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

Early Phase 1

Terminated

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

• Registration Number: NCT03380936
• Lead Sponsor: University of Colorado, Denver

Brief Summary

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

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 Timeline

• Study First Submitted: 2017-10-26
• Study First Submitted QC: 2017-12-19
• Study First Posted: 2017-12-21
• Study Start: 2018-01-17
• Primary Completion: 2019-10-16
• Study Completion: 2019-10-16
• Status Verified: 2020-10
• Last Update Submitted: 2020-10-23
• Last Update Posted: 2020-10-27

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 4

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1 - conversion to Envarsus XR	Tacrolimus Extended Release Oral Tablet [Envarsus]	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
Arm 2 - plasma exchange and IVIG	Plasma Exchange and IVIG (Intravenous Immunoglobulin )	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.

Primary Outcome Measures

Name	Time	Method
Change in Acute Inflammatory Histologic Parameters	Baseline and 6 months	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.

Secondary Outcome Measures

Name	Time	Method
Change in MDRD GFR (Modification of Diet in Renal Disease Glomerular Filtration Rate)	6 and 12 months	Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests.
Change in Donor-Specific Antibody (DSA) Mean Fluorescence Intensity (MFI) Level	6 and 12 months	Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests.
Patient Survival	6 and 12 months	Total and death-censored calculated using Kaplan-Meier methods and compared using logrank tests.
Change in serum creatinine	6 and 12 months	Comparison of these levels and any changes of levels/rates using two-sided two-sample t-tests.
Graft Survival	6 and 12 months	Total and death-censored calculated using Kaplan-Meier methods and compared using logrank tests.
Evaluation of Adverse Events	6 and 12 months	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.

Trial Locations

Locations (1)

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States