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

• ClinicalTrials.gov Identifier: NCT03380936
• Recruitment Status: Terminated
• First Posted: December 21, 2017
• Last Update Posted: October 27, 2020
• Sponsor: University of Colorado, Denver
• Collaborator: Veloxis Pharmaceuticals
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Kidney Transplant Rejection	Drug: Tacrolimus Extended Release Oral Tablet [Envarsus]; Other: Plasma Exchange and IVIG (Intravenous Immunoglobulin )	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 4 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention 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)
• Primary Purpose: Treatment
• Official Title: A Randomized Pilot Study of Treatment for Subclinical Antibody-Mediated Rejection in Kidney Transplant Recipients
• Actual Study Start Date: January 17, 2018
• Actual Primary Completion Date: October 16, 2019
• Actual Study Completion Date: October 16, 2019

Arms and Interventions

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 Name: 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.

Outcome Measures

Primary Outcome Measures :

1. Change in Acute Inflammatory Histologic Parameters [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Colorado

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

Veloxis Pharmaceuticals

Investigators

• Principal Investigator: James Cooper, M.D.; University of Colorado, Denver
• Principal Investigator: Scott Davis, M.D.; University of Colorado, Denver

More Information

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT03380936
• Other Study ID Numbers: 17-1812
• First Posted: December 21, 2017
• Last Update Posted: October 27, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by University of Colorado, Denver:

subclinical; graft rejection; AMR (antibody-mediated rejection); AMBR (acute antibody-mediated rejection); DSA (donor specific antibodies)

Additional relevant MeSH terms:

Tacrolimus; Immunoglobulins; Immunoglobulins, Intravenous; Antibodies; gamma-Globulins; Rho(D) Immune Globulin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action