Ignite Creation Date:
2024-05-05 @ 12:05 PM
Last Modification Date:
2024-10-26 @ 9:20 AM
Study NCT ID:
NCT00235781
Status:
TERMINATED
Last Update Posted:
2006-10-16
First Post:
2005-10-06
Brief Title:
Single Dose Thymoglobulin for Induction in Adult Renal Allograft Recipients
Sponsor:
Washington University School of Medicine
Organization:
Washington University School of Medicine
Study Overview
Official Title:
Non-Phased Study of the Use of a Single Dose of Thymoglobulin for Immunosuppressive Induction in Renal Transplant Recipients as Compared to a Standard Four Dose Regimen
Status:
TERMINATED
Status Verified Date:
2006-10
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:
None
Brief Summary:
The aim of this trial is to compare the safety and efficacy of a single dose of Thymoglobulin rabbit derived antithymocyte globulin Thymoglobulin SangStat Fremont CA to our standard four dose four day Thymoglobulin induction regimen from the time of transplantation through a six month follow-up period The primary endpoint will be the incidence of acute rejection Secondary endpoints will include serious adverse events evaluation of renal function patient and graft survival incidence of infectious complications incidence of post-transplantation lymphoproliferative disorder PTLD duration and extent of lymphocyte depletion and immunoassays for evidence of recipient immune response to the allograft as well as duration of hospital stay
Detailed Description:
Induction therapy using polyclonal or monoclonal antibody preparations as an adjunct immunosuppressive agent during the initial transplant period has helped to decrease the incidence of acute rejection significantly In the 1980s acute rejection occurred in approximately 50 of renal transplant recipients In the current era of transplantation the combination of potent induction agents and newly available maintenance immunosuppressive agents has reduced the acute rejection rate to less than 20 at most transplant centers Our center has routinely achieved acute rejection rates of approximately 5 using a standard induction protocol with the polyclonal antibody agent Thymoglobulin
Preventing acute rejection significantly decreases the requirement for re-hospitalization the need for diagnostic renal allograft biopsy and subsequent exposure to high dose corticosteroids and other immunosuppressive agents The threat of early allograft loss secondary to rejection refractory to treatment or permanent injury and shortened graft survival following treatment of a severe rejection is also circumvented
Polyclonal antibody preparations are produced by immunizing animals with human lymphocytes or thymocytes Polyclonal antibody preparations are approved for treatment of acute renal allograft rejection but are routinely used as induction agents and for prevention of rejection in all solid organ allografts Commercially available preparations in the United States are equinethymocyte derived Atgam Pharmacia Upjohn Kalamazoo MI and rabbitthymocyte derived Thymoglobulin Genzyme Cambridge MA
Rabbit derived preparations are thought to be potentially more efficacious than equine derived products Studies performed at this renal transplant center demonstrated that Thymoglobulin has superior efficacy compared to Atgam in the prevention of rejection 1 Not only was the acute rejection rate lower but graft survival was also better at 1 and 5-years 1 Hardinger 2004 18 This result has been attributed in part to a more pronounced and prolonged lymphopenia induced by Thymoglobulin 2
The broad specificity of polyclonal agents to multiple cell signaling and adhesion molecules provides a theoretic advantage compared to monoclonal antibodies In addition to inducing a profound and prolonged lymphopenia through complement-dependent lysis or by opsonization and phagocytosis the broad specificity of polyclonal antibody agents affects multiple costimulatory and adhesion molecules involved in cellular and antibody mediated immune processes The effects on adhesion molecules cytokines chemokines and platelets may be critical to the noted decrease in the incidence of delayed renal allograft function associated with initiation of Thymoglobulin therapy intraoperatively 3 Prevention of delayed graft function may also subsequently decrease the incidence of acute rejection and prolong allograft survival
The use of a potent induction agent such as Thymoglobulin also allows for a delayed introduction of maintenance immunosuppression with calcineurin inhibitors in the immediate post-transplant setting The ability to delay the introduction of therapeutic doses of calcineurin inhibitors when necessary can also assist in decreasing the incidence of delayed graft function and simplifies patient management in this time period
Thymoglobulin has now become the preferred polyclonal agent used for induction in renal transplantation The most recent complete yearly data from the Scientific Registry of Transplant Recipients in 2003 indicated that 70 of all renal transplant recipients in that calendar year received some form of induction therapy Thymoglobulin 34 of patients was the most commonly administered agent while one of two available monoclonal antibody preparations directed against the interleukin-2 receptor IL2-R was administered to approximately 35 of renal transplant recipients 4
When Thymoglobulin is used in the treatment of acute rejection a total dose of 10-12mgkg is often administered over the course of several days 5 The optimal dose of Thymoglobulin that should be administered for induction is unclear although a primate model suggests a total human equivalent dose of approximately 6mgkg may be appropriate 6 Most transplant centers using Thymoglobulin for induction have administered a total dose of 6-10mgkg given at varying intervals usually daily or every other day with each individual dose usually given as 1 to 15mgkgday over approximately six hours Our standard induction protocol has been 15mgkgday for a total of four doses total dose 6mgkg
