DNA monitoring of Torque-Teno-Virus (TTV). The aim of the study is to investigate an individual adaptation of the calcineurin inhibitor tacrolimus (tailored calcineurin inhibitor dosing) by a non-invasive biomarker (TTV viral load in whole blood) compared to conventional calcineurin inhibitor dosing. Indicator for toxicity will be the glomerular filtration rate (GFR), which will be estimated using the CKD-EPI formula. 250 patients (age ≥ 18 years) with 21 to 42 days after de novo lung transplantation (bilateral or combined) will be screened as possible subjects eligible for the study. N = 144 patients have to be randomized in two study arms. In Arm 1 tacrolimus doses will be adapted according to the tacrolimus blood level (conventional therapeutic drug monitoring - TDM) and additionally depending on TTV viral load. In Arm 2 tacrolimus doses will be adapted according to TDM.

Official Title
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Viral Load Guided Immunosuppression After Lung Transplantation, an Open-label, Randomized, Controlled, Parallel-group, Multicenter Trial

Conditions
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Transplantation Lung

Intervention / Treatment
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* Other: Tailored tacrolimus dosing
* Other: Conventional tacrolimus dosing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients 21 to 42 days after primary de novo lung transplantation (bilateral including combined) age ≥ 18 years tacrolimus based immunosuppression written informed consent detectable TTV load at randomization (>2,7 log 10) negative serum pregnancy test in women of childbearing potential. women of childbearing capacity 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. Exclusion Criteria: patients after unilateral or re-do lung transplantation history or high-risk of obstructive airway complications after lung transplantation respiratory failure (need for oxygen therapy or ventilation at screening after lung transplantation) inability to undergo transbronchial biopsy advanced kidney failure (GFR CKD-EPI <30 ml/min/1.73m2 at inclusion and/or current renal replacement therapy at inclusion or randomization advanced liver cirrhosis (CHILD-Pugh Score C) after lung transplantation fluctuating tacrolimus drug levels (less than 20% in target range after transplantation) symptoms of significant mental illness and with inability to cooperate or communicate with the investigator. unlikeliness to comply with the study requirements HIV positivity evidence of unsolved drug or alcohol addiction breastfeeding women simultaneous participation in other clinical trials if not permitted by the steering committee

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tailored tacrolimus dosing<br>Tacrolimus doses will be adapted according to tacrolimus blood level (conventional therapeutic drug monitoring - TDM) and additionally depending on TTV viral load. | Other: Tailored tacrolimus dosing<br>* Tacrolimus doses will be adapted according to tacrolimus blood level (conventional therapeutic drug monitoring -TDM) and additionally depending on TTV viral load.<br>|
| Active Comparator: Conventional tacrolimus dosing<br>Tacrolimus doses will be adapted according to tacrolimus blood level (conventional therapeutic drug monitoring - TDM). | Other: Conventional tacrolimus dosing<br>* Tacrolimus doses will be adapted according to tacrolimus blood level (conventional therapeutic drug monitoring - TDM).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ΔGFR change of the glomerular filtration rate GFR | 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. | Between randomization and 12 months thereafter | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GFR (CKD-EPI) | Glomerular filtration rate (the Chronic Kidney Disease Epidemiology Collaboration - CKD-EPI) formula | 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization | 
| GFR (Cystatin) | Glomerular filtration rate (Cystatin) | At randomization and 12 months after randomization | 
| proportion of patients with biopsy-proven acute cellular rejection (grade A1 or higher) |  | Between randomization and 12 months after randomization | 
| proportion of patients with an episode of biopsy-proven lymphocytic bronchitis (grade B1R or higher) |  | Between randomization and 12 months after randomization | 
| proportion of patients with cytomegalovirus (CMV)-infection and number of CMV-disease episodes |  | Between randomization and 12 months after randomization | 
| proportion of patients with community-acquired respiratory viral infection (CARV) |  | Between randomization and 12 months after randomization | 
| proportion of patients with fungal and bacterial infections |  | Between randomization and 12 months after randomization | 
| proportion of patients with any of the above mentioned infections |  | Between randomization and 12 months after randomization | 
| proportion of patients with unscheduled or emergency hospitalizations |  | Between randomization and 12 months after randomization | 
| proportion of patients with ICU admissions |  | Between randomization and 12 months after randomization | 
| quality of life (EQ-5D visual analog scale) | European Quality of Life 5 Dimensions - EQ-5D | 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization | 
| proportion of patients with new or progressive malignancy |  | Between randomization and 12 months after randomization | 
| tacrolimus trough levels |  | 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization | 
| daily tacrolimus dose [mg] |  | 1 and 2 months after transplantation (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 |  | 1 and 2 months after transplantation (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 |  | 0, 6 and 12 months after randomization | 
| proportion of patients with presence of donor specific antibodies |  | 0, 6 and 12 months after randomization | 
| FEV1 in % baseline value |  | 1 and 2 months after transplantation (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 |  | 0, 6 and 12 months after randomization | 
| proportion of patients with rescue immunotherapy (defined by the use of ATG, Rituximab, Alemtuzumab, plasma exchange, immunoadsorption) |  | Between randomization and 12 months thereafter | 
| time from randomization to graft loss (defined as re-do transplantation or death) |  | randomization until 12 months thereafter | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lung transplantation, dosing immunosuppression, toxicity