Pilot Study of Treatment for Subclinical AMR (Antibody-mediated Rejection) in Kidney Transplant Recipients

Study Overview
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Brief Summary
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This is a pilot study to determine if extended release Envarsus at an optimal level is just as effective as more invasive standard therapies for subclinical (mild) AMR (antibody mediated rejection) in kidney transplant patients. Subjects will be randomized to either conversion to Envarsus XR (extended release); or, to a standard of care regimen of plasma exchange/IVIG (intravenous immunoglobulin)/rituximab treatments.

Detailed Description
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There is currently minimal data to guide treatment of mild graft damage in kidney transplant patients. Some of the current therapies used often come with dangerous complications (infections, malignancies, etc.). This is a pilot study to determine if extended release Envarsus at an optimal level is just as effective as more invasive standard therapies for subclinical (mild) AMR (antibody mediated rejection) in kidney transplant patients. The subjects will be randomized to either conversion from their current tacrolimus regimen to Envarsus XR (a once a day, extended release version of tacrolimus); or, to a regimen of 5 plasma exchanges/IVIG (intravenous immunoglobulin) treatments and one treatment with rituximab. Subjects who are within their first year of transplant will visit their doctor monthly for regular tests and checks and then will have a kidney biopsy at 6 months. Subjects who had their transplant over a year prior will see the doctor for tests and checks at 1, 3 and 5 months and then will have a biopsy of the kidney at month 6.

Official Title
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A Randomized Pilot Study of Treatment for Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients

Conditions
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Kidney Transplant Rejection

Intervention / Treatment
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* Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]
* Other: Plasma Exchange and IVIG (Intravenous Immunoglobulin )


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (18+ years) recipients of kidney or kidney/pancreas transplants Willing to sign an IRB (institutional review board)-approved consent and to comply with study requirements DSA (donor specific antibodies) detected by SAB (single antigen beads) screening with MFI ≥ 2000 Graft biopsy performed within prior 30 days Stable renal function defined by serum creatinine increase ≤ 30% over prior 6 months Subacute antibody-mediated rejection on biopsy defined by ptc + g + C4d ≥ 2 by Banff 2013 criteria Exclusion Criteria: Kidney/liver or kidney/heart recipient Unwilling/unable to undergo screening biopsy HIV (human immunodeficiency virus), HCV (hepatitis-C virus), or HBsAg (hepatitis-B surface antigen) positive Active/untreated infection Acute cellular rejection with Banff grade 1b, 2a, 2b on initial biopsy requiring rATG (rabbit anti-thymocyte globulin) therapy Pregnant or nursing females

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 79 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Only patients meeting histologic criteria for AMR by Banff 2013 criteria will be randomized (ptc + g + c4d ≥ 2). Subjects will be randomized to either undergo optimization (conversion to Envarsus with goal trough tacrolimus level > 8 ng/ml, mycophenolic acid at 720 mg, prednisone at current dose (5mg) or continue taper to 5mg per center standard of care protocol of or treatment.); or, to treat clinical AMR (antibody mediated rejection) with plasma exchange x 5 treatments, each followed by IVIG (intravenous immunoglobulin) 200 mg/kg except last dose of 1 gm/kg. Rituximab 375 mg/m2 following final plasma exchange treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 - conversion to Envarsus XR<br>Optimize: conversion to Envarsus XR (Tacrolimus Extended Release Oral Tablet [Envarsus]) with goal trough tac level > 8 ng/ml, MPA at 720 mg bid unless medically contraindicated, prednisone at current dose (5mg) or continue taper to 5mg per center standard of care protocol | Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]<br>* Switching from current version of tacrolimus to the extended release, once a day version (Envarsus) and titrating dose to achieve an optimal trough level. Goal trough tac level > 8 ng/ml, MPA at 720 mg bid unless medically contraindicated, prednisone at current dose (5mg) or continue taper to 5mg per center standard of care protocol.<br>* Other names: Envarsus XR;|
| Active Comparator: Arm 2 - plasma exchange and IVIG<br>Treat clinical AMR: Plasma exchange x 5 treatments, each followed by IVIG 200 mg/kg except last dose of 1 gm/kg. Rituximab 375 mg/m2 following final plasma exchange treatment. | Other: Plasma Exchange and IVIG (Intravenous Immunoglobulin )<br>* Plasma exchange x 5 treatments, each followed by IVIG 200 mg/kg except last dose of 1 gm/kg. Rituximab 375 mg/m2 following final plasma exchange treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Acute Inflammatory Histologic Parameters | Any increase or reduction in ptc+g+C4d score by Banff 2013 criteria) from baseline (pre-treatment) to 6 month (post-treatment initiation). Analysis will comprise exact chi-squared tests for comparison of binomial proportions of histological response between the two treatment groups. | Baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in MDRD GFR (Modification of Diet in Renal Disease Glomerular Filtration Rate) | Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests. | 6 and 12 months | 
| Change in Donor-Specific Antibody (DSA) Mean Fluorescence Intensity (MFI) Level | Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests. | 6 and 12 months | 
| Change in serum creatinine | Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests. | 6 and 12 months | 
| Graft Survival | Total and death-censored calculated using Kaplan-Meier methods and compared using logrank tests. | 6 and 12 months | 
| Patient Survival | Total and death-censored calculated using Kaplan-Meier methods and compared using logrank tests. | 6 and 12 months | 
| Evaluation of Adverse Events | All potential adverse events will be captured and recorded by study coordinators during post-treatment standard of care clinic visits, and reviewed by PI. Adverse events will be reported for each group separately and compared using exact chi-squared tests. | 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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subclinical, graft rejection, AMR (antibody-mediated rejection), AMBR (acute antibody-mediated rejection), DSA (donor specific antibodies)