Complication of Transplanted LiverNCT02784080
Donor Specific HLA Alloantibodies in Liver Transplantation
An observational study of Complication of Transplanted Liver, run by Copenhagen University Hospital, Rigshospitalet at 5 sites in 4 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Complication of Transplanted Liver
- What is being tested?
- HLA-alloantibodies exposure
- How many people
- 858 participants
- Where
- 5 sitesin 4 countries
- Study dates
- 15 Aug 2015to Dec 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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.
Who may be able to join
- Undergo a liver transplanted during the study period.
- Pre-transplant serum sample of minimum 4 ml (relevant for pediatric patients)
- Informed consent is given.
Who cannot join
- Withdrawal of informed consent.
- Blinding broken in a non-protocoled manner the patient will be excluded.
Trial locations and contacts
5 sites in 4 countries.
5 sites in 4 countries
Sweden2 sites
Surgery Department, Transplantation and Liver Surgery Unit, Sahlgrenska University Hospital
Gothenburg, 413 45
Division of Transplantation Surgery, Karolinska Institutet
Stockholm, 14186
Denmark1 site
Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital
Copenhagen, 2100
Finland1 site
Transplantation and Liver Surgery Clinic, Helsinki University Hospital
Helsinki, PL 372, 00029 HUS
Norway1 site
Department of Transplantation Medicine, Oslo University Hospital
Oslo, 0424
About this study
Official title: 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.
Read more
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.
Read the 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:
- 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.
- 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.
- 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.
In 2021 it was decided to split the study in a preformed and de novo study.
Preformed DSA
- Our primary objective is to investigate if preformed and persistent DSA class I and II affect survival and re-transplantation.
- The secondary objective is to investigate if preformed and persistent DSA class I and II is correlated with increased risk of acute rejection and early allograft dysfunction.
Preformed DSA will be analysed in 4 different ways separately for donor specific HLA class I and class II antibodies.
- Dichotomous analysis defined as any DSA class I or II MFI >1000 is considered positive.
- Number of different class I or II DSA will be analyzed as an ordinal variable.
- A continuous variable by MFI, as a sum of all. Homozygous donors will not be accounted for.
- Analysis will be done for no antibodies versus: 1) HLA-DQ (including DRB5 subtypes) 2) HLA-DR 3) HLA-DQ and -DR. Both as categorical and binary.
- Conditions
- Complication of Transplanted Liver
- Being tested
- HLA-alloantibodies exposure
- Keywords
- Liver Transplantation, HLA alloantibodies, donor specific antibodies, Mortality, Re-transplantation, Rejection, Acute rejection, Chronic rejection, Biliary complications, Biliary stricture, Arterial thrombosis, Arterial stenosis, Portal vein thrombosis, Fibrosis, Single antigen bead, Cross-match
- Medical subject headings
- Rejection, Psychology, Fibrosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HLA-alloantibodies exposureOther
Following analyzes will be done:
LABScreen® Single Antigen, One Lambda, CA
C1qScren™, One Lambda, CA (planned for later study)
PE-conjugated IgG3 antibody (planned for later study)
LABScreen® Mixed, One Lambda, CA (never analysed in the study)
| Study group | Role | What they receive |
|---|---|---|
| HLA-alloantibodies exposure | Preformed, persistent, and de novo HLA-alloantibody exposure in the whole cohort. Receives: Other: HLA-alloantibodies exposure |
What is being measured
The primary outcome is the main question the study is designed to answer.
All-cause mortality or re-transplantation (graft loss)
Measured: Minimum 1 year, accrual to study end
Secondary outcomes (6)
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.
Measured: 7 days after transplantation
Acute rejection, both cellular and humoral rejection, as defined by Banff classification.
Measured: 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".
Measured: Minimum 1 year, accrual to study end
Fibrosis, defined by METAVIR score.
Measured: Minimum 1 year, accrual to study end
Vascular complications (hepatic arterial stenosis, hepatic arterial thrombosis, portal vein thrombosis).
Measured: Minimum 1 year, accrual to study end
Biliary complications (biliary leakage, anastomotic biliary stricture, non-anastomotic biliary stricture, liver abscess, cholangitis, other).
Anastomotic strictures and non-anastomotic strictures will be investigated as a combined and solitary outcome.
Measured: Minimum 1 year, accrual to study end
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2016 (estimated)
- Study start15 Aug 2015
- Primary completionSep 2024
- Study completionDec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Complication of Transplanted LiverStudies of the same condition, open and under way.
