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Abstract
Introduction Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds to and inactivates this immune-suppressive lipid mediator. Human albumin solution (HAS) could thus be repurposed as an immune-restorative drug in these patients.
This is a phase III randomised controlled trial (RCT) to verify whether targeting a serum albumin level of ≥35 g/L in hospitalised patients with decompensated cirrhosis using repeated intravenous infusions of 20% HAS will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or discharge if <14 days) compared with standard medical care.
Methods and analysis Albumin To prevenT Infection in chronic liveR failurE stage 2 is a multicentre, open-label, interventional RCT. Patients with decompensated cirrhosis admitted to the hospital with a serum albumin of <30 g/L are eligible, subject to exclusion criteria. Patients randomised to intravenous HAS will have this administered, according to serum albumin levels, for up to 14 days or discharge. The infusion protocol aims to increase serum albumin to near-normal levels.
The composite primary endpoint is: new infection, renal dysfunction or mortality within the trial treatment period. Secondary endpoints include mortality at up to 6 months, incidence of other organ failures, cost-effectiveness and quality of life outcomes and time to liver transplant. The trial will recruit 866 patients at more than 30 sites across the UK.
Ethicsanddissemination Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001–0001). The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the National Institute for Health Research (ISRCTN14174793). This manuscript refers to version 6.0 of the protocol. Results will be disseminated through peer-reviewed journals and international conferences. Recruitment of the first participant occurred on 25 January 2016.
- adult gastroenterology
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Footnotes
Contributors All authors read and approved the final manuscript. LC: protocol development, writing of this manuscript. ZS, RH, SB, TC: protocol development, protocol implementation, manuscript review. AAM, NB, DG: protocol development, scientific oversight. SSS: protocol development, statistical oversight, manuscript review. KB: protocol development, statistical input, manuscript review. EHF: protocol development, manuscript review. AOB: concept and design, protocol development, writing of this manuscript.
Funding The work is supported by the Health Innovation Challenge fund (Wellcome Trust and Department of Health) award number 164699. The trial sponsor is UCL with trial management activities conducted by the UCL Comprehensive Clinical Trials Unit.
Competing interests None declared.
Patient consent Not required.
Ethics approval Research ethics positive opinion and approval was given by the London-Brent Research Ethics Committee (ref: 15/LO/0104) which specialise in trials involving patients who lack the capacity to consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Primary and secondary outcomes will be published in a peer-reviewed journal as an open access paper. Deindentified participant data will be shared, as part of the trial results. The full study protocol and statistical analysis plans can be requested by emailing attire@ucl.ac.uk.
Author note Trial management and monitoring Research Steering Group: The Research Steering Group (RSG) operates on behalf of the funders to ensure that appropriate milestones have been met in the delivery of the trial. It consists the CI, an independent expert and representatives of the Welcome Trust and Department of Health. Trial Management Group: The Trial Management Group (TMG) comprises the CI, Clinical Research Fellow, Clinical Project Manager, Trial Statistician, Trial Manager, Data Manager, Health Economist and five trial site PIs. The TMG is responsible for developing the design, co-ordination and strategic management of the trial. Trial Steering Committee: The Trial Steering Committee (TSC) is the independent group responsible for oversight of the trial in order to safeguard the interests of trial patients. The TSC provides advice to the CI, CTU, funder and sponsor on all aspects of the trial through its independent chair. Independent Data Monitoring Committee: The Independent Data Monitoring Committee (IDMC) is responsible for safeguarding the interests of trial patients, monitoring the accumulating data and making recommendations to the TSC on whether the trial should continue as planned. It comprises a clinical chair (independent Hepatologist), independent Gastroenterologist and an independent statistician all with expertise in Clinical Trials.