Belatacept to Prevent Organ Rejection in Kidney Transplant Patients

Study Overview
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Brief Summary
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Belatacept is an experimental medication shown in clinical trials to have immune system suppression properties in people who have had renal (e.g., kidney) transplants. This study will determine whether a combination of anti-rejection drugs, including belatacept, can prevent the rejection of a first-time, non-human leukocyte antigen (HLA) identical renal transplant and allow patients to be safely withdrawn from anti-rejection therapy one year post-transplant.

Detailed Description
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Drugs that suppress the immune system have contributed to increased success of transplantation; however, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives. These drugs make patients more susceptible to infection and certain kinds of cancer. Belatacept is an experimental medication that specifically targets immune reactions against transplanted organs and has been shown to be effective in preventing kidney transplant rejection in previous clinical trials. Both thymoglobulin, an antibody, and sirolimus, an anti-rejection drug, prevent rejection by lowering the response of the immune system to the transplanted organ. This study will evaluate whether belatacept, along with thymoglobulin and sirolimus, is safe in kidney transplant patients. The study will also evaluate this regimen's potential to allow tapering and eventual discontinuation of all immunosuppressive drugs. This study will last up to 4 years. At the time of transplant, participants will begin an immunosuppressive treatment regimen consisting of thymoglobulin, sirolimus, and belatacept. Participants will receive infusions of thymoglobulin on days 1 through 4, and a combination of oral sirolimus (daily) and belatacept infusions at day 5, then weeks 2, 4, 8, and monthly for at least 2 years. Dose reduction of belatacept will occur at 12 weeks post-transplant. At Year 2, eligible participants may choose to begin drug withdrawal or continue study therapy through the end of the study. Study visits will occur weekly for the first two months, then monthly. These visits will include belatacept treatment, general medical assessments, blood and urine collection, and other assessments to determine overall health of the recipient's immune system and kidney transplant and to better understand the way the immune system works in the acceptance or rejection of organ transplants. *** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Official Title
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The Safety and Efficacy of Belatacept, Antithymocyte Globulin, and Sirolimus in Recipients of Non-HLA-identical Living-donor Renal Transplants (ITN023ST)

Conditions
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Renal Transplant

Intervention / Treatment
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* Drug: Belatacept
* Drug: Sirolimus
* Drug: Anti-thymocyte globulin
* Drug: methylprednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Receiving first renal (e.g., kidney) transplant Transplant is from a non-HLA-identical living donor Willing to use acceptable forms of contraception Exclusion Criteria: Positive for anti-human globulin (AHG) or T-cell cross-match with the donor Receiving multiple-organ transplant History of cancer within the 5 years prior to study entry. Patients who have certain nonmelanoma skin cancers are not excluded Human immunodeficiency virus (HIV) infected Hepatitis B (HBV) or C (HCV) virus infected Other active infections Active tuberculosis (TB) infection within the 3 years prior to study entry Pregnancy or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belatacept<br>Immunosuppressive protocol consisting of belatacept, glucocorticoids, antithymocyte globulin (ATG), and sirolimus. | Drug: Belatacept<br>* 10 mg/kg given intravenously (IV) on transplant (day 1), day 5, and at weeks 2, 4, 8 and 12, then 5 mg/kg IV every 4 weeks<br>* Other names: Nulojix;Drug: Sirolimus<br>* 4 mg/day (oral tablet) at transplant (day 1), then dose adjusted to maintain serum trough level of 8-12 ng/mL for at least 1 year<br>* Other names: Rapamune;Drug: Anti-thymocyte globulin<br>* 1.5 mg/kg given IV daily on days 1 through 4. Subjects are premedicated with glucocorticoids, acetaminophen 650 mg by mouth, and diphenhydramine 25- 50 mg by mouth prior to each dose.<br>* Other names: Thymoglobulin®;Drug: methylprednisolone<br>* 500 mg given IV at transplant (day 1), then given 250 mg IV on day 2 and given 0.5 mg/kg IV or prednisone 0.5 mg/kg given by mouth on days 3 and 4<br>* Other names: glucocorticoid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Rejection at 6-Months | Cumulative incidence of acute rejection[1] at 6 months post-transplant based on local pathology biopsy reads Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater[2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 | 6 months post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Survival at 12 Months Post-Transplant |  | 12 months post-transplant | 
| Acute Rejection at 12-Months | Incidence of acute rejection[1] at 12 months post-transplant Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater[2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 | 12 months post-transplant | 
| Tolerance Induction | Time from transplantation to initiation of sirolimus withdrawal. | 48 months | 
| Renal Function as Measured by Glomerular Filtration Rate (GFR) at 24 Weeks | GFR utilizing clearance of iothalamate. GFR is an index of level of kidney function. A higher value means better kidney function. | 24 weeks post-transplant | 
| Graft Survival at 12 Months Post-transplant |  | 12 months post-transplant | 
| Time From Transplant to Acute Rejection | Time (days) from transplant to occurrence of acute rejection[1] Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater[2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 | Transplantation until rejection occurs (participants followed up to four years post-transplantation) | 
| Proportion of Participants Requiring Antilymphocyte Therapy for Acute Rejection | Proportion of participants who experienced acute rejection[1] requiring antilymphocyte therapy Diagnosis of acute rejection was made by renal (kidney) biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater[2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999 | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With Post-transplant Infections | Proportion of participants who experienced infections post-transplant. Participants were checked for any type of opportunistic infection at all study visits post-transplantation (up to 4 years post-transplantation) | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With Wound Complications |  | Start of study to end of study | 
| Proportion of Participants With Malignancies |  | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With a Sirolimus Associated Adverse Event |  | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With Chronic Allograft Nephropathy |  | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With Delayed Graft Function |  | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 
| Proportion of Participants With Post-transplant Diabetes Mellitus |  | Participants followed from transplantation until completion of study (up to four years post-transplantation) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal transplantation, kidney transplantation, renal allograft recipient, anti-rejection drugs, immunosuppression protocol, immunosuppression withdrawal