Plain English Summary
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 and the Wellcome Trust
Who is the main contact?
Miss Zainib Shabir
Trial website
Additional identifiers
EudraCT number
2014-002300-24
ClinicalTrials.gov number
Protocol/serial number
18450
Study information
Scientific title
Albumin To prevenT Infection in chronic liveR failurE
Acronym
ATTIRE
Study hypothesis
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
NRES Committee London-Brent, 26/01/15/LO/0104; First MREC approval date 26/01/2015
Study design
Both; Interventional; Design type: Prevention, Treatment
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use contact details to request a patient information sheet
Condition
Topic: Hepatology; Subtopic: Hepatology; Disease: All Hepatology
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 35g/l. The following suggested protocol will be provided for clinicians:
1. If serum albumin 30-34g/l give 100mls 20% HAS
2. If serum albumin 26-29g/l, give 200mls 20% HAS
3. If serum albumin 20-25g/l, give 300mls 20% HAS
4. If serum albumin <20g/l, give 400mls 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
Other
Phase
Phase II/III
Drug names
Primary outcome measure
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.
Secondary outcome measures
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
Overall trial start date
30/04/2015
Overall trial end date
30/10/2017
Reason abandoned (if study stopped)
Eligibility
Participant 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)
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 946; UK Sample Size: 946
Participant 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)
Recruitment start date
30/04/2015
Recruitment end date
30/10/2017
Locations
Countries of recruitment
United Kingdom
Trial participating centre
University College London
Gower Street
London
WC1E 6BT
United Kingdom
Funders
Funder type
Government
Funder name
National Institute for Health Research
Alternative name(s)
NIHR
Funding Body Type
government organisation
Funding Body Subtype
Federal/National Government
Location
United Kingdom
Funder name
Wellcome Trust
Alternative name(s)
Wellcome
Funding Body Type
private sector organisation
Funding Body Subtype
international
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
2016 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/26810999