The ability to administer Thymoglobulin as a single large dose has several potential pharmacoeconomic benefits This administration protocol would simplify post-transplant care in the hospital and allow for earlier patient discharge Cost savings would result from both a shorter hospital stay and decreased administration costs associated with fewer intravenous administrations
The administration of a single large dose infusion of Thymoglobulin has been used in an attempt to induce prope Latin for almost allograft tolerance 7 In this study that included 50 renal allograft recipients a single dose infusion of Thymoglobulin 5mgkg was used in conjunction with a marked minimization of maintenance immunosuppression The induction protocol was well tolerated and maintenance immunosuppression consisted of monotherapy with tacrolimus
Another study described the administration of Thymoglobulin 5mgkgday given as two separate doses 10mgkg total in 39 renal allograft recipients 8 One dose was administered on the day of transplantation and the subsequent dose on post-transplant day number one No patients in this study were withdrawn secondary to adverse events and the acute rejection rate was 6 with a patient and graft survival of 95 at a mean follow-up of 145 months
We have previously performed a short course Thymoglobulin induction study using an initial dose of 3mgkg with subsequent doses of 15mgkg on post-transplant days one and two 9 This regimen was well tolerated and resulted in a low acute rejection rate of 5 a one year graft survival of 95 and earlier hospital discharge compared to a previously standard seven day Thymoglobulin induction protocol
Thus we hypothesize that a single dose of Thymoglobulin 6mgkg initiated intraoperatively and administered over the course of 24 hours will have comparable safety and efficacy as compared to our current standard induction protocol of four separate doses of Thymoglobulin 15mgkg total dose 6mgkg Single dose administration of Thymoglobulin should provide a low rate of acute rejection a low rate of delayed graft function allow for delayed introduction of calcineurin inhibitors if indicated and potentially allow for earlier patient discharge while consuming fewer resources If this single dose induction protocol demonstrates similar safety and efficacy to our current standard four dose induction protocol it may become our standard of care This study may also be a bridge to subsequent dose finding studies for single dose Thymoglobulin administration and subsequent comparative studies of single-dose Thymoglobulin to other induction agents
1 Brennan DC Flavin K Lowell JA et al A randomized double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients Transplantation 19996771011-1018
2 Hardinger KL Schnitzler MA Miller B et al Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation Transplantation 2004781136-141
3 Goggins WC Pascual MA Powelson JA et al A prospective randomized clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients Transplantation 2003765798-802
4 Shapiro R Young JB Milford EL et al Immunosuppression evolution in practice and trends 1993-2003 Am J Transplant 200554 Pt 2874-886
5 Gaber AO First MR Tesi RJ et al Results of the double-blind randomized multicenter phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation Transplantation 199866129-37
6 Preville X Flacher M LeMauff B et al Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model Transplantation 2001713460-468
7 Starzl TE Murase N Abu-Elmagd K et al Tolerogenic immunosuppression for organ transplantation Lancet 200336193681502-1510
8 Uslu A Nart A Coker I et al Two-day induction with thymoglobulin in kidney transplantation risks and benefits Transplant Proc 200436176-79
9 Agha IA Rueda J Alvarez A et al Short course induction immunosuppression with thymoglobulin for renal transplant recipients Transplantation 2002733473-475
Preventing acute rejection significantly decreases the requirement for re-hospitalization the need for diagnostic renal allograft biopsy and subsequent exposure to high dose corticosteroids and other immunosuppressive agents The threat of early allograft loss secondary to rejection refractory to treatment or permanent injury and shortened graft survival following treatment of a severe rejection is also circumvented
Polyclonal antibody preparations are produced by immunizing animals with human lymphocytes or thymocytes Polyclonal antibody preparations are approved for treatment of acute renal allograft rejection but are routinely used as induction agents and for prevention of rejection in all solid organ allografts Commercially available preparations in the United States are equinethymocyte derived Atgam Pharmacia Upjohn Kalamazoo MI and rabbitthymocyte derived Thymoglobulin Genzyme Cambridge MA
Rabbit derived preparations are thought to be potentially more efficacious than equine derived products Studies performed at this renal transplant center demonstrated that Thymoglobulin has superior efficacy compared to Atgam in the prevention of rejection 1 Not only was the acute rejection rate lower but graft survival was also better at 1 and 5-years 1 Hardinger 2004 18 This result has been attributed in part to a more pronounced and prolonged lymphopenia induced by Thymoglobulin 2
The broad specificity of polyclonal agents to multiple cell signaling and adhesion molecules provides a theoretic advantage compared to monoclonal antibodies In addition to inducing a profound and prolonged lymphopenia through complement-dependent lysis or by opsonization and phagocytosis the broad specificity of polyclonal antibody agents affects multiple costimulatory and adhesion molecules involved in cellular and antibody mediated immune processes The effects on adhesion molecules cytokines chemokines and platelets may be critical to the noted decrease in the incidence of delayed renal allograft function associated with initiation of Thymoglobulin therapy intraoperatively 3 Prevention of delayed graft function may also subsequently decrease the incidence of acute rejection and prolong allograft survival
