Donor Specific HLA Alloantibodies in Liver Transplantation

February 24, 2020 updated by: Andreas Arendtsen Rostved, Rigshospitalet, Denmark

Donor Specific HLA Alloantibodies in Liver Transplantation: a Prospective Blinded Multicenter Prognostic Study

The aim is to evaluate the impact of donor specific HLA alloantibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, fibrosis, vascular, and biliary complications. Furthermore, all biopsies will be C4d stained. The hypothesizes is that donor specific HLA alloantibodies facilitate an immune mediated damage to the liver allograft that impairs function and lead to various complications.

The investigators will do a prospective blinded multicenter cohort study in the Scandiatransplant organ sharing organization region.

Both preformed, persistent, and de novo donor specific HLA alloantibodies will studied. Blood samples will be taken immediately prior to transplantation, and 14 days, 3 months, and 1 year after transplantation. All liver biopsies performed during the study period will be evaluated for a humoral component and blood samples will be obtained prior to liver biopsies to investigate the presence of DSA.

Investigations will be fully blinded for the treatment responsible doctors.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

The outcome after liver transplantation has improved drastically over time, but this development has stagnated in recent years to a graft failure rate of 9-15 % within the first year and approximately 20-30 % at 5 years [1]. The primary goal is to improve the outcome after liver transplantation.

The impact of donor specific antibodies (DSA) on all-cause mortality and re-transplantation, early allograft dysfunction, acute and chronic rejection, vascular and biliary complications and fibrosis will be investigated.

Objectives:

  1. The primary objective is to investigate if DSA both pre-formed, persistent, and de novo affect survival and allograft loss. For patients diagnosed with HLA antibodies a standard Luminex single antigen IgG analysis, a Luminex C1q and an IgG3 single antigen assay will be performed.
  2. The secondary objective is to investigate if donor specific antibodies, both pre-formed, persistent, and de novo increase the risk of early allograft dysfunction, acute and chronic rejection, fibrosis, de novo autoimmune hepatitis (pediatric patients only), vascular and biliary complications. All liver biopsies will be stained by C4d and a DSA analysis will be undertaken.
  3. Continuous measurements will be used to establish the kinetics of both preformed og de novo DSA after liver transplantation.

Pediatric patients will be analyzed separately.

Study Type

Observational

Enrollment (Anticipated)

1162

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

  • Denmark
      • Copenhagen, Denmark, 2100
        • Recruiting
        • Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Andreas A Rostved, MD
        • Principal Investigator:
          • Allan Rasmussen, MD
        • Sub-Investigator:
          • Helle Bruunsgaard, MD, DMSc
  • Finland
      • Helsinki, Finland, PL 372, 00029 HUS
        • Recruiting
        • Transplantation and Liver Surgery Clinic, Helsinki University Hospital
        • Contact:
        • Principal Investigator:
          • Helena Isoniemi, MD, PhD
        • Sub-Investigator:
          • Johanna Arola, MD, PhD
  • Norway
      • Oslo, Norway, 0424
        • Recruiting
        • Department of Transplantation Medicine, Oslo University Hospital
        • Contact:
        • Principal Investigator:
          • Pål-Dag Line, MD, PhD
  • Sweden
      • Göteborg, Sweden, 413 45
        • Recruiting
        • Surgery Department, Transplantation and Liver Surgery Unit, Sahlgrenska University Hospital
        • Contact:
        • Principal Investigator:
          • William Bennet, MD, PhD
        • Sub-Investigator:
          • Maria Castedal, MD, PhD
      • Stockholm, Sweden, 14186
        • Recruiting
        • Division of Transplantation Surgery, Karolinska Institutet
        • Contact:
        • Principal Investigator:
          • Bo-Göran Ericzon, Professor
        • Sub-Investigator:
          • Carl Jons, MD, PhD

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

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

All liver transplant recipients, both children and adults, in the Scandiatransplant region. The Scandiatransplant is an organ exchange organization that comprise of five centers in the Nordic countries: Norway, Sweden, Finland and Denmark. The five centers cover the need for liver transplantation in approximately 25 million people. From 2010-2015 the following number of transplants were done in Scandiatransplant according to the number of available donors: 323, 352, 353, 365, 388, and 401.

Preliminary sample size calculations have estimated inclusion of 1062 adult and 100 pediatric patients during a study period of 3 years. Interim sample size calculations will be done, if necessary the study period will be prolonged.

Pediatric patients will be analyzed separately.

Description

Inclusion Criteria:

  • Undergo a liver transplanted during the study period.
  • Pre-transplant serum sample of minimum 4 ml (relevant for pediatric patients)
  • Informed consent is given.

Exclusion Criteria:

  • Withdrawal of informed consent.
  • Blinding broken in a non-protocoled manner the patient will be excluded.

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

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
HLA-alloantibodies exposure
Preformed, persistent, and de novo HLA-alloantibody exposure in the whole cohort.
Other: HLA-alloantibodies exposure

Following analyzes will be done:

LABScreen® Mixed, One Lambda, CA LABScreen® Single Antigen, One Lambda, CA C1qScren™, One Lambda, CA PE-conjugated IgG3 antibody

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
All-cause mortality or re-transplantation (graft loss)
Time Frame: Minimum 1 year, accrual to study end
Minimum 1 year, accrual to study end

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Early allograft dysfunction are defined as total bilirubin >10 mg/dl or INR >1.6 at day 7 after liver transplantation or ALT >2000 IU/L within the first 7 days after liver transplantation.
Time Frame: 7 days after transplantation
7 days after transplantation
Acute rejection, both cellular and humoral rejection, as defined by Banff classification.
Time Frame: Minimum 1 year, accrual to study end
Minimum 1 year, accrual to study end
Chronic rejection, as defined by Banff classification, and as proposed by O'leary et al "Proposed Diagnostic Criteria for Chronic Antibody-Mediated Rejection in Liver Allografts".
Time Frame: Minimum 1 year, accrual to study end
Minimum 1 year, accrual to study end
Fibrosis, defined by METAVIR score.
Time Frame: Minimum 1 year, accrual to study end
Minimum 1 year, accrual to study end
Vascular complications (hepatic arterial stenosis, hepatic arterial thrombosis, portal vein thrombosis).
Time Frame: Minimum 1 year, accrual to study end
Minimum 1 year, accrual to study end
Biliary complications (biliary leakage, anastomotic biliary stricture, non-anastomotic biliary stricture, liver abscess, cholangitis, other).
Time Frame: Minimum 1 year, accrual to study end
Anastomotic strictures and non-anastomotic strictures will be investigated as a combined and solitary outcome.
Minimum 1 year, accrual to study end

Collaborators and Investigators

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

Sponsor

Rigshospitalet, Denmark

Collaborators

Karolinska Institutet
Oslo University Hospital
Helsinki University Central Hospital
Sahlgrenska University Hospital, Sweden

Investigators

  • Study Chair: Allan Rasmussen, MD, Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark
  • Principal Investigator: Andreas A Rostved, MD, Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark
  • Study Director: Helle Bruunsgaard, MD, DMSc, Department of Clinical Immunology, Centre of Diagnostic Investigation, Rigshospitalet - Copenhagen University Hospital

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)

August 1, 2015

Primary Completion (Anticipated)

September 1, 2021

Study Completion (Anticipated)

September 1, 2021

Study Registration Dates

First Submitted

May 24, 2016

First Submitted That Met QC Criteria

May 24, 2016

First Posted (Estimate)

May 26, 2016

Study Record Updates

Last Update Posted (Actual)

February 26, 2020

Last Update Submitted That Met QC Criteria

February 24, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-15007823

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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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