Ignite Creation Date:
2024-05-05 @ 5:20 PM
Last Modification Date:
2024-10-26 @ 9:30 AM
Study NCT ID:
NCT00436722
Status:
TERMINATED
Last Update Posted:
2009-05-20
First Post:
2007-02-16
Brief Title:
Induction Treatment Followed by Immunosuppression Withdrawal in Liver Transplantation A Comparative Trial
Sponsor:
Hospital Clinic of Barcelona
Organization:
Hospital Clinic of Barcelona
Study Overview
Official Title:
Study of ATEGE-Fresenius Induction in Liver Transplantation Followed by Tacrolimus Weaning
Status:
TERMINATED
Status Verified Date:
2009-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Experimental arm induction low dose tacrolimus not effective
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ATEGE-LIVER
Brief Summary:
This is a randomized controlled trial in liver transplantation in which conventional immunosuppressive treatment will be compared with a therapeutic strategy consisting in pre-transplant antibody-mediated T cell depletion followed by reduced calcineurin inhibitor usage The working hypothesis is that antibody induction followed by calcineurin inhibitor minimization may promote development of tolerogenic mechanisms allowing the eventual withdrawal of all immunosuppressive therapy
Detailed Description:
This is an open-label randomised controlled study in which patients will be randomised according to a 11 ratio to receive conventional immunosuppressive treatment or induction treatment plus reduced tacrolimus dosage All transplanted patients enrolled in the study will be followed during 12 months and evaluated according to an intention-to-treat approach
Specific Aim 1 To determine the proportion of liver recipients in whom tacrolimus usage can be significantly reduced 1 year after transplantation Patients will be considered as successfully receiving a reduced tacrolimus regimen if this drug is given as a single dose every other day or at the most administered as a single dose daily with trough levels 5ngmL
Specific Aim 2 To determine the effect of induction treatment plus minimized immunosuppression on graft and patient survival
Specific Aim 3 To determine the impact of induction treatment plus minimized immunosuppression on the development of acute and chronic allograft rejection hepatitis C virus graft recurrence opportunistic infections bone fractures kidney failure tacrolimus-related neurotoxicity dyslipidemia and arterial hypertension
Specific Aim 4 To establish whether the use of ATG induction followed by reduced doses of tacrolimus differentially affects anti-donor immune responses andor promotes the development of T cell dependent immunoregulatory networks
Conventional immunosuppressive protocol
1 Methylprednisolone iv 500 mg before laparotomy and 500 mg at the time of reperfusion
2 Methylprednisolone iv according to the following schedule postoperative day 1 200 mg day 2 160mg day 3 120 mg day 4 80 mg day 5 40 mg and thereafter 20 mg oral prednisone
3 Oral tacrolimus q12h starting on postoperative day 1 in order to reach trough drug levels between 10 and 15 ngmL These levels will be maintained in this range during the first month after transplantation Subsequently tacrolimus levels will be gradually reduced as follows month 1-3 8-15 ngml month 4-12 7-12 ngml afterwards 5-10 ngml
4 Progressive prednisone withdrawal between month 6 and 9 after transplantation
5 Treatment of acute rejection episodes according to our conventional clinical protocol All efforts must be done in order to histologically document the rejection episode Hence empirical treatment should be avoided if possible
Induction protocol
1 ATG-Fresenius 9mgkg pre-transplantation preceded by administration of 500 mg iv methylprednisolone Infusion of ATG-F will be started whenever the surgeon confirms the suitability of the graft and will take place during 6 hours
2 Oral tacrolimus q12h starting on postoperative day 1 at the required dosages in order to reach through drug levels between 5 and 12 ngmL
3 Reduction of tacrolimus dosages starting 3 months after transplantation in stable patients with no evidences of graft rejection in the previous 60 days and according to the following protocol
posttransplant month 3 1 dose per day
posttransplant month 6 1 dose every 48 hours
posttransplant month 9 ½ dose every 48 hours
posttransplant month 12 evaluate the possibility of complete drug withdrawal or alternatively establish the optimal maintenance dose
4 Treatment of acute rejection episodes mild to moderate acute rejection episodes re-start 1-2 daily doses of tacrolimus Severe acute rejection episodes or those mild to moderate episodes that do not improve after 10 days of treatment 1-2 daily doses of tacrolimus plus methylprednisolone 05-1 g for 3 days Resolution of the rejection episode will be followed by resumption of the above mentioned protocol If a new rejection episode takes place after treatment of the acute episode no further attempts to reduce tacrolimus dosages will be attempted In all cases rejection will be confirmed by liver biopsy
5 Patients suffering from hepatitis C virus infection will be treated as above unless alpha-interferon treatment is considered In this case daily tacrolimus will be administered
6 All patients will receive CMV prophylaxis with iv ganciclovir for 14 days and oral valganciclovir to complete 3 months after transplantation
Sample collection during the study period
In addition to routine diagnostic tests all enrolled patients will undergo the following procedures
Cryopreservation of donor spleen cells to measure anti-donor immune responses
