6.0

University College London (UCL)

Gower Street, London, United Kingdom, WC1E 6BT

CCTU Enquiry Desk, University College London (UCL), CCTU-enquiries@ucl.ac.uk

CCTU Enquiry Desk, University College London (UCL), CCTU-enquiries@ucl.ac.uk

No

No

No

Final

11 Dec 2019

Yes

29 Oct 2019

Yes

11 Dec 2019

No

This was a phase III randomised controlled trial to verify whether targeting a serum albumin level of >30g/l in patients hospitalised with acutely decompensated cirrhosis using repeated 20% HAS infusions will reduce incidence of infection, renal dysfunction and mortality for the treatment period (maximum 14 days or until discharge/assessed as medically fit for discharge prior to 14 days) compared to standard medical care. In AD patients, the frequent course of events is that infection precipitates organ dysfunction and this combination is the commonest cause of hospital mortality. Equally data are emerging to indicate that even in survivors, long term mortality is also substantially reduced i.e. this represents a “tipping point” in the clinical course of cirrhosis. Preventing infection and subsequent organ dysfunction would be expected to therefore improve short and long term mortality.

The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures (SOPs), the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act, and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). International sites complied with the approved protocol, UCL CCTU SOPs, the principles of GCP as laid down by ICH topic E6 (Note for Guidance on GCP), Commission Directive 2005/28/EC, the European Directive 2001/20/EC (where applicable) and other national and local applicable regulations. While HAS is routinely given to patients with liver disease and its safety is well established, provision for stopping in the rare event of severe reactions (such as shock) was made in the trial protocol. In case of hypersensitivity or allergic reactions, in some cases severe anaphylaxis, it was noted in the protocol that epinephrine would be available immediately to treat any acute hypersensitivity reaction. Albumin was prescribed to participants on the 20% HAS arm, as per the suggested protocol, which could be amended by the prescribing clinician with the clinical reasons for this recorded in the trial documentation. If the prescribing clinician or the ward staff administering the 20% HAS had safety concerns with the continuation of treatment, infusions could be halted until/if it was deemed safe to resume treatment. Where 20% HAS was halted due to safety concerns this was not considered to be a protocol deviation. Three reasons was provided in the trial protocol for albumen being given in the standard of care arm: Large Volume Paracentesis (LVP), Spontaneous Bacterial Peritonitis (SBP), Hepatorenal Syndrome (HRS).

30 Apr 2015

No

Yes

United Kingdom: 777

777

0

0

0

0

0

0

0

667

108

2

Baseline

Randomised - controlled

Yes

20% Human Albumin Solution (HAS)

Solution for infusion

Intravenous use

20% HAS prescribed daily according to the patient’s serum albumin concentration that day (or closest previous measurement). A suggested dosing protocol was: a. If serum albumin 30-34g/l, give 100mls 20% HAS b. If serum albumin 26-29g/l, give 200mls 20% HAS c. If serum albumin 20-25g/l, give 300mls 20% HAS d. If serum albumin <20g/l, give 400mls 20% HAS This is based on clinical experience and also the reported regimen used in the ALBIOS study (that examines the repeated use of albumin infusions in patients with sepsis on intensive care). HAS may be prescribed using another regimen as long as the aim is to raise albumin level to >30g/l, but this must be fully recorded in the Case Reports Forms (CRF) and medical notes. Equally differing regimens may be used to cover paracentesis procedures or treat HRS and SBP as per local trial site and national guidelines but HAS must be prescribed and given if serum albumin <35g/l, unless there are any safety concerns.

No investigational medicinal product assigned in this arm

Endpoints

Randomised - controlled

Yes

20% Human Albumin Solution (HAS)

Solution for infusion

Intravenous use

20% HAS prescribed daily according to the patient’s serum albumin concentration that day (or closest previous measurement). A suggested dosing protocol was: a. If serum albumin 30-34g/l, give 100mls 20% HAS b. If serum albumin 26-29g/l, give 200mls 20% HAS c. If serum albumin 20-25g/l, give 300mls 20% HAS d. If serum albumin <20g/l, give 400mls 20% HAS This is based on clinical experience and also the reported regimen used in the ALBIOS study (that examines the repeated use of albumin infusions in patients with sepsis on intensive care). HAS may be prescribed using another regimen as long as the aim is to raise albumin level to >30g/l, but this must be fully recorded in the Case Reports Forms (CRF) and medical notes. Equally differing regimens may be used to cover paracentesis procedures or treat HRS and SBP as per local trial site and national guidelines but HAS must be prescribed and given if serum albumin <35g/l, unless there are any safety concerns.

No investigational medicinal product assigned in this arm

Albumin

Standard Care

Albumin

Standard Care

Albumin

Standard Care

A composite endpoint comprising incidence of infection, renal dysfunction and mortality occurring between treatment day 3 and day 15 (end of treatment period), or date of discharge/being assessed as medically fit for discharge if prior to day 15. The definition of the three components of the endpoint are: 1. New Infection: indicated by clinician diagnosis and clinical evidence provided on completed infection CRFs. 2. Renal Dysfunction: indicated by a serum creatinine increase of ≥50% as compared to serum creatinine at randomisation OR the patient initiated on renal replacement support (either haemodialysis or haemofiltration) OR a rise in serum creatinine of ≥26.5 μmol/L within 48hours. If patients are on renal replacement support at baseline, they will not be able to reach this outcome. 3. Death

Primary

A composite endpoint comprising incidence of infection, renal dysfunction and mortality occurring between treatment day 3 and day 15 (end of treatment period), or date of discharge/being assessed as medically fit for discharge if prior to day 15.

For the primary outcome, we fitted a mixed-effects logistic regression model, with binary treatment indicator and stratification variables included as fixed effects, and random intercepts for sites. We also performed a time to event analysis, with patients censored at the earliest of: hospital discharge, day deemed fit for discharge, or study day 15.

Albumin v Standard Care

777

Pre-specified

0.98

2-sided

Incidence of new Infection

Albumin v Standard Care

777

Pre-specified

1.22

2-sided

Incidence of renal dysfunction

Albumin v Standard Care

777

Pre-specified

0.68

2-sided

Incidence of death

Albumin v Standard Care

777

Pre-specified

0.95

2-sided

Albumin v Standard Care

777

Pre-specified

0.86

2-sided

Standard Care v Albumin

777

Pre-specified

1.05

2-sided

Albumin v Standard Care

777

Pre-specified

1.27

2-sided

Albumin v Standard Care

777

Pre-specified

142.6

2-sided

Investigators would notify UCL CCTU of any SAEs occurring from the time of enrolment until the last protocol treatment administration. SARs and SUSARs notified to UCL CCTU until trial closure.

18.1

Albumin

Standard Care