Belatacept Conversion in Proteinuric Kidney Transplant Recipients

The B7-1 Study": Belatacept Conversion in Proteinuric Renal Transplant Recipients: an Interventional Multi-Center Trial

Background: Proteinuria develops in about 30% of kidney transplant recipients and is a strong predictor of graft loss. The amount of proteinuria has a direct correlation with the risk of graft failure. Novel therapies are urgently needed to reduce proteinuria and prevent graft loss in transplant recipients, since ACE inhibitors carry a number of limitations in the transplant setting, including significant reduction in renal function, anemia and hyperkalemia.

Preliminary data: B7-1 is expressed at significant levels in about 10% of kidney allograft biopsies with predominance in patients with proteinuria.

Hypothesis: We hypothesize that B7-1 targeting therapy may reduce proteinuria and improve graft survival in proteinuric transplant recipients that have B7-1 staining on allografts. In addition, the absence of CNI nephrotoxicity and the potential protective effect of Belatacept on DSA production may be of benefit in this subset of transplant patients.

Objectives:

Primary: Determine the effect of Belatacept conversion in reducing proteinuria by 25% at 12 months in renal transplant recipients (≥1gram/d) that are either B7-1-positive or negative on kidney biopsy.

Secondary: Assess the effect of Belatacept conversion in the percent change of renal function from baseline to 12 months; donor-specific anti-HLA antibodies presence and intensity (MFI); correlation of B7-1 positivity on immunofluorescence on biopsy with B7-1-expression in urine extracellular vesicles; adverse events; acute rejection episodes; blood pressure control; new onset diabetes; hyperlipidemia; graft survival; and patient survival.

Study Overview

• Status: Completed
• Conditions: Proteinuria
• Intervention / Treatment: Drug: Belatacept

Detailed Description

A total of 36 patients will be recruited.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Male or female adult kidney transplant recipients older than 18 years old
2. eGFR ≥30 ml/min
3. ≥6 months after transplantation
4. Proteinuria ≥1 gram/day in spot urine protein/creatinine ratio
5. Ability to provide written informed consent for the study.
6. Maintenance immunosuppression of CNI (cyclosporine or tacrolimus), antiproliferative agent (azathioprine, MMF or MPA) with either steroids or not.

Exclusion Criteria:

1. Age <18 years
2. eGFR<30 ml/min
3. active acute cellular rejection (ACR; higher than borderline) or ACR in the previous 6 months; active acute antibody-mediated rejection
4. recurrent FSGS
5. EBV IgG negative
6. patient on mTOR inhibitor (e.g. Everolimus, Sirolimus)
7. patient only on CNI (cyclosporine or tacrolimus) and steroids

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: Proteinuric Kidney Transplant Recipients; Belatacept conversion	Drug: Belatacept; Conversion from calcineurin-inhibitor to Belatacept maintenance immunosuppression.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Proteinuria by 25%	Change in proteinuria by 25%: daily proteinuria is estimated by spot urine protein (mg/dL) to creatinine (mg/dL) ratio at baseline (before the belatacept conversion) and post-conversion 12 months; and interval % change was calculated by getting the ratio of difference between the two time points to the baseline value.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Renal Function (eGFR in mL/Min/1.73 m^2)		from baseline to 12 months
Acute Rejection Episodes	Acute rejection episodes [Time Frame: 12 months]: Number of biopsy-proven rejection episodes from belatacept conversion to post-conversion 12 months.	12 months
Change in Blood Pressure Measurement (mm Hg)	Change in Blood pressure measurement (mm Hg) [Time Frame: 12 months]: The mmHg difference in systolic and diastolic blood pressures between the baseline (pre-belatacept conversion) and post-conversion 12 months is assessed. Blood pressure measurement done at the office visits at baseline and 12 months after at least 5 minutes of resting.	12 months
Change in Fasting Glucose	New onset diabetes [Time Frame: 12 months]: Number of new onset diabetes per American Diabetes Association 2015 Criteria from belatacept conversion to post-conversion 12 months	12 months
Hyperlipidemia	Hyperlipidemia [ Time Frame: 12 months]: Changes (mg/dL) in serum total cholesterol, LDL, HDL, and triglyceride levels from pre-belatacept conversion to post-conversion 12 months.	12 months
Graft Survival	Graft survival [Time Frame: 12 months]: Number of patients who developed end stage kidney disease and required kidney replacement therapy within 12 months post-belatacept conversion.	12 months
Patient Survival		12 months

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Leonardo V Riella, MD, PhD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): September 1, 2020
• Study Completion (Actual): October 1, 2020

Study Registration Dates

• First Submitted: December 22, 2014
• First Submitted That Met QC Criteria: December 24, 2014
• First Posted (Estimate): December 30, 2014

Study Record Updates

• Last Update Posted (Actual): November 9, 2022
• Last Update Submitted That Met QC Criteria: October 17, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Proteinuria; Kidney transplantation; Belatacept; Allograft dysfunction; B7-1
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Urination Disorders; Proteinuria; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Immune Checkpoint Inhibitors; Abatacept
• Other Study ID Numbers: 2015P000154