Secretin in Ex-situ Liver Perfusion

June 11, 2026 updated by: Prof. Robert J. Porte, Erasmus Medical Center

Secretin Therapy During Ex-Situ Normothermic Liver Machine Perfusion: A Critical Factor for Restoration of Bile Duct Physiology and the Protective "Bicarbonate Umbrella"

The main objective is to assess whether the use of human synthetic secretin in a clinical (COR-)NMP procedure can restore physiological HCO3- content of the bile during ex-situ NMP.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

Liver transplantation is the only curative treatment option for patients with end-stage liver disease, but it is limited by a large gap between the number of patients in need and donor organs available. Strikingly, in 2021, 38% of available donor livers were disposed being assessed as non-transplantable in The Netherlands, while approximately 20% of patients on the liver transplant waitlist died or became too sick to be transplanted. Similar or even higher discard rates are observed in other countries, such as the US. Acceptance of extended criteria donor (ECD) livers, referring to suboptimal grafts from older, obese, or otherwise comorbid donors and organs from donation after circulatory death (DCD), is proposed to meet this growing demand. However, transplantation of these livers is associated with a higher rate of post-operative complications, increased hospital costs and reduced graft survival, compared to standard grafts.

Machine perfusion (MP) is a dynamic, isolated platform to preserve liver grafts out-of-the-body by circulation of an oxygenated perfusate. While dual hypothermic oxygenated perfusion (DHOPE) reconditions the graft in a hypometabolic state, normothermic MP (NMP) allows full assessment of metabolic function at physiological temperatures. The sequential protocol of both perfusion techniques, with controlled oxygenated rewarming for 60 minutes (COR), named DHOPE-COR-NMP is currently used in clinical practice for viability assessment of high-risk ECD-livers prior to transplantation. The decision moment whether a liver is suitable for transplantation is after 150 minutes of NMP. Unfortunately, one third of these tested livers are currently discarded, mainly because of not meeting the predefined criteria for cholangiocyte viability (own, unpublished data). The platform of MP allows graft reconditioning in an isolated circuit, with no systemic effects of administered therapeutics in the recipient as the liver is thoroughly flushed out before implantation in the recipient, thereby limiting side-effects.

Secretin is a hormone with a short half-life that is produced in the duodenum, with systemic effects. In the liver, secretin stimulates cholangiocytes through the secretin receptor. This leads to an increase in intracellular cyclic AMP (cAMP), subsequently activating Protein kinase A (PKA), eventually leading to a downstream excretion of chloride through the CFTR channels. Chloride is a leading force in bicarbonate excretion, as this excreted chloride is resorbed through Anion-Exchanger-2 (AE2) and exchanged for bicarbonate. In a physiological setting, cholangiocytes are protected from bile-acid injury by this "bicarbonate umbrella". With the excretion of bicarbonate, water is also excreted through Aquaporin-1 (AQP-1), and thus increasing total bile production. The increase in bile production is one of the main reasons for secretin to be administered during Magnetic Resonance Cholangio-Pancreatography (MRCP) imaging of the biliary tree in its current application as diagnostic tool.

The perfusate that is used for NMP, is based on an oxygen carrier (currently red blood cells), colloids and certain supplements to reach a near-physiological environment in oncotic pressure and nutrients. In physiological conditions, bile contains high amounts of bicarbonate, resulting in an alkalotic fluid. This earlier mentioned "bicarbonate umbrella" protects the cholangiocytes from bile acid-induced injury. During NMP, bile pH and bile bicarbonate levels are lower compared to a physiological setting (own, unpublished data). The investigators hypothesize that cholangiocytes during NMP are not able to demonstrate their full potential, as they are not stimulated by secretin like in-vivo physiology. As explained earlier, the increase in bile production is a result of increasing bicarbonate excretion, and thereby biliary pH, creating a more physiological environment for the liver and bile ducts. Possible further injury of the bile duct from bile acid toxicity could be prevented by adding secretin to the perfusate during COR-NMP. This however, can only be researched after this initial validation of the safety and efficacy of secretin as a missing component to reach physiological conditions during ex-situ liver NMP.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Phase 2
  • Phase 1

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

  • Netherlands
    • South Holland
      • Rotterdam, South Holland, Netherlands, 3015 GD
        • Erasmus 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

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Adult patients (>18 years old)
  • Donor livers that required resuscitation and viability assessment through the previously published sequential hypo- and normothermic liver machine perfusion (DHOPE-COR-NMP) protocol based on a blood-based perfusate.

