Cytokine Filtration in Lung Transplantation: A Swedish National Study (GLUSorb)

Study Overview
=================
Brief Summary
-----------------
Lung transplantation (LTx) remains the gold standard for treating patients with irreversible end-stage pulmonary disease. Of the major organs transplanted, survival in LTx recipients remains the lowest (mean 5 years). Despite improvements, primary graft dysfunction (PGD), as defined by respiratory insufficiency and edema up to 72 hours post LTx, remains the leading cause of early mortality and contributes to the development of chronic lung allograft dysfunction (CLAD) which is the leading cause of late mortality. PGD develops within the first 72 hours after LTx. The development of CLAD increases quickly with cumulative incidence of 40-80 % within the first 3-5 years. There is a general lack of efficient treatments for PGD and CLAD. Prevention of PGD is therefore of crucial importance and has a direct impact on survival. The present study is a randomized controlled study which aims to compare patients undergoing LTx with and without the utilization of cytokine adsorption.

Detailed Description
-----------------
Early intolerance to the newly transplanted lung starts at the time of transplantation and results in PGD driven by an intense inflammatory response. Cytokines play a critical role as signaling molecules that initiate, amplify, and maintain inflammatory responses both locally and systemically. The use of cytokine filtration devices to target middle- and low-molecular weight molecules has been shown to reduce levels of a diverse number of cytokines. These results have been demonstrated in the in vitro reduction of pathogen-associated molecular pattern molecules (PAMPS) and damage associated molecular patterns (DAMPS) as well as in in vivo studies involving orthotopic heart transplantation and kidney transplantation. Cytokine adsorption has been used successfully in clinical applications to both heart and kidney transplantation. The present study is a randomized controlled study which aims to collect preliminary data on the efficacy of a medical device through the comparison of patients undergoing LTx with and without cytokine adsorption.

Official Title
-----------------
Cytokine Filtration in Lung Transplantation - a Randomised, Controlled, Multicentre Clinical Trial (GLUSorb)

Conditions
-----------------
Lung Transplant Failure, Lung Transplant; Complications

Intervention / Treatment
-----------------
* Device: Device: CytoSorb


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: • Eligibility to undergo double lung transplantation at either trial site Exclusion Criteria: Age <18 years Previous organ transplantation Presence of any conditions at the time of surgery that require immunosuppressive therapy. Immunosuppressive therapy is defined as: Cyclosporine, Tacrolimus, Everolimus, or Sirolimus, minimum 1 month of treatment prior to transplantation and active treatment at the time of transplantation. Any form of antibody-based treatment that is known for having an immunomodulatory effect taken up to 1 week before transplantation. Non-consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The model consists of a randomized controlled in human patients using a cytokine adsorption device. Lung transplant recipients are randomized to either the treatment group which undergoes cytokine adsorption using the medical device compared to the control group which has not received the cytokine adsorber.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treated<br>Treatment using the medical cytokine adsorption device in conjunction with lung transplantation | Device: Device: CytoSorb<br>* Medical device used hemoperfusion and cytokine adsorption in conjunction with lung transplantation.<br>|
| No Intervention: Non-treated<br>No additional treatment in conjunction with lung transplantation | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine whether cytokine reduction by cytokine filtration leads to improved oxygenation in patients undergoing lung transplantation. | Higest value of oxygenation expressed as the PaO2/FiO2 ratio. | First 72 hours after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration leads to improved oxygenation in patients undergoing lung transplantation. Oxygenation at 24 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 24 hours | 24 hours after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration leads to improved oxygenation in patients undergoing lung transplantation. Oxygenation at 48 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 48 hours | 48 hours after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration leads to improved oxygenation in patients undergoing lung transplantation. Oxygenation at 72 hours | Oxygenation expressed as the PaO2/FiO2 ratio at 72 hours | 72 hours after lung transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine whether cytokine reduction by cytokine filtration improves levels of plasma inflammatory markers (including cytokines) in patients undergoing lung transplantation. | Plasma levels of inflammatory markers: interleukin (IL)-10, IL-1β, soluble IL-2 receptor, IL-6, IL-8, and tumour necrosis factor (TNF)α before and immediately after transplantation and at 6, 12, 24, 48, and 72 hours after transplantation, and C-reactive protein (CRP) and white blood cells before and immediately after transplantation and at day 1, 2, and 3 after transplantation | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration decreases lung infiltrates and oedema in patients undergoing lung transplantation | Infiltrates and oedema measured by chest x-ray and/or CT scan of the thorax at day 1, 2, and 3 after transplantation | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration improves arterial blood gas measures in patients undergoing lung transplantation | Highest daily arterial blood gas measurements recorded on day 1, 2, and 3 after transplantation, as a measure of lung function | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration decreases severity of primary graft dysfunction (PGD) in patients undergoing lung transplantation | PGD severity as evaluated per standard clinical procedures using a rating scale from 0-3 on day 1, 2, and 3 after transplantation, as a measure of lung function | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration decreases incidence of primary graft dysfunction (PGD) in patients undergoing lung transplantation | Presence of any grade of PGD on day 1, 2, and 3 after transplantation, as a measure of lung function | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration decreases need for norepinephrine in patients undergoing lung transplantation | Total dose of norepinephrine administered in the first 72 h | 0-72 hours (0-3 days) after lung transplantation | 
| To determine whether cytokine reduction by cytokine filtration decreases mortality in patients undergoing lung transplantation | Mortality up to 48 months after transplantation | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves diffusion capacity of the lungs (DLCO) in patients undergoing lung transplantation | Lung diffusion capacity, measured by carbon monoxide (CO) diffusion, at 6, 12, 24, and 48 months after transplantation, as a measure of lung function | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves forced expiratory volume (FEV1), forced vital capacity (FVC), and total lung capacity in patients undergoing lung transplantation | Forced expiratory volume (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) measured by spirometry at 1, 3, 6, 12, 24 and 48 months after transplantation, as a measure of lung function | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves occurrence of any acute rejection episodes in patients undergoing lung transplantation | Occurrence of any acute rejection episodes (clinically treated and/or biopsy verified) up to 48 months after transplantation, as a measure of lung function | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves Chest CT in patients undergoing lung transplantation | Chest CT findings at 1, 3, 6, 12, 24, 36 and 48 months after transplantation | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves presence of any CLAD in patients undergoing lung transplantation | Presence of any CLAD and CLAD subtypes up to 48 months after transplantation, as a measure of lung function | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves kidney function in patients undergoing lung transplantation | Kidney function evaluated by measurement of serum creatinine levels; calculated glomerular filtration rate (GFR); and need for renal replacement therapy on day 1, 2, and 3 and at 1, 3, 6, 9, 12, 24, and 48 months after transplantation; urea levels on day 1, 2, and 3 after transplantation; and iohexol clearance at 3, 6, 9, 12, 24, 36, and 48 months after transplantation | First 4 years | 
| To determine whether cytokine reduction by cytokine filtration improves quality of life (QOL) in patients undergoing lung transplantation | QOL evaluated by the 36-Item Short Form Health Survey (SF-36) at 24 and 48 months after transplantation | First 4 years |