The use of a potent induction agent such as Thymoglobulin also allows for a delayed introduction of maintenance immunosuppression with calcineurin inhibitors in the immediate post-transplant setting The ability to delay the introduction of therapeutic doses of calcineurin inhibitors when necessary can also assist in decreasing the incidence of delayed graft function and simplifies patient management in this time period
Thymoglobulin has now become the preferred polyclonal agent used for induction in renal transplantation The most recent complete yearly data from the Scientific Registry of Transplant Recipients in 2003 indicated that 70 of all renal transplant recipients in that calendar year received some form of induction therapy Thymoglobulin 34 of patients was the most commonly administered agent while one of two available monoclonal antibody preparations directed against the interleukin-2 receptor IL2-R was administered to approximately 35 of renal transplant recipients 4
When Thymoglobulin is used in the treatment of acute rejection a total dose of 10-12mgkg is often administered over the course of several days 5 The optimal dose of Thymoglobulin that should be administered for induction is unclear although a primate model suggests a total human equivalent dose of approximately 6mgkg may be appropriate 6 Most transplant centers using Thymoglobulin for induction have administered a total dose of 6-10mgkg given at varying intervals usually daily or every other day with each individual dose usually given as 1 to 15mgkgday over approximately six hours Our standard induction protocol has been 15mgkgday for a total of four doses total dose 6mgkg
The ability to administer Thymoglobulin as a single large dose has several potential pharmacoeconomic benefits This administration protocol would simplify post-transplant care in the hospital and allow for earlier patient discharge Cost savings would result from both a shorter hospital stay and decreased administration costs associated with fewer intravenous administrations
The administration of a single large dose infusion of Thymoglobulin has been used in an attempt to induce prope Latin for almost allograft tolerance 7 In this study that included 50 renal allograft recipients a single dose infusion of Thymoglobulin 5mgkg was used in conjunction with a marked minimization of maintenance immunosuppression The induction protocol was well tolerated and maintenance immunosuppression consisted of monotherapy with tacrolimus
Another study described the administration of Thymoglobulin 5mgkgday given as two separate doses 10mgkg total in 39 renal allograft recipients 8 One dose was administered on the day of transplantation and the subsequent dose on post-transplant day number one No patients in this study were withdrawn secondary to adverse events and the acute rejection rate was 6 with a patient and graft survival of 95 at a mean follow-up of 145 months
We have previously performed a short course Thymoglobulin induction study using an initial dose of 3mgkg with subsequent doses of 15mgkg on post-transplant days one and two 9 This regimen was well tolerated and resulted in a low acute rejection rate of 5 a one year graft survival of 95 and earlier hospital discharge compared to a previously standard seven day Thymoglobulin induction protocol
Thus we hypothesize that a single dose of Thymoglobulin 6mgkg initiated intraoperatively and administered over the course of 24 hours will have comparable safety and efficacy as compared to our current standard induction protocol of four separate doses of Thymoglobulin 15mgkg total dose 6mgkg Single dose administration of Thymoglobulin should provide a low rate of acute rejection a low rate of delayed graft function allow for delayed introduction of calcineurin inhibitors if indicated and potentially allow for earlier patient discharge while consuming fewer resources If this single dose induction protocol demonstrates similar safety and efficacy to our current standard four dose induction protocol it may become our standard of care This study may also be a bridge to subsequent dose finding studies for single dose Thymoglobulin administration and subsequent comparative studies of single-dose Thymoglobulin to other induction agents
1 Brennan DC Flavin K Lowell JA et al A randomized double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients Transplantation 19996771011-1018
2 Hardinger KL Schnitzler MA Miller B et al Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation Transplantation 2004781136-141
3 Goggins WC Pascual MA Powelson JA et al A prospective randomized clinical trial of intraoperative versus postoperative Thymoglobulin in adult cadaveric renal transplant recipients Transplantation 2003765798-802
4 Shapiro R Young JB Milford EL et al Immunosuppression evolution in practice and trends 1993-2003 Am J Transplant 200554 Pt 2874-886
5 Gaber AO First MR Tesi RJ et al Results of the double-blind randomized multicenter phase III clinical trial of Thymoglobulin versus Atgam in the treatment of acute graft rejection episodes after renal transplantation Transplantation 199866129-37
6 Preville X Flacher M LeMauff B et al Mechanisms involved in antithymocyte globulin immunosuppressive activity in a nonhuman primate model Transplantation 2001713460-468
7 Starzl TE Murase N Abu-Elmagd K et al Tolerogenic immunosuppression for organ transplantation Lancet 200336193681502-1510
8 Uslu A Nart A Coker I et al Two-day induction with thymoglobulin in kidney transplantation risks and benefits Transplant Proc 200436176-79
9 Agha IA Rueda J Alvarez A et al Short course induction immunosuppression with thymoglobulin for renal transplant recipients Transplantation 2002733473-475
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