A trial to investigate whether giving albumin to patients with advanced liver cirrhosis will reverse immune suppression and improve outcome for infection

ISRCTN	ISRCTN14174793
DOI	https://doi.org/10.1186/ISRCTN14174793
Clinical Trials Information System (CTIS)	2014-002300-24
Protocol serial number	18450
Sponsor	University College London (UK)
Funders	National Institute for Health Research, Wellcome Trust

Submission date: 18/03/2015
Registration date: 20/03/2015
Last edited: 25/11/2021

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Digestive System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Liver disease is the fifth most common cause of death in the UK and is caused largely by alcohol, viruses and fatty liver disease resulting in liver damage and loss of function. People can survive with large amounts of liver damage but often have severe health complications leading to frequent hospital admissions. In particular, patents have weak immune systems and are highly prone to bacterial infection with over a third developing an infection in hospital. Infection is the major cause of death in these patients and therefore represents a huge challenge to the NHS. Currently infection in liver patients is treated with antibiotics, however the rates of death in these patients have shown little improvement over 20 years. Antibiotics may also cause harmful side-effects (e.g. diarrhoea) and overuse has led to antibiotic resistant bacteria which makes these drugs useless and will be one of medicines’ greatest challenges over the next decade. Albumin is a protein found naturally in blood and is made in the liver. As liver function reduces so does albumin production and blood levels fall. Albumin is safe and currently used in patients with liver failure; however, prescription is varied and although considered beneficial the effects haven’t been tested in clinical trials. Our study aims to see if giving liver patients Human Albumin Solution (HAS) restores their immune response and helps both prevent and improve treatment of infections.

Who can participate?
Aults (aged over 18) admitted to hospital with acute or worsening complications of cirrhosis of the liver.

What does the study involve?
This study includes a feasibility study, to verify whether it is possible to restore albumin levels to near normal. This is followed by a randomised control trial to confirm whether restoring albumin levels improves survival from infection compared to standard treatment. For the feasibility study, all participants are given 20% HAS during their hospital stay up to a maximum of 14 days. The dose given is dependent on how much albumin is found in the participants blood. For the randomized controlled trial, participants are randomly allocated into one of two groups. Those in group 1 are given the immune restorative albumin protocol 20% HAS (dose dependent on blood albumin levels) during their hospital stay up to a maximum of 14 days. Those in group 2 are given standard medical care.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
The study will take place at up to 44 NHS sites in England, Wales and Scotland.

When is the study starting and how long is it expected to run for?
April 2015 to October 2017

Who is funding the study?
The National Institute for Health Research (NIHR) and the Wellcome Trust (both UK)

Who is the main contact?
James Blackstone, j.blackstone@ucl.ac.uk

Contact information

Mr James Blackstone
Scientific

Comprehensive Clinical Trials Unit at UCL
Institute of Clinical Trials & Methodology
90 High Holborn 2nd Floor
London
WC1V 6LJ
United Kingdom

ORCID ID	0000-0003-4335-5269
Phone	+44 (0)203 108 6584
Email	j.blackstone@ucl.ac.uk

