Periodic Reporting for period 2 - TTV GUIDE TX (PERSONALISATION OF IMMUNOSUPPRESSION BY MONITORING VIRAL LOAD POST KIDNEY TRANSPLANTATION - A RANDOMISED CONTROLLED PHASE II TRIAL)
Okres sprawozdawczy: 2022-11-01 do 2023-10-31
Our project is establishing a tool to quantify the activity of the immune system in kidney transplant patients and thereby reducing infections and organ rejections.
End stage renal disease (ESRD) causes a high socioeconomic burden for citizens and the healthcare system in Europe. If the kidneys stop working, a kidney transplant can restore the kidney function. However, the immune system would recognize the new kidney as foreign and attack it. Therefore kidney-transplant recipients need drugs to reduce the function of their immune system. These drugs are called immunosuppressive drugs. If the patients take too many of these drugs though, their immune system gets weak, and they get other life-threatening infections.
Therefore, transplant physicians need a tool to quantify the activity of the immune system and optimize the drug dose. The recently discovered TT virus might be able to do this job: TT is naturally occurring in the blood of almost every healthy person and every kidney transplant recipient, but it causes no disease. If the immune system is strong, the TT virus load is low; this indicates a risk for organ rejection. If the immune system is weak, the TT virus load is high; this indicates a risk for infection.
The quantification of the TT virus load in the blood of kidney transplant recipients might help optimize immunosuppressive drugs and thus reduce infections and rejection. Within the TTV GUIDE TX project TT virus guided dosing of immunosuppressive drugs is being tested in a clinical trial including hundreds of kidney transplant recipients from all over Europe. Once established in routine clinical care, TT virus guidance might reduce thousands of infections and kidney transplant rejection each year. In the future the TT virus might not only help kidney transplant recipients but also patients with liver, heart and lung transplantation and guide therapy in autoimmune, infectious, and oncologic diseases.
The main aim of the project therefore can be summarised in demonstrating the safety and preliminary efficacy of TT virus-guided dosing of immunosuppressive drugs in kidney transplant recipients. In parallel, the scientific rationale for the routine clinical application of a commercially available TTV assay will be provided.
End stage renal disease (ESRD) causes a high socioeconomic burden for citizens and the healthcare system in Europe. If the kidneys stop working, a kidney transplant can restore the kidney function. However, the immune system would recognize the new kidney as foreign and attack it. Therefore kidney-transplant recipients need drugs to reduce the function of their immune system. These drugs are called immunosuppressive drugs. If the patients take too many of these drugs though, their immune system gets weak, and they get other life-threatening infections.
Therefore, transplant physicians need a tool to quantify the activity of the immune system and optimize the drug dose. The recently discovered TT virus might be able to do this job: TT is naturally occurring in the blood of almost every healthy person and every kidney transplant recipient, but it causes no disease. If the immune system is strong, the TT virus load is low; this indicates a risk for organ rejection. If the immune system is weak, the TT virus load is high; this indicates a risk for infection.
The quantification of the TT virus load in the blood of kidney transplant recipients might help optimize immunosuppressive drugs and thus reduce infections and rejection. Within the TTV GUIDE TX project TT virus guided dosing of immunosuppressive drugs is being tested in a clinical trial including hundreds of kidney transplant recipients from all over Europe. Once established in routine clinical care, TT virus guidance might reduce thousands of infections and kidney transplant rejection each year. In the future the TT virus might not only help kidney transplant recipients but also patients with liver, heart and lung transplantation and guide therapy in autoimmune, infectious, and oncologic diseases.
The main aim of the project therefore can be summarised in demonstrating the safety and preliminary efficacy of TT virus-guided dosing of immunosuppressive drugs in kidney transplant recipients. In parallel, the scientific rationale for the routine clinical application of a commercially available TTV assay will be provided.
During the last 30 months
• the clinical trial protocol was finalised,
• the CTIS registration was completed,
• the trial was initiated at all centres, and
• the Ethical, Legal and Social Issues (ELSI) study has been desidned and approved in all clinical centers and data collection has begun.
• Specific training on the inclusion of sex and gender in biomedical research for healthcare professionals and researchers has been provided.
• All virology departments participating in the Y2 interventional clinical study received validation for their appropriate use of the TTV qPCR as highlighted by the 2023 External Quality Assessment program.
• Reliable TTV load quantification from patient samples is confirmed for the second year of the trial.
• Various exploitation, communication and dissemination actions were taken to maximise the project’s visibility and impact.
• More than half of the planned patients could be randomised.
• Patient safety was reviewed at two meetings of the Data Safety Monitoring Board and no objections were raised against the continuation of the study in both meetings.
Project coordination, monitoring, reporting, and quality assurance was set in motion at the project start and continued supporting the project partners throughout the first two project periods.
Members of the Ethics and Governance Council (EGC) were chosen, nominated, and meetings took place frequently throughout the first 30 months of the project. Recommendations by the EGC members were implemented into the project.
The TTV test and quantification has been set up in all the virology laboratories.
The clinical trial received approval through the Clinical Trial Information System in July 2021. This marks one of the first multinational academic clinical trials that requested approval directly in the new system and did not migrate from VHP (Voluntary Harmonization Procedure). The trial is now being carried out in 6 countries: Austria, Czech Republic, France, Germany, Netherlands and Spain.
Dissemination and communication activities were performed to inform the projects stakeholders about the ongoing activities and first results. A project website was set up, including FAQs for patients and clinicians, videos, podcasts and folders were produced and the project was continuously present on its Social Media channels.
