E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with advanced cirrhosis (serum creatinine ≥ 1.2 mg/dl, serum sodium ≤ 130 mEq/l and/or serum bilirubin ≥4 mg/dl) and urinary infection, pneumonia, spontaneous or secondary bacteremia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection will be included |
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E.1.1.1 | Medical condition in easily understood language |
Patients with advanced cirrhosis, and urinary infection, pneumonia, spontaneous or secondary bacteremia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection will be included |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008954 |
E.1.2 | Term | Chronic liver disease and cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024667 |
E.1.2 | Term | Liver cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10019641 |
E.1.2 | Term | Hepatic cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064704 |
E.1.2 | Term | Decompensated cirrhosis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009213 |
E.1.2 | Term | Cirrhosis of liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009211 |
E.1.2 | Term | Cirrhosis liver |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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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 |
In hospital mortality reduction in patients with advance cirrhosis, infection other than spontaneous bacterial peritonitis and high risk mortality in both treatment arms. |
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E.2.2 | Secondary objectives of the trial |
All secondary objectives are assessed across both treatment arms:
* 28-day survival * 90-day survival * Incidence of AKI during hospitalization * Incidence of renal dysfunction during hospitalization * Incidence of type-1 and type-2 HRS during hospitalization * Changes in plasma levels of renin and noradrenaline and in serum lactate levels during treatment of infection * Changes in serum levels of IL-6, TNF-alpha and NOX and in plasma levels of vWF:Ag * Changes in blood leukocyte count and serum CRP levels during treatment of infection * Changes in CLIF-SOFA, CLIF-Consortium, CHILD-PUGH and MELD scores * Incidence of new individual organ failures during hospitalization * Incidence of ACLF (type 1, 2 and 3 according to the Canonic Study) during hospitalization * Risk factors of HRS and ACLF * Risk factors of short-term mortality * Causes of death * Length of hospital stay |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male and Female patients with age >/= 18 years. - Diagnosis of liver cirrhosis established by histology or by the combination of clinical, analytical and ultrasonographic data. - Diagnosis of urinary infection, pneumonia, spontaneous or secondary bacteremia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection at hospital admission or during hospitalisation. Diagnostic criteria at inclusion will be the following: (a) urinary infections signs of systemic imflammation and more than 10 leukocytes per high-power field in urine or a positive reagent; (b) pneumonia - signs of infection and presence of new infiltrates on chest x-ray; (c) skin/soft tissue infection - signs of infection and physical exam findings of swelling, erythema, heat and tenderness in the skin; (d) acute cholangitis - signs of infection and cholestasis, compatible symptoms (right upper quadrant pain and jaundice) and radiological data of biliary obstruction; (e) Spontaneous bacteremia: positive blood cultures and no cause of bacteremia; (f) Secondary bacteremia: positive blood and catheter cultures or bacteremia within 24h after invasive procedure; (g) Suspected bacterial infection: signs of systemic inflammation but no identifiable origin of this infection (polymorphonuclear cells in ascitic and pleural fluid < 250/mm3, normal urine sediment and chest X-ray). Patients with uncomplicated urinary infections or suspected bacterial infections will require the presence of signs of systemic inflammation: at least 1 diagnostic criterion of systemic inflammatory response syndrome (SIRS) and high serum CRP levels ≥1 mg/dl (10mg/L). This criterion will not be required for the rest of infections. - Presence of renal and/or liver dysfunction (serum creatinine ≥1.2 mg/dl, serum bilirubin ≥4 mg/dl or serum sodium ≤ 130 mEq/l). Patients with pneumonia or documented bacteremia (positive blood cultures) will require the presence of at least 1 of these analytical criteria to be included in the study. Two or more criteria will be required in patients with urinary infection, skin/soft tissue infection, acute cholangitis or suspected bacterial infection.
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E.4 | Principal exclusion criteria |
- > 72h after the diagnosis of infection. - Pre-menopausal women (last menstruation ≤ 12 months prior to enrolment) who are nursing or pregnant or are of child bearing potential and are not practicing an acceptable method of birth control. The methods considered as acceptable are: intrauterine devices, double barrier method (condom or diaphragm with spermicide), hormonal methods (oral contraceptives, contraceptive patch, long acting injectable contraceptive) and tubal ligation. - Acute or subacute liver failure without underlying cirrhosis. - Septic shock (mean arterial pressure below 60 mmHg during more than 1 hour despite adequate fluid resuscitation and need of vasopressor drugs). - Severe acute respiratory distress syndrome [PaO2/Fi02 ≤100 or a pulse oximetric saturation (SpO2) to FiO2 ratio ≤89]. - Active or recent variceal bleeding (unless controlled for >48h). - Ongoing Type-1 HRS (IAC criteria: serum creatinine ≥ 2.5 mg/dl). - Type-3 ACLF. - Hemodialysis or other type of renal replacement therapy. - Evidence of current malignancy (except for hepatocellular carcinoma within Milan criteria or non-melanocytic skin cancer), - Previously known moderate or severe chronic heart failure (NYHA class II, III or IV). - Previously known severe chronic pulmonary disease (GOLD IV). - Previously known severe psychiatric disorders that prevent the patient from giving informed consent and from making autonomous decisions. - Previous Liver transplantation - Previously known HIV infection (except for patients under antiretroviral therapy with undetectable viral load, CD4 levels >200/mm3 and no previous history of opportunistic infections diagnostic of AIDS). - Contraindications to albumin (allergy, signs of pulmonary edema) - Albumin administration of >/=80g of albumin in the last 2 days - Refusal to participate. - Patients who cannot provide prior informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent. - Physician and team not committed to intensive care if needed. - Usage of any investigational drug within 90 days prior to randomization or the planned use of an investigational drug during the course of the current study. All patients meeting the inclusion criteria will be entered on a screening log. If the patient is not enrolled, the screening log will include information explaining why enrollment did not occur.
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E.5 End points |
E.5.1 | Primary end point(s) |
* To evaluate the effect of albumin administration on hospital survival |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At day 3, day of infection resolution (or day 7 and every 7 days) |
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E.5.2 | Secondary end point(s) |
* Effect of albumin administration on 28-day survival. * Effect of albumin administration on 90-day survival. * Effect of albumin infusion on the incidence of AKI, renal dysfunction, type-1 and type-2 HRS during hospitalization. * Effect of albumin on circulatory function estimated by changes in plasma levels of renin and noradrenaline and by changes in serum lactate levels among infection diagnosis, day 3 and infection resolution. * Effect of albumin on serum levels of IL-6, TNF-alpha and NOX and on plasma levels of vWF:Ag at infection diagnosis and at infection resolution. * Effect of albumin on blood leukocyte count and serum CPR levels during infection. * Effect of albumin on the development of other individual organ failures (renal, liver, cerebral, circulatory, coagulation and respiratory), acute-on-chronic liver failure (ACLF type 1, 2 and 3 according to the Canonic Study), CLIF-SOFA score, CLIF-Consortium score, Child-Pugh score and MELD score during hospitalization. * Evaluation of predictive factors of HRS and ACLF development in non-SBP infections. * Samples (blood, plasma, serum and urine) will be obtained and stored for genomic, proteomic and standard biochemical investigations in future ancillary studies related to the aim of the study. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At day 3, day of infection resolution (or day 7 and every 7 days) day 28 and day 90 |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 26 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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The definition of end of the trial is last patient last visit (LVLS)
Premature termination based on: * Post-consent determination of ineligibility based on safety or eligibility criteria * Physician's judgment