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

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

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.

Study Overview

• Status: Terminated
• Conditions: Kidney Transplant Rejection
• Intervention / Treatment: Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]; Other: Plasma Exchange and IVIG (Intravenous Immunoglobulin )

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 - conversion to Envarsus XR; 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]; 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.; Other Names: Envarsus XR
Active Comparator: Arm 2 - plasma exchange and IVIG; 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 ); 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Veloxis Pharmaceuticals
• Investigators: Principal Investigator: James Cooper, M.D., University of Colorado, Denver; Principal Investigator: Scott Davis, M.D., University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2018
• Primary Completion (Actual): October 16, 2019
• Study Completion (Actual): October 16, 2019

Study Registration Dates

• First Submitted: October 26, 2017
• First Submitted That Met QC Criteria: December 19, 2017
• First Posted (Actual): December 21, 2017

Study Record Updates

• Last Update Posted (Actual): October 27, 2020
• Last Update Submitted That Met QC Criteria: October 23, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: graft rejection; subclinical; AMR (antibody-mediated rejection); AMBR (acute antibody-mediated rejection); DSA (donor specific antibodies)
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous; Tacrolimus; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: 17-1812

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No