E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Infection in liver disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001558 |
E.1.2 | Term | Albumin |
E.1.2 | System Organ Class | 100000004848 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Feasibility Trial Primary objective: This is a trial to determine whether it is possible to restore and maintain blood albumin levels to near normal in patients admitted to hospital with complications due to advanced liver disease. The patients will be given repeated doses of 100ml 20% Human Albumin Solution (HAS) straight into their veins. HAS will be prescribed according to the albumin levels in the blood measured by standard blood tests.
Randomised Control Trial Primary objective: This is a trial to confirm whether increasing the blood albumin level to near normal in patients admitted to hospital with advanced liver disease using repeated dosing of HAS will reduce chances of the development of hospital-acquired infection, renal dysfunction and death for the treatment period. Patients will be allocated at random to receive either HAS or standard medical care to compare the two treatments.
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E.2.2 | Secondary objectives of the trial |
Feasibility Secondary objectives: We shall look at how well the white blood cells (which fight infection) function in patients while they are in the study. For this study immune suppression will be considered improved by albumin if white blood cell function improves following albumin dosing. Clinical data will be collected on: 1. Safety 2. Rate of infection 3. In-hospital mortality 4. Total amount of fluid given 5. Intensive Care Unit admission 6. Organ dysfunction 7. Duration of hospital stay Patients in the feasibility trial will not be followed up following discharge.
Randomised Clinical Trial Secondary objectives: 1. Mortality at 28 days post randomisation and at 3 & 6 months post discharge 2. Time to outcome (first event of infection/organ dysfunction/death) 3. Transplant within six months of treatment 4. Total amount of albumin administered during the treatment period 5. Duration of hospital stay 6. Prognostic sores (predictive scores for liver disease an |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• 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 • Over 18 years of age • Predicted hospital admission > 5 days at trial enrolment, which must be within 72 hours of admission • Serum albumin <30g/l at screening • Documented informed consent to participate (or consent given by a legal representative)
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E.4 | Principal exclusion criteria |
• Advanced hepatocellular carcinoma with life expectancy of less than 8 weeks • Patients who will receive palliative treatment only during their hospital admission • Patients who are pregnant • Severe cardiac dysfunction • Any clinical condition which the investigator considers would make the patient unsuitable for the trial • 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) • Trial investigators unable to identify the patient (by NHS number) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Feasibility Study: Daily serum albumin level for the duration of the treatment period (maximum of 14 day or when the patient is considered fit for discharge if < 14 days)
RCT: A composite endpoint comprising incidence of nosocomial infection, renal dysfunction and mortality within the treatment period (for a maximum of 14 days OR when the patient is considered fit for discharge if < 14 days). The three components of the composite endpoint are: 1. Nosocomial Infection indicated by any new (or change in) prescribed antibiotics. Blinded data from a clinically representative sample of patients will be scrutinised for presence of infection by a Clinical Trial Endpoint Review Committee. The committee will contain an experienced microbiologist who will validate the presence of infection according to peer reviewed criteria. 2. Renal dysfunction, defined as 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 (within the treatment period) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary outcomes will be collected on a daily basis for the until the end of the intervention period (up to 14 days following randomisation). The data will be evaluated at the end of the trial. For the feasibility stutdy the IDMC will comment on the feasibility report and advise the TSC of any concerns againt the RCT. No formal interim anaylysis is planned for the RCT, howevere the perioic reports will be submitted to the IDMC. |
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E.5.2 | Secondary end point(s) |
Feasibility Study: Daily Leukocyte Function assessed by our laboratory based leukocyte bioassay. Information will also be collected on: Total volume of albumin infused; Safety; Rate of nosocomial infections; In-hospital mortality; Total amount of fluid administered; ICU admission; Organ dysfunction/prognostic score (UKELD, MELD, Child’s Pugh, CLIF-SOFA scores); Duration of hospital stay.
RCT: 1. Mortality at 28 days post randomisation and 3 & 6 months post discharge 2. Time to outcome (first event of infection/organ dysfunction/death) 3. Transplant within six months of trial treatment 4. Total amount of HAS administered during the treatment period 5. Duration of hospital stay 6. Prognostic score (assessed by UKELD, MELD, CPS) at baseline and end of treatment 7. Worst daily NEWS Score during treatment period 8. Incidence of Systemic Inflammatory Response Syndrome (SIRS) during trial intervention period 9. Incidence of Septic Shock during trial treatment period 10. Days in ICU during trial treatment period 11. Incremental cost and cost-effectiveness for up to 6 month post discharge 12. Impact on quality of life for up to 6 month post discharge 13. Safety and tolerability of HAS as indicated by Serious Adverse Events (SAEs) 14. Requirement for nutritional support (nasogastric feed, nutritional supplements or total parenteral nutrition) during the trial treatment period
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the secondary outcomes, this will be evaluated following intervention period in the feasilibility trial and 6 months following discharge for the RCT. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard Clinical practice |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 40 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Trial closure is defined as the date when all data has been received, cleaned and all queries resolved at all sites. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 1 |