Exclusion Criteria:

  • Multiorgan transplantation
  • Split liver transplant
  • Living donor liver transplantation
  • Organ donation after Euthanasia
  • Previous donor organ perfusion (e.g. Normothermic Regional Perfusion)

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

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Historical control group
Historical cases of sequential hypo- to normothermic machine perfusion, linked with controlled oxygenated rewarming for 60 minutes (DHOPE-COR-NMP) livers that did not receive synthetic human secretin during the perfusion.
Experimental: Secretin administration during liver machine perfusion (COR-NMP)
These livers will be treated during ex-situ machine perfusion with a blood-based perfusate with doses of human synthetic secretin.
Drug: Secretin administration during ex-situ liver machine perfusion

In at least 20 cases of sequential hypo- to normothermic machine perfusion, linked with controlled oxygenated rewarming (COR) for 60 minutes (DHOPE-COR-NMP) livers, the investigators will add 16mcg of synthetic human secretin to the perfusate at the start of COR phase of the protocol and a second dose of 16mcg during the NMP phase after the decision moment whether to transplant or not. This number was chosen based on an average acceptance rate of 70%, and therefore would generate 14 transplanted livers while 6 livers are expected not to be transplanted (not passing the standard viability criteria).

As the acceptance rate is subject to fluctuations over time (due to variations in the quality of donor offers), the investigators want to include at least 14 transplanted livers and 6 livers that are not transplanted (not passing the standard viability criteria), in order to have the best representative situation. When both numbers are reached, inclusions will stop.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cholangiocellular viability assessment - Biliary Bicarbonate
Time Frame: Periprocedural
A comparison will be made between livers that pass cholangiocyte viability assessment and livers that do not pass cholangiocyte viability assessment in the secretin cohort of this study. Analysis will be performed on bile composition, with the main outcome being the response in biliary bicarbonate increase 30 minutes after the second dose of administration (directly after viability assessment with the go-no go for transplantation).
Periprocedural

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cholangiocellular viability assessment - Bile production
Time Frame: Periprocedural
A comparison will be made between livers that pass cholangiocyte viability assessment and livers that do not pass cholangiocyte viability assessment in the secretin cohort of this study. Analysis will be performed on bile production with the volume (mL) increase 30 minutes after the second dose of administration (directly after viability assessment with the go-no go for transplantation).
Periprocedural

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Comparison with historical cohort - Biliary complications
Time Frame: Until 6 months post-transplant
The cohort of livers that are transplanted and were subjected to Secretin at the beginning of controlled oxygenated rewarming (COR) will be compared to similar cases in our historical cohort of transplanted livers after sequential hypo- to normothermic machine perfusion linked with COR (DHOPE-COR-NMP). For descriptive purposes, complication rate, especially anastomotic strictures, ischemic cholangiopathy, bile leaks will be registered, but based on the small numbers and short follow-up in this pilot study will not be analysed.
Until 6 months post-transplant

Collaborators and Investigators

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

Sponsor

Erasmus Medical Center

Investigators

  • Principal Investigator: Robert J Porte, MD, PhD, Erasmus 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)

April 26, 2025

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

October 1, 2026

Study Registration Dates

First Submitted

January 26, 2026

First Submitted That Met QC Criteria

June 11, 2026

First Posted (Actual)

June 16, 2026

Study Record Updates

Last Update Posted (Actual)

June 16, 2026

Last Update Submitted That Met QC Criteria

June 11, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Other Study ID Numbers

  • MEC-2024-0678

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

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

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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