Study information

Primary study design	Interventional
Study design	Both; Interventional; Design type: Prevention, Treatment
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	Albumin To prevenT Infection in chronic liveR failurE
Study acronym	ATTIRE
Study objectives	1. Increased circulating concentrations of Cyclooxygenase (COX)-derived eicosanoid prostaglandin E2 (PGE2) drives cirrhosis-associated leukocyte dysfunction and hence the propensity to infection observed in these patients. 2. Infection triggers an acute clinical deterioration with progression of liver failure, development of liver-related complications, organ failure and mortality in patients with cirrhosis. 3. Albumin reduces PGE2 bioavailability and plays a key role in modulating PGE2-mediated immune dysfunction. As it is synthesised in the liver, circulating albumin levels are approximately 50% lower than in patients without advanced liver disease. 4. Therefore in vivo administration of 20% HAS to these patients will improve their leukocyte function thus enhancing their ability to combat infection, reducing the incidence of second/nosocomial infection. This will lead to fewer cases of organ failure and improved mortality.
Ethics approval(s)	NRES Committee London-Brent, 26/01/15/LO/0104; First MREC approval date 26/01/2015
Health condition(s) or problem(s) studied	Liver cirrhosis
Intervention	Feasibility Study: In stage 1, a Phase II feasibility study, all patients will receive a daily intravenous infusion of 20% Human Albumin Solution (HAS) during of their admission (maximum of 14 days from randomisation). The dose will be administered to target a daily serum albumin of 35 g/l. T he following suggested protocol will be provided for clinicians: 1. If serum albumin 30-34 g/l give 100 ml 20% HAS 2. If serum albumin 26-29 g/l, give 200 ml 20% HAS 3. If serum albumin 20-25 g/l, give 300 ml 20% HAS 4. If serum albumin <20 g/l, give 400 ml 20% HAS Randomised Control Trial (RCT): In stage 2, a phase III RCT, patients will receive a daily intravenous infusion of either the immune restorative albumin protocol 20% HAS (dose based on the same suggested protocol as the feasibility study) or standard medical care for the duration of their admission (maximum of 14 days from trial randomisation).
Intervention type	Biological/Vaccine
Phase	Phase II/III
Drug / device / biological / vaccine name(s)	20% Human Albumin Solution
Primary outcome measure(s)	Current primary outcome measures as of 14/09/2020: Feasibility Study: 1. Daily serum albumin level for the duration of trial treatment period (maximum 14 days or discharge/death (if less than 14 days) Patients will not be followed up after trial treatment. RCT: Composite outcome of incidences of 1. Nosocomial infection 2. Renal dysfunction 3. Mortality As measured during the trial treatment period (maximum 14 days or discharge/death (if less than 14 days) Patients in the RCT will be followed up for up to 6 months following discharge from hospital. _____ Previous primary outcome measures: Feasibility Study: 1. Daily serum albumin level for the duration of trial treatment period (maximum 14 days or discharge/death (if less than 14 days) Patients will not be followed up after trial treatment. RCT: Composite outcome of incidences of 1. Nosocomial infection 2. Extra hepatic organ dysfunction 3. Mortality As measured during the trial treatment period (maximum 14 days or discharge/death (if less than 14 days) Patients in the RCT will be followed up for up to 6 months following discharge from hospital.
Key secondary outcome measure(s)	Feasibility Study: 1. Daily leukocyte function assessed by laboratory based leukocyte bioassay RCT: 2. Mortality at 28 days post randomisation and 3 & 6 months post discharge 3. Time to outcome (first event of infection/organ dysfunction/death) 4. Transplant within six months of treatment 5. Total amount of HAS administered during treatment period 6. Duration of hospital stay 7. Prognostic score (assessed by UKELD, MELD, Child’s Pugh scores) at baseline and end of treatment 8. Worst daily NEWS score during the treatment period 9. Incidence of SIRS during treatment period 10. Incidence of Septic Shock during treatment period 11. Days in ICU during treatment period 12. Incremental cost and cost-effectiveness up to 6 months post discharge 13. Impact on quality of life (QOL) up to 6 months post discharge 14. Safety and tolerability of HAS as indicated by Serious Adverse Events (SAEs) 15. Requirement for nutritional support (nasogastric feed, nutritional supplements or total parenteral nutrition) during treatment period
Completion date	31/12/2019

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	946
Total final enrolment	777
Key inclusion criteria	1. All patients admitted to hospital with acute onset or worsening of complications of cirrhosis e.g. alcoholic hepatitis, hepatic encephalopathy, ascites, hepatic hydrothorax, hyperbilirubinaemia, oesophageal variceal bleed, any infection precipitating acute decompensation or any other presentation of acute decompensation / acute onset chronic liver failure 2. Over 18 years of age 3. Predicted hospital admission > 5 days at trial enrolment, which must be within 72 hours of admission 4. Serum albumin <30g/l at screening 5. Documented informed consent to participate (or consent given by a legal representative)
Key exclusion criteria	1. Advanced hepatocellular carcinoma with life expectancy of less than 8 weeks 2. Patients who will receive palliative treatment only during their hospital admission 3. Pregnancy 4. Known or suspected severe cardiac dysfunction 5. Any clinical condition which the investigator considers would make the patient unsuitable for the trial 6. The patient has been involved in a clinical trial of Investigational Medicinal Products (IMPs) within the previous 30 days (including re-randomisation into the RCT) 7. Trial investigator unable to identify the patient (by NHS number)
Date of first enrolment	30/04/2015
Date of final enrolment	30/06/2019

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

University College London

Gower Street
London
WC1E 6BT
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan	Not provided at time of registration

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	feasibility study results	01/05/2018	15/11/2019	Yes	No
Results article	feasibility study results	01/05/2018	15/11/2019	Yes	No
Results article	results	04/03/2021	05/03/2021	Yes	No
Results article		01/11/2021	25/11/2021	Yes	No
Protocol article	protocol	25/01/2016		Yes	No
Protocol article	protocol	21/10/2018		Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes

Editorial Notes

25/11/2021: Publication reference added.
05/03/2021: The following changes have been made:
1. Publication reference added.
2. The final enrolment number has been added from the reference.
14/09/2020: The following changes have been made:
1. The primary outcome measures have been changed.
2. The intention to publish date has been added.
3. The scientific contact has changed and the plain English summary has been updated accordingly.
15/11/2019: Publication reference added.
03/04/2019: The condition has been changed from "Topic: Hepatology; Subtopic: Hepatology; Disease: All Hepatology" to "Liver cirrhosis" following a request from the NIHR.
23/10/2018: The following changes were made:
1. Publication reference added.
2. The recruitment end date was updated from 30/10/2017 to 30/06/2019.
3. The overall trial end date was updated from 30/10/2017 to 31/12/2019.
27/01/2016: Publication reference added.