Condition category
Infections and Infestations
Date applied
18/03/2015
Date assigned
20/03/2015
Last edited
27/01/2016
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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

Contact information

Type

Scientific

Primary contact

Miss Zainib Shabir

ORCID ID

Contact details

University College London
Gower Street
London
WC1E 6BT
United Kingdom

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 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.

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

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

Sponsor information

Organisation

University College London (UK)

Sponsor details

Gower Street
London
WC1E 6BT
United Kingdom

Sponsor type

Hospital/treatment centre

Website

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)

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

Results - basic reporting

Publication summary

2016 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/26810999

Publication citations

Additional files

Editorial Notes

RP 27/01/2016: Publication reference added.