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Randomized Controlled Trial
. 2024 Feb 14;14(2):e079309.
doi: 10.1136/bmjopen-2023-079309.

Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial

Nikolaj Torp  1   2 , Mads Israelsen  3   2 , Minneke Coenraad  4 , Maria Papp  5 , Debbie Shawcross  6 , Marko Korenjak  7 , Paolo Angeli  8   9 , Wim Laleman  10   11 , Adria Juanola  12   13   14 , Pere Gines  12   13   14   15 , Jonel Trebicka  9   11 , Aleksander Krag  1   2 ; MICROB-PREDICT Consortium
Collaborators, Affiliations
Randomized Controlled Trial

Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL - a randomised clinical biomarker validation trial

Nikolaj Torp et al. BMJ Open. .

Abstract

Introduction: Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites.

Methods and analysis: ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis.

Ethics and dissemination: The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion.

Trial registration number: NCT05056220 EU CT: 2022-501006-34-01.

Keywords: health economics; hepatobiliary disease; hepatology; neglected diseases; protocols & guidelines; randomized controlled trial.

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Conflict of interest statement

Competing interests: PG received grants form Gilead and Grifols, served on advisory boards for Gilead, RallyBio, SeaBeLife, Merck Sharp and Dohme, Ocelot Bio, Behring and received speaking fees from Pfizer. JT has received speaking and/or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Alexion, Falk, Mallinckrodt, Grifols and CSL Behring and was supported by the German Research Foundation (DFG) project ID 403224013-SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875) and IHMCSA (project ID 964590) projects have received funding from the European Union’s Horizon 2020 research and innovation programme. AK has served as speaker for Novo Nordisk, Norgine, Siemens and Nordic Bioscience and participated in advisory boards for Norgine, Siemens, Resalis Therapeutics and Novo Nordisk, all outside the submitted work. Research support; Norgine, Siemens, Nordic Bioscience, Astra, Echosense. Consulting Takeda, Resalis Therapeutics, Zealand Pharma, Novo Nordisk, B&I. Board member and co-founder Evido. All other authors have no competing interests to declare.

Figures

Figure 1
Figure 1
Trial overview. Overview of the trial from the perspective of the participant. All enrolled patients will undergo an open-label, weight-adjusted, human albumin challenge. Treatment response biomarker will be collected 1–3 days after this challenge. Within 14 days shall the biomarker response be available, so that stratification (high-expected or low-expected effect) and randomisation (20% human albumin or 0.9% NaCl) can occur. Patients will receive blinded treatment infusion of their assigned intervention up until day 180 after inclusion.
Figure 2
Figure 2
Trial design. Overview of the trial design. ALB-TRIAL is a multinational trial with recruiting sites from Spain, Germany, Belgium, Hungary, the UK, Denmark and the Netherlands. In total, 240 participants will be enrolled and undergo a biomarker-based stratification according to their expected response to human albumin infusions, before they are randomisation into an active treatment group (albumin) or corresponding placebo (saline). SMT, standard medical treatment.
Figure 3
Figure 3
Primary outcome: recurrent event model. Left part of the figure depicts the conceptual model of the primary outcome (composite end point of liver-related events). Participants are followed and treated for up to 6 months. Decompensation episodes, insertion of a transjugular intrahepatic portosystemic shunt (TIPS), liver transplantation (LTx) and death are counting events. TIPS and LTx are in addition to death censoring events for the purpose of the primary analysis. Right part of the figure shows the potential scenarios and outcome of the primary analysis. The primary analysis is based on the comparison between the number of events in the high-expected and low-expected effect strata. The predictive biomarker of treatment response to human albumin is considered validated if the rate of events between treatment arms (albumin compared with placebo) is lower in the high-expected effect stratum compared with the low-expected effect stratum.
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References

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