Clinical trial NCT04198506: Viral Load Guided Immunosuppression After Lung Transplantation
Official title: Viral Load Guided Immunosuppression After Lung Transplantation, an Open-label, Randomized, Controlled, Parallel-group, Multicenter Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Transplantation Lung
Keywords: lung transplantation
dosing immunosuppression
toxicity
Lead sponsor: Philipps University Marburg
Sponsor class: OTHER
First posted: 2019-12-13
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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 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:

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. 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

Primary outcomes:
measure: ΔGFR change of the glomerular filtration rate GFR
timeFrame: Between randomization and 12 months thereafter
Secondary outcomes:
measure: GFR (CKD-EPI)
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: GFR (Cystatin)
timeFrame: At randomization and 12 months after randomization
measure: proportion of patients with biopsy-proven acute cellular rejection (grade A1 or higher)
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with an episode of biopsy-proven lymphocytic bronchitis (grade B1R or higher)
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with cytomegalovirus (CMV)-infection and number of CMV-disease episodes
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with community-acquired respiratory viral infection (CARV)
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with fungal and bacterial infections
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with any of the above mentioned infections
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with unscheduled or emergency hospitalizations
timeFrame: Between randomization and 12 months after randomization
measure: proportion of patients with ICU admissions
timeFrame: Between randomization and 12 months after randomization
measure: quality of life (EQ-5D visual analog scale)
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: proportion of patients with new or progressive malignancy
timeFrame: Between randomization and 12 months after randomization
measure: tacrolimus trough levels
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: daily tacrolimus dose [mg]
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: proportion of patients with increased/unchanged/decreased (compared to previous visit) target trough levels of tacrolimus
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: exercise capacity measured by the percent predicted distance achieved in the 6-minute walk test (6-MWT)
timeFrame: at randomization and 12 months thereafter
measure: CD4-Lymphocytes counts
timeFrame: 0, 6 and 12 months after randomization
measure: proportion of patients with presence of donor specific antibodies
timeFrame: 0, 6 and 12 months after randomization
measure: FEV1 in % baseline value
timeFrame: 1 and 2 months after transplantation (screening visits) and 0, 3, 6, 9 and 12 months after randomization
measure: incidence of chronic lung allograft dysfunction
timeFrame: Between randomization and 12 months thereafter
measure: IgG-level
timeFrame: 0, 6 and 12 months after randomization
measure: proportion of patients with rescue immunotherapy (defined by the use of ATG, Rituximab, Alemtuzumab, plasma exchange, immunoadsorption)
timeFrame: Between randomization and 12 months thereafter
measure: time from randomization to graft loss (defined as re-do transplantation or death)
timeFrame: randomization until 12 months thereafter
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Medizinische Universität Wien, Klinische Abteilung für Thoraxchirurgie
city: Hannover
country: Germany
facility: Klinik für Pneumologie OE 6870, Medizinische Hochschule Hannover
Study officials:
affiliation: Klinik für Pneumologie OE 6870, Medizinische Hochschule Hannover (MHH)
name: Jens Gottlieb, Prof. MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gottlieb J, Reuss A, Mayer K, Weide K, Schade-Brittinger C, Hoyer S, Jaksch P. Viral load-guided immunosuppression after lung transplantation (VIGILung)-study protocol for a randomized controlled trial. Trials. 2021 Jan 11;22(1):48. doi: 10.1186/s13063-020-04985-w.