Longitudinal Changes in Donor-Derived Cell-Free DNA With Tocilizumab Treatment for Chronic Antibody-Mediated Rejection

February 5, 2024 updated by: Edmund Huang, Cedars-Sinai Medical Center

Use of Donor-Derived Cell-Free DNA to Characterize Response to Therapy With Tocilizumab for Chronic Antibody-Mediated Rejection in Kidney Transplantation

Our group recently reported that tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, may be effective when administered monthly to patients with chronic antibody-mediated rejection (ABMR). The current paradigm to assess response to therapy involves serial monitoring for donor-specific antibodies, measurement of kidney function with creatinine, and periodic kidney transplant biopsies to survey for histologic findings indicative of ongoing ABMR.

A new non-invasive blood test, donor-derived cell-free DNA (Allosure) has recently reported to have a high degree of discrimination for rejection and may be used to assess the likelihood of rejection. It has not been tested to see if it can be used to assess treatment response for rejection.

This study will assess longitudinal changes in donor-derived cell-free DNA measurements in response to monthly therapy with tocilizumab for chronic ABMR and correlate these measurements to histologic changes on a follow-up kidney transplant biopsy.

Study Overview

Status

Active, not recruiting

Conditions

Detailed Description

Chronic antibody-mediated rejection (ABMR) is now recognized as the leading cause of late kidney transplant failure (1). A number of new immunosuppressive medications have been introduced to the field of kidney transplantation over the last twenty years, leading to a reduction in early acute rejection rates (2). However, long-term graft survival has not improved, primarily because of failure to make a timely diagnosis of chronic ABMR and a lack of effective therapeutic options. To date, treatment options for chronic ABMR are limited and include intravenous immunoglobulin (IVIg), rituximab, and plasmapheresis. These agents are effective for treatment of acute ABMR; however, they are generally ineffective in sustaining kidney function and prolonging graft survival in chronic ABMR.

Interleukin-6 (IL-6) blockade has emerged as a promising therapy for chronic ABMR. Our group recently reported that tocilizumab, a humanized monoclonal antibody against the IL-6 receptor, administered monthly to patients with chronic ABMR is associated with a reduction in donor specific antibodies (DSA), stabilization of renal function, improvement in histologic features of chronic ABMR, and excellent patient and graft survival up to six years (3).

The diagnostic criteria for antibody-mediated rejection in kidney transplantation requires serologic evidence of donor-specific antibodies to human leukocyte antigen (HLA) or other antigens in conjunction with histologic findings of ABMR on biopsy for a definitive diagnosis of ABMR (4). The criteria recognize that the mere presence of DSA alone is not sufficient to classify a patient as having ABMR, as has been described previously (5). Among patients treated for ABMR, a reduction in DSA is associated with a favorable response but is only observed in a small percentage of treated patients (6). Among patients with chronic ABMR who are treated, there is a subset with persistence of high titer DSA, yet stable renal function and resolution of active lesions of ABMR on follow-up kidney biopsy. Although these patients may not warrant continuing therapy with tocilizumab, they cannot be distinguished from patients with persistently active ABMR without undergoing an additional allograft biopsy. A non-invasive test for ABMR is preferred, as allograft biopsies are invasive, resource-intensive, carry a risk of bleeding, and are time-consuming for the patient. If validated, non-invasive testing for ABMR can be useful for monitoring for a treatment response and may help guide therapy for ABMR.

Because donor-derived cell-free DNA (Allosure) is predictive of rejection n kidney transplantation, longitudinal changes in the percentage of donor-derived cell free DNA detected in plasma of kidney transplant recipients with chronic ABMR may correlate with a histologic and clinical response to treatment. The primary objective is to assess whether longitudinal changes in donor-derived cell-free DNA correlate with histologic and clinical response to treatment with tocilizumab for chronic ABMR. The secondary objectives are to assess the test performance of donor-derived cell-free DNA measured against histologic findings on biopsy, provide molecular evidence for response to tocilizumab therapy, and to describe the time course of treatment effect of tocilizumab in chronic ABMR.

Study Type

Observational

Enrollment (Actual)

10

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars-Sinai Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Adult recipients of a kidney transplant alone who have chronic active ABMR on kidney transplant biopsy and are recommended for treatment with tocilizumab

Description

Inclusion Criteria:

  • Age ≥18 years
  • Enrolled within six months of biopsy-proven evidence of chronic active ABMR defined by Banff 2017 diagnostic criteria
  • Evidence of DSA detected in the blood within 6 months prior to consent.
  • Able to understand and provide informed consent.

Exclusion Criteria:

  • Known contraindications for therapy with tocilizumab:
  • Hypersensitivity
  • Elevated liver enzymes
  • Patients at risk for GI perforation
  • Absolute neutrophil count <500/mm3
  • Platelet count <50,000/mm3
  • Active infection
  • Contraindications for kidney transplant biopsy, including bleeding diathesis or technical/anatomical infeasibility for biopsy.
  • Contraindications to donor-derived cell-free DNA (AlloSure) testing:
  • Recipient of multiple transplanted organs.
  • Recipient of a transplant from an identical twin.
  • Pregnant
  • Under the age of 18.
  • Less than two weeks post-transplant.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Chronic ABMR
Single arm; patients with chronic ABMR diagnosed by Banff 2017 criteria and recommended for monthly treatment with tocilizumab will undergo monthly testing for donor-derived cell-free DNA (Allosure) and then have a follow-up biopsy after six monthly infusions of tocilizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the percentage of donor-derived cell-free DNA
Time Frame: 12 months
Change in % donor-derived cell-free DNA/month
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Difference in Change in Donor-Derived Cell-Free DNA Between Responders and Non-Responders
Time Frame: 6 months
Difference in the mean delta of donor-derived cell-free DNA from baseline to six months among histologic responders and non-responders (paired t-test)
6 months
Change in estimated glomerular filtration rate (GFR)
Time Frame: 12 months
Change in estimated glomerular filtration rate (GFR) measured by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation over 12 months from initiation of tocilizumab treatment (linear mixed effects model)
12 months
Change in glomerulitis histology score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; g-score)
6 months
Change in peritubular capillaritis histology score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; ptc-score)
6 months
Change in C4d score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; C4d-score)
6 months
Change in glomerular double contours score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; cg-score)
6 months
Change in interstitial fibrosis score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; ci-score)
6 months
Change in tubular atrophy score with treatment
Time Frame: 6 months
Change in histologic features of ABMR before and after 6 months of treatment with tocilizumab (paired t-test; ct-score)
6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Cedars-Sinai Medical Center

Investigators

  • Principal Investigator: Edmund Huang, M.D., Cedars-Sinai Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2019

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

December 31, 2024

Study Registration Dates

First Submitted

February 25, 2019

First Submitted That Met QC Criteria

February 27, 2019

First Posted (Actual)

March 1, 2019

Study Record Updates

Last Update Posted (Actual)

February 7, 2024

Last Update Submitted That Met QC Criteria

February 5, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Other Study ID Numbers

  • Pro00053105

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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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