- More trials run by Copenhagen University Hospital, RigshospitaletThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 858 participants (actual)
Sponsor and investigators
- Lead sponsor
- Copenhagen University Hospital, Rigshospitalet
- Sponsor type
- University, hospital or other
- Collaborators
- Sahlgrenska University Hospital, Karolinska Institutet, Helsinki University Central Hospital, Oslo University Hospital
- Responsible party
- Principal investigator, Andreas Arendtsen Rostved, Copenhagen University Hospital, Rigshospitalet
- Investigators
- Allan Rasmussen, MD, Study chair, Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, DenmarkAndreas A Rostved, MD, Principal investigator, Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, DenmarkHelle Bruunsgaard, MD, DMSc, Study director, Department of Clinical Immunology, Centre of Diagnostic Investigation, Rigshospitalet - Copenhagen University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02784080
- Sponsor's protocol ID
- H-15007823
- Status last verified
- Sep 2024
- First submitted
- 24 May 2016
- Last updated
- 19 Sep 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Kim WR, Smith JM, Skeans MA, Schladt DP, Schnitzler MA, Edwards EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant. 2014 Jan;14 Suppl 1:69-96. doi: 10.1111/ajt.12581.
PubMed 24373168
Study at a glance
From the registry record, last updated by the sponsor on 19 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Donor Specific HLA Alloantibodies in Liver Transplantation: a Prospective Blinded Multicenter Prognostic Study
- ClinicalTrials.gov ID
- NCT02784080
- Acronym / sponsor ID
- H-15007823
- Conditions
- Complication of Transplanted Liver
- Keywords
- Liver Transplantation, HLA alloantibodies, donor specific antibodies, Mortality, Re-transplantation, Rejection, Acute rejection, Chronic rejection
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 858 participants (actual)
- Lead sponsor
- Copenhagen University Hospital, RigshospitaletUniversity, hospital or other
- Collaborators
- Sahlgrenska University Hospital, Karolinska Institutet, Helsinki University Central Hospital, Oslo University Hospital
- Study start
- 15 Aug 2015 (actual)
- Primary completion
- Sep 2024 (actual)
- Study completion
- Dec 2024 (estimated)
- First posted
- 26 May 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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:
- 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.
- 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.
- 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.
In 2021 it was decided to split the study in a preformed and de novo study.
Preformed DSA
- Our primary objective is to investigate if preformed and persistent DSA class I and II affect survival and re-transplantation.
- The secondary objective is to investigate if preformed and persistent DSA class I and II is correlated with increased risk of acute rejection and early allograft dysfunction.
Preformed DSA will be analysed in 4 different ways separately for donor specific HLA class I and class II antibodies.
- Dichotomous analysis defined as any DSA class I or II MFI >1000 is considered positive.
- Number of different class I or II DSA will be analyzed as an ordinal variable.
- A continuous variable by MFI, as a sum of all. Homozygous donors will not be accounted for.
- Analysis will be done for no antibodies versus: 1) HLA-DQ (including DRB5 subtypes) 2) HLA-DR 3) HLA-DQ and -DR. Both as categorical and binary.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| HLA-alloantibodies exposure | – | Other: HLA-alloantibodies exposurePreformed, persistent, and de novo HLA-alloantibody exposure in the whole cohort. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- 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.
Key inclusion criteria (3 listed)
- Undergo a liver transplanted during the study period.
- Pre-transplant serum sample of minimum 4 ml (relevant for pediatric patients)
- Informed consent is given.
Key exclusion criteria (2 listed)
- Withdrawal of informed consent.
- Blinding broken in a non-protocoled manner the patient will be excluded.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| HLA-alloantibodies exposureFollowing analyzes will be done: LABScreen® Single Antigen, One Lambda, CA C1qScren™, One Lambda, CA (planned for later study) PE-conjugated IgG3 antibody (planned for later study) LABScreen® Mixed, One Lambda, CA (never analysed in the study) | Other | HLA-alloantibodies exposure |
Primary outcome
All-cause mortality or re-transplantation (graft loss)
Time frame: Minimum 1 year, accrual to study end
6 secondary outcomes
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
Acute rejection, both cellular and humoral rejection, as defined by Banff classification.
Time frame: 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
Fibrosis, defined by METAVIR score.
Time frame: 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
Biliary complications (biliary leakage, anastomotic biliary stricture, non-anastomotic biliary stricture, liver abscess, cholangitis, other).
Time frame: Minimum 1 year, accrual to study end
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Sep 2024.
- Background: PubMed 24373168Kim WR, Smith JM, Skeans MA, Schladt DP, Schnitzler MA, Edwards EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BL. OPTN/SRTR 2012 Annual Data Report: liver. Am J Transplant. 2014 Jan;14 Suppl 1:69-96. doi: 10.1111/ajt.12581.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Allan Rasmussen, MD study chair
Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark
Andreas A Rostved, MD principal investigator
Department of Surgical Gastroenterology and Transplantation, Rigshospitalet - Copenhagen University Hospital, Denmark
Helle Bruunsgaard, MD, DMSc study director
Department of Clinical Immunology, Centre of Diagnostic Investigation, Rigshospitalet - Copenhagen University Hospital
5 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Complication of Transplanted Liver, run by Copenhagen University Hospital, Rigshospitalet at 5 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 19 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Sweden, Denmark, Finland, Norway. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
All-cause mortality or re-transplantation (graft loss) (time frame: Minimum 1 year, accrual to study end). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02784080, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Sep 2024.