• the clinical trial protocol was finalised,
• the CTIS registration was completed,
• the trial was initiated at all centres, and
• the Ethical, Legal and Social Issues (ELSI) study has been desidned and approved in all clinical centers and data collection has begun.
• Specific training on the inclusion of sex and gender in biomedical research for healthcare professionals and researchers has been provided.
• All virology departments participating in the Y2 interventional clinical study received validation for their appropriate use of the TTV qPCR as highlighted by the 2023 External Quality Assessment program.
• Reliable TTV load quantification from patient samples is confirmed for the second year of the trial.
• Various exploitation, communication and dissemination actions were taken to maximise the project’s visibility and impact.
• More than half of the planned patients could be randomised.
• Patient safety was reviewed at two meetings of the Data Safety Monitoring Board and no objections were raised against the continuation of the study in both meetings.
Project coordination, monitoring, reporting, and quality assurance was set in motion at the project start and continued supporting the project partners throughout the first two project periods.
Members of the Ethics and Governance Council (EGC) were chosen, nominated, and meetings took place frequently throughout the first 30 months of the project. Recommendations by the EGC members were implemented into the project.
The TTV test and quantification has been set up in all the virology laboratories.
The clinical trial received approval through the Clinical Trial Information System in July 2021. This marks one of the first multinational academic clinical trials that requested approval directly in the new system and did not migrate from VHP (Voluntary Harmonization Procedure). The trial is now being carried out in 6 countries: Austria, Czech Republic, France, Germany, Netherlands and Spain.
Dissemination and communication activities were performed to inform the projects stakeholders about the ongoing activities and first results. A project website was set up, including FAQs for patients and clinicians, videos, podcasts and folders were produced and the project was continuously present on its Social Media channels.
The measurement of TT virus (TTV) levels is a novel, innovative and holistic concept that allows for global assessment of the immune system and, thus, goes beyond state of the art. There have been no major improvements in immunosuppressive drug efficacy and safety realised in the recent years and no novel compounds are on the horizon. The personalisation of existing drugs is a novel and innovative concept in solid organ transplantation though. Thus, the optimisation of drugs via TTV personalisation is a promising strategy.
In Europe, the prevalence of kidney transplantation recipients is 500k and the incidence of kidney transplantation is 30k per year. The percentage of patients suffering from clinically relevant infections is 10% per year and the 5-year death rate is 10%, with 15% of deaths due to infections. The 5-year graft loss rate is 20%, with 50% lost due to rejection, and the percentage of patients suffering from acute rejection in the first year after transplantation is 15%. In total, 50k kidney transplant recipients suffer from infections and 1500 die due to infection each year, 3000 kidney grafts are lost due to rejection per year in the first 5 years and 4000 patients experience acute rejection within the first year after transplantation in Europe. The anticipated 20% reduction in rejection and infection rates by TTV-guided immunosuppression would prevent 10k infections, 300 deaths due to infection, 800 rejections and 600 graft losses in Europe per year.
Lower infection and rejection rates achieved through optimisation of immunosuppression will result in reduced hospitalisation and harm due to the side effects of antimicrobial and anti-rejection therapy. The prolongation of graft survival reduces the need for dialysis, which is a very burdensome procedure for ESRD patients, and thus improvs quality of life. Improved graft survival would also reduce the number of patients re-entering the waiting-list for a kidney transplant after terminal graft failure, thereby shortening the time for ESRD patients on the waiting list for a suitable kidney. These changes would result in significant improvement in health-related quality of life for ESRD patients.
The assessment of an individual patient’s immune function enables their clinician to personalise immunosuppression, thereby benefiting patients with ESRD. Moreover, the project will act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical application: for example, emerging oncologic therapies, including checkpoint inhibitors that enhance the immune function and thus control tumour growth, or biological disease-modifying agents in rheumatologic disease might also benefit from TTV guidance. In addition, TTV-guided therapy might be applicable to transplantation of other solid organs, including heart, lung and liver.
In Europe, the prevalence of kidney transplantation recipients is 500k and the incidence of kidney transplantation is 30k per year. The percentage of patients suffering from clinically relevant infections is 10% per year and the 5-year death rate is 10%, with 15% of deaths due to infections. The 5-year graft loss rate is 20%, with 50% lost due to rejection, and the percentage of patients suffering from acute rejection in the first year after transplantation is 15%. In total, 50k kidney transplant recipients suffer from infections and 1500 die due to infection each year, 3000 kidney grafts are lost due to rejection per year in the first 5 years and 4000 patients experience acute rejection within the first year after transplantation in Europe. The anticipated 20% reduction in rejection and infection rates by TTV-guided immunosuppression would prevent 10k infections, 300 deaths due to infection, 800 rejections and 600 graft losses in Europe per year.
Lower infection and rejection rates achieved through optimisation of immunosuppression will result in reduced hospitalisation and harm due to the side effects of antimicrobial and anti-rejection therapy. The prolongation of graft survival reduces the need for dialysis, which is a very burdensome procedure for ESRD patients, and thus improvs quality of life. Improved graft survival would also reduce the number of patients re-entering the waiting-list for a kidney transplant after terminal graft failure, thereby shortening the time for ESRD patients on the waiting list for a suitable kidney. These changes would result in significant improvement in health-related quality of life for ESRD patients.
The assessment of an individual patient’s immune function enables their clinician to personalise immunosuppression, thereby benefiting patients with ESRD. Moreover, the project will act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical application: for example, emerging oncologic therapies, including checkpoint inhibitors that enhance the immune function and thus control tumour growth, or biological disease-modifying agents in rheumatologic disease might also benefit from TTV guidance. In addition, TTV-guided therapy might be applicable to transplantation of other solid organs, including heart, lung and liver.