Belatacept to Prevent Organ Rejection in Kidney Transplant Patients (BESTT)

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

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rejection of a first-time, non-human leukocyte antigen (HLA) identical renal transplant and allow patients to be safely withdrawn from anti-rejection therapy one year post-transplant.

Study Overview

• Status: Terminated
• Conditions: Renal Transplant
• Intervention / Treatment: Drug: Belatacept; Drug: Sirolimus; Drug: Anti-thymocyte globulin; Drug: methylprednisolone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Belatacept; Immunosuppressive protocol consisting of belatacept, glucocorticoids, antithymocyte globulin (ATG), and sirolimus.

Drug: Belatacept; 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; Other Names: Nulojix; LEA29Y; Drug: Sirolimus; 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; Other Names: Rapamycin; Rapamune; Drug: Anti-thymocyte globulin; 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.; Other Names: ATG; Thymoglobulin®; anti-thymocyte immunoglobulin; Drug: methylprednisolone; 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; Other Names: Medrol; glucocorticoid

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Immune Tolerance Network (ITN)
• Investigators: Principal Investigator: Flavio Vincenti, MD, University of California, San Francisco; Principal Investigator: Christian Larsen, MD, Emory University

Publications and helpful links

General Publications

• Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G, Lang P, Grinyo J, Halloran PF, Solez K, Hagerty D, Levy E, Zhou W, Natarajan K, Charpentier B; Belatacept Study Group. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005 Aug 25;353(8):770-81. doi: 10.1056/NEJMoa050085.

Helpful Links

• National Institute of Allergy and Infectious Diseases (NIAID) website
• Division of Allergy, Immunology, and Transplantation (DAIT) website
• Immune Tolerance Network (ITN) website

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: June 27, 2006
• First Submitted That Met QC Criteria: June 27, 2006
• First Posted (Estimate): June 29, 2006

Study Record Updates

• Last Update Posted (Actual): April 21, 2017
• Last Update Submitted That Met QC Criteria: March 23, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: kidney transplantation; renal transplantation; anti-rejection drugs; immunosuppression withdrawal; renal allograft recipient; immunosuppression protocol
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Immune Checkpoint Inhibitors; Methylprednisolone; Immunoglobulins; Sirolimus; Abatacept; Thymoglobulin; Antilymphocyte Serum; Glucocorticoids
• Other Study ID Numbers: DAIT ITN023ST

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data access is provided to the public in Participant level data and additional relevant materials are available to the public in : 1.) the Immunology Database and Analysis Portal (ImmPort), a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts that also provides data analysis tools available to researchers; and 2.) TrialShare, the Immune Tolerance Network (ITN) Clinical Trials Research Portal that makes data from the consortium's clinical trials publicly available.

Study Data/Documents

1. Individual Participant Data Set
   Information identifier: SDY674
   Information comments: ImmPort study identifier is SDY674
2. Study Protocol
   Information identifier: SDY674
   Information comments: ImmPort study identifier is SDY674. The study protocol is available in the Design tab section.
3. Study summary, -design, -synopsis,- medications, -demographics, -lab tests, -files
   Information identifier: SDY674
   Information comments: ImmPort study identifier is SDY674
4. Individual Participant Data Set
   Information identifier: ITN023ST
   Information comments: TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available.
5. Protocol synopsis, -data and reports, -specimens availability
   Information identifier: ITN023ST
   Information comments: TrialShare is a clinical trials research portal developed by the Immune Tolerance Network (ITN) that makes data from the consortium's clinical trials publicly available.