Ignite Creation Date:
2024-05-06 @ 8:22 PM
Last Modification Date:
2024-10-26 @ 3:26 PM
Study NCT ID:
NCT06354179
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-11
First Post:
2024-04-03
Brief Title:
Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation EASY
Sponsor:
University Hospital Limoges
Organization:
University Hospital Limoges
Study Overview
Official Title:
Evaluation of the Benefits of Administering Immunosuppressive Drugs as Single Daily Doses Over the First Year After Liver Transplantation
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
EASY
Brief Summary:
World Health Organization considers non-adherence has a strong negative impact on the health of patients with chronic diseases In transplantation adherence to immunosuppressive drug regimens associates with late rejection and graft loss making it a critical determinant of patient outcome The prevalence of non-adherence in transplant patients including liver transplant patients can be as high as 40 Among others life-long intake and complexity of immunosuppressive regimen make patients prone to non-adherence For instance non-adherence is more prevalent among patients with higher numbers of immunosuppressive drugs One of the most commonly cited causes of non-adherence is forgetfulness and disruptions in routine with the evening dose of twice daily regimens being the most likely to be affected6 Besides non-adherence the constraints generated in everyday life by immunosuppression including timely and regular drug intake and the complexity of the immunosuppressive regimens represent a burden for the patients and are probably associated with a health-related quality of life deterioration Therefore long-term adherence and quality of life after liver transplantation might be improved by using a well-tolerated and easy-to-handle immunosuppressive regimen
The immunosuppressive regimen after liver transplantation is in most cases based on different combinations of tacrolimus mycophenolate mofetil and corticosteroids While corticosteroids are administered once daily tacrolimus can be administered either twice-daily BID as an immediate-release or once-daily QD as an extended-release formulation Among once-daily tacrolimus formulations LCP-tacrolimus ENVARSUS XR is approved for the prevention of transplant rejection in adult liver allograft recipients It has demonstrated similar outcomes compared to immediate-release tacrolimus BID in both kidney and liver transplantation Mycophenolate has only been approved for BID administration preventing from taking all immunosuppressive drugs once daily Yet single daily dosing would probably contribute to better adherence and quality of life in patients receiving a life-long treatment
Although the half-life of mycophenolic acid MPA the active moiety of mycophenolate mofetil MMF is compatible with once-daily administration no published randomized clinical study has ever evaluated the efficacy and safety of MMF administered QD
The narrow therapeutic index and wide pharmacokinetic variability of tacrolimus and mycophenolate justify individual dose adjustment by means of therapeutic drug monitoring TDM in order to minimize the risk of acute rejection and the occurrence of adverse events For tacrolimus TDM is generally based on the trough concentration C0 and sometimes on the area under the concentration-time curve AUC while for mycophenolate it should be based on the AUC of MPA However the dose adjustment of MMF in liver transplant patients is most of the time performed a posteriori based on clinical signs of inefficacy of toxicity
Limited sampling strategies with maximum a posteriori Bayesian estimation have been developed by our team for both molecules in adult liver transplant patients to estimate their AUC which is considered the best marker of exposure for both Therefore tacrolimus AUC0-24h can be estimated by Bayesian estimation using samples collected before administration C0 8 C8h and 12 C12h hours after the administration of ENVARSUS XR or 1 and 3 hours after the administration of PROGRAF and ADVAGRAF For mycophenolate the MPA AUC can be estimated using samples collected 20 min 1 and 3 hours after MMF administration by Bayesian estimation
Even if limited to 2 or 3 blood samples tacrolimus TDM for ENVARSUS requires late sampling 12h post-dose To overcome the necessity of a longer hospital stay microsampling devices MSD such as the Volumetric absorptive microsampling VAMS device Mitra can be used by the patients to take samples themselves at home Moreover they are less invasive than venipuncture and collect low but accurate volumes of blood for analysis
In this context we propose a randomized controlled non-inferiority study to demonstrate that in liver transplant recipients an immunosuppressive strategy based on single daily doses of LCP-tacrolimus ENVARSUS XR and mycophenolate mofetil CELLCEPT started at M6 post-transplantation is not inferior to XR-tacrolimus ADVAGRAF and MMF administered BID in terms of incidence of treatment failure see below at the end of the first year after transplantation and to obtain adherence quality of life and safety data In order to compare solely MMF QD to MMF BID patients on ENVARSUS XR and MMF QD will be compared to a third group of patients receiving ENVARSUS XR and MMF BID A direct comparison of efficacy and safety quality of life adherence and exposure indices will be performed between ENVARSUS XR and ADVAGRAF
The immunosuppressive regimen after liver transplantation is in most cases based on different combinations of tacrolimus mycophenolate mofetil and corticosteroids While corticosteroids are administered once daily tacrolimus can be administered either twice-daily BID as an immediate-release or once-daily QD as an extended-release formulation Among once-daily tacrolimus formulations LCP-tacrolimus ENVARSUS XR is approved for the prevention of transplant rejection in adult liver allograft recipients It has demonstrated similar outcomes compared to immediate-release tacrolimus BID in both kidney and liver transplantation Mycophenolate has only been approved for BID administration preventing from taking all immunosuppressive drugs once daily Yet single daily dosing would probably contribute to better adherence and quality of life in patients receiving a life-long treatment
Although the half-life of mycophenolic acid MPA the active moiety of mycophenolate mofetil MMF is compatible with once-daily administration no published randomized clinical study has ever evaluated the efficacy and safety of MMF administered QD
The narrow therapeutic index and wide pharmacokinetic variability of tacrolimus and mycophenolate justify individual dose adjustment by means of therapeutic drug monitoring TDM in order to minimize the risk of acute rejection and the occurrence of adverse events For tacrolimus TDM is generally based on the trough concentration C0 and sometimes on the area under the concentration-time curve AUC while for mycophenolate it should be based on the AUC of MPA However the dose adjustment of MMF in liver transplant patients is most of the time performed a posteriori based on clinical signs of inefficacy of toxicity
Limited sampling strategies with maximum a posteriori Bayesian estimation have been developed by our team for both molecules in adult liver transplant patients to estimate their AUC which is considered the best marker of exposure for both Therefore tacrolimus AUC0-24h can be estimated by Bayesian estimation using samples collected before administration C0 8 C8h and 12 C12h hours after the administration of ENVARSUS XR or 1 and 3 hours after the administration of PROGRAF and ADVAGRAF For mycophenolate the MPA AUC can be estimated using samples collected 20 min 1 and 3 hours after MMF administration by Bayesian estimation
Even if limited to 2 or 3 blood samples tacrolimus TDM for ENVARSUS requires late sampling 12h post-dose To overcome the necessity of a longer hospital stay microsampling devices MSD such as the Volumetric absorptive microsampling VAMS device Mitra can be used by the patients to take samples themselves at home Moreover they are less invasive than venipuncture and collect low but accurate volumes of blood for analysis
In this context we propose a randomized controlled non-inferiority study to demonstrate that in liver transplant recipients an immunosuppressive strategy based on single daily doses of LCP-tacrolimus ENVARSUS XR and mycophenolate mofetil CELLCEPT started at M6 post-transplantation is not inferior to XR-tacrolimus ADVAGRAF and MMF administered BID in terms of incidence of treatment failure see below at the end of the first year after transplantation and to obtain adherence quality of life and safety data In order to compare solely MMF QD to MMF BID patients on ENVARSUS XR and MMF QD will be compared to a third group of patients receiving ENVARSUS XR and MMF BID A direct comparison of efficacy and safety quality of life adherence and exposure indices will be performed between ENVARSUS XR and ADVAGRAF
Detailed Description:
None
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None