HCV viral load quantification pre-transplantation and at post-transplant months 1 6 and 12
All patients will undergo liver biopsy 1 year after transplantation and yearly thereafter In addition HCV positive patients will be undergo liver biopsy 3 months after transplantation A portion of all liver biopsies will be cryopreserved for gene expression studies
Anti-donor and anti-HCV T cell immune responses will be quantified before transplantation and 6 and 12 months after transplantation by gamma-interferon ELISpot assay
Peripheral blood mononuclear cells will be harvested and cryopreserved before transplantation 6 months and 12 months after transplantation to perform gene expression and flow cytometry studies
A sample of recipient DNA will be cryopreserved to perform DNA polymorphism studies
Specific Aim 1 To determine the proportion of liver recipients in whom tacrolimus usage can be significantly reduced 1 year after transplantation Patients will be considered as successfully receiving a reduced tacrolimus regimen if this drug is given as a single dose every other day or at the most administered as a single dose daily with trough levels 5ngmL
Specific Aim 2 To determine the effect of induction treatment plus minimized immunosuppression on graft and patient survival
Specific Aim 3 To determine the impact of induction treatment plus minimized immunosuppression on the development of acute and chronic allograft rejection hepatitis C virus graft recurrence opportunistic infections bone fractures kidney failure tacrolimus-related neurotoxicity dyslipidemia and arterial hypertension
Specific Aim 4 To establish whether the use of ATG induction followed by reduced doses of tacrolimus differentially affects anti-donor immune responses andor promotes the development of T cell dependent immunoregulatory networks
Conventional immunosuppressive protocol
1 Methylprednisolone iv 500 mg before laparotomy and 500 mg at the time of reperfusion
2 Methylprednisolone iv according to the following schedule postoperative day 1 200 mg day 2 160mg day 3 120 mg day 4 80 mg day 5 40 mg and thereafter 20 mg oral prednisone
3 Oral tacrolimus q12h starting on postoperative day 1 in order to reach trough drug levels between 10 and 15 ngmL These levels will be maintained in this range during the first month after transplantation Subsequently tacrolimus levels will be gradually reduced as follows month 1-3 8-15 ngml month 4-12 7-12 ngml afterwards 5-10 ngml
4 Progressive prednisone withdrawal between month 6 and 9 after transplantation
5 Treatment of acute rejection episodes according to our conventional clinical protocol All efforts must be done in order to histologically document the rejection episode Hence empirical treatment should be avoided if possible
Induction protocol
1 ATG-Fresenius 9mgkg pre-transplantation preceded by administration of 500 mg iv methylprednisolone Infusion of ATG-F will be started whenever the surgeon confirms the suitability of the graft and will take place during 6 hours
2 Oral tacrolimus q12h starting on postoperative day 1 at the required dosages in order to reach through drug levels between 5 and 12 ngmL
3 Reduction of tacrolimus dosages starting 3 months after transplantation in stable patients with no evidences of graft rejection in the previous 60 days and according to the following protocol
posttransplant month 3 1 dose per day
posttransplant month 6 1 dose every 48 hours
posttransplant month 9 ½ dose every 48 hours
posttransplant month 12 evaluate the possibility of complete drug withdrawal or alternatively establish the optimal maintenance dose
4 Treatment of acute rejection episodes mild to moderate acute rejection episodes re-start 1-2 daily doses of tacrolimus Severe acute rejection episodes or those mild to moderate episodes that do not improve after 10 days of treatment 1-2 daily doses of tacrolimus plus methylprednisolone 05-1 g for 3 days Resolution of the rejection episode will be followed by resumption of the above mentioned protocol If a new rejection episode takes place after treatment of the acute episode no further attempts to reduce tacrolimus dosages will be attempted In all cases rejection will be confirmed by liver biopsy
5 Patients suffering from hepatitis C virus infection will be treated as above unless alpha-interferon treatment is considered In this case daily tacrolimus will be administered
6 All patients will receive CMV prophylaxis with iv ganciclovir for 14 days and oral valganciclovir to complete 3 months after transplantation
Sample collection during the study period
In addition to routine diagnostic tests all enrolled patients will undergo the following procedures
Cryopreservation of donor spleen cells to measure anti-donor immune responses
HCV viral load quantification pre-transplantation and at post-transplant months 1 6 and 12
All patients will undergo liver biopsy 1 year after transplantation and yearly thereafter In addition HCV positive patients will be undergo liver biopsy 3 months after transplantation A portion of all liver biopsies will be cryopreserved for gene expression studies
Anti-donor and anti-HCV T cell immune responses will be quantified before transplantation and 6 and 12 months after transplantation by gamma-interferon ELISpot assay
Peripheral blood mononuclear cells will be harvested and cryopreserved before transplantation 6 months and 12 months after transplantation to perform gene expression and flow cytometry studies
A sample of recipient DNA will be cryopreserved to perform DNA polymorphism studies
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None