Ignite Creation Date:
2024-05-05 @ 11:20 AM
Last Modification Date:
2024-10-26 @ 9:02 AM
Study NCT ID:
NCT00001984
Status:
COMPLETED
Last Update Posted:
2016-10-27
First Post:
2000-01-26
Brief Title:
Effectiveness of the Investigational Drug Campath-1H in Preventing Rejection of Transplanted Kidneys
Sponsor:
National Institute of Diabetes and Digestive and Kidney Diseases NIDDK
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Tolerance Induction Following Human Renal Transplantation Using Treatment With a Humanized Monoclonal Antibody Against CD52 Campath-1H
Status:
COMPLETED
Status Verified Date:
2016-09
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:
This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability to induce a state of permanent allograft acceptance or tolerance when administered in combination with a brief course of the immunosuppressive drug deoxyspergualin DSG at the time of human renal allotransplantation Campath-1H is specific for the common lymphocyte and monocyte antigen CD52 Its administration temporarily depletes mature lymphocytes and some monocytes without altering neutrophils or hematopoietic stem cells Deoxyspergualin inhibits the NFkB pathway thus preventing monocyte and macrophage activation
Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion Three subsequent doses of Campath-1H will be administered on the first third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft In addition patients will be treated with DSG for 14 days beginning on the day prior to surgery This trial expands on pilot studies at the NIH of 15 patients in which Campath was given alone at the time of transplantation In those studies excellent peripheral depletion occurred after just one dose of Campath though central depletion required additional dosing This allowed for greatly reduced immunosuppression to be used to prevent rejection but to date all patients have required some immunosuppressive medication It is hoped that the addition of DSG will eliminate the need for long-term immunosuppression
Patients will be followed closely in the post transplant period If patients experience rejection they will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent In the previous phase of this study without DSG this maneuver has in all cases been successful in returning the allograft to normal function
In addition to evaluating graft function following transplantation this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG and during immune system recovery after transplantation
Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion Three subsequent doses of Campath-1H will be administered on the first third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft In addition patients will be treated with DSG for 14 days beginning on the day prior to surgery This trial expands on pilot studies at the NIH of 15 patients in which Campath was given alone at the time of transplantation In those studies excellent peripheral depletion occurred after just one dose of Campath though central depletion required additional dosing This allowed for greatly reduced immunosuppression to be used to prevent rejection but to date all patients have required some immunosuppressive medication It is hoped that the addition of DSG will eliminate the need for long-term immunosuppression
Patients will be followed closely in the post transplant period If patients experience rejection they will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent In the previous phase of this study without DSG this maneuver has in all cases been successful in returning the allograft to normal function
In addition to evaluating graft function following transplantation this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG and during immune system recovery after transplantation
Detailed Description:
This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability to induce a state of permanent allograft acceptance or tolerance when administered in combination with a brief course of the immunosuppressive drug deoxyspergualin DSG at the time of human renal allotransplantation Campath-1H is specific for the common lymphocyte and monocyte antigen CD52 Its administration temporarily depletes mature lymphocytes and some monocytes without altering neutrophils or hematopoietic stem cells Deoxyspergualin inhibits the Rel-B NFkB pathway thus preventing monocyte and macrophage activation Extensive preliminary data have been accumulated in humans using Campath-1H and its non-humanized predecessors Additionally data have been generated using a similar depleting scheme with and without DSG in non-human primates Both the human and non-human primate data suggest that profound mature mononuclear cell depletion establishes a window of opportunity during which foreign tissue can be transplanted without the need for additional immunosuppression Regulatory events occuring during mature cell repopulation in the presence of allografted tissue created a state in which the graft may not be rejected even in the absence of chronic immunosuppression
Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion Three subsequent doses of Campath-1H will be administered on the first third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft In addition patients will be treated with DSG 4mgkgd x 1 beginning on day 12 and then 25 mgkgd for an additional 13 days This trial expands on pilot studies at the NIH of 17 patients in which Campath was dosed both prior to and after transplantation with and without DSG In those studies excellent peripheral depletion occured after just one dose of Campath though central depletion required additional dosing Thus the goal of pre-reperfusion depletion can be achieved with a single pre-operative dose but thorough depletion requires additional post-operative dosing Lasting rejection-free survival was not realized without the addition of some albeit reduced immunosuppression This is thought to be due to residual post-operative monocytes that infiltrated the allograft causing modest reversible allograft dysfunction The current dosing regimen with DSG is thus designed to accomplish both pre-operative depletion and more thorough post operative elimination of donor and recipient cells mobilizing as a result of reperfusion combined with therapy aimed at preventing the activation of monocytes that escape depletion The timing of the DSG is meant to correspond with the peripheral repopulation of monocytes seen in previous patients
Patients will be followed closely in the post transplant period for evidence of a detrimental immune response to the allograft In the previous patients experiencing graft directed immunity the graft dysfunction was preceded by a rise in activated monocytes in the peripheral blood and augmented transcription of the cytokine Tumor Necrosis Factor-alpha TNF-a in the allograft This syndrome has been resistant to treatment with the TNF-a sequestrant Infliximab and is now thought to require more comprehensive monocyte directed therapy If patients progress and graft dysfunction occurs patients will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent This maneuver has in all cases been successful in returning the allograft to normal function Sirolimus has been chosen since it does not act by interfering with specific T cell receptor function and thus provides immunosuppressive coverage during cell repopulation without interfering with the antigen specific T cell events important for tolerance induction Non-human primate and human clinical data support both of these approaches
In addition to evaluating graft and patient outcome following transplantation this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG and during immune system recovery after transplantation
Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion Three subsequent doses of Campath-1H will be administered on the first third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft In addition patients will be treated with DSG 4mgkgd x 1 beginning on day 12 and then 25 mgkgd for an additional 13 days This trial expands on pilot studies at the NIH of 17 patients in which Campath was dosed both prior to and after transplantation with and without DSG In those studies excellent peripheral depletion occured after just one dose of Campath though central depletion required additional dosing Thus the goal of pre-reperfusion depletion can be achieved with a single pre-operative dose but thorough depletion requires additional post-operative dosing Lasting rejection-free survival was not realized without the addition of some albeit reduced immunosuppression This is thought to be due to residual post-operative monocytes that infiltrated the allograft causing modest reversible allograft dysfunction The current dosing regimen with DSG is thus designed to accomplish both pre-operative depletion and more thorough post operative elimination of donor and recipient cells mobilizing as a result of reperfusion combined with therapy aimed at preventing the activation of monocytes that escape depletion The timing of the DSG is meant to correspond with the peripheral repopulation of monocytes seen in previous patients
Patients will be followed closely in the post transplant period for evidence of a detrimental immune response to the allograft In the previous patients experiencing graft directed immunity the graft dysfunction was preceded by a rise in activated monocytes in the peripheral blood and augmented transcription of the cytokine Tumor Necrosis Factor-alpha TNF-a in the allograft This syndrome has been resistant to treatment with the TNF-a sequestrant Infliximab and is now thought to require more comprehensive monocyte directed therapy If patients progress and graft dysfunction occurs patients will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent This maneuver has in all cases been successful in returning the allograft to normal function Sirolimus has been chosen since it does not act by interfering with specific T cell receptor function and thus provides immunosuppressive coverage during cell repopulation without interfering with the antigen specific T cell events important for tolerance induction Non-human primate and human clinical data support both of these approaches
In addition to evaluating graft and patient outcome following transplantation this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG and during immune system recovery after transplantation
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
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 00-DK-0013 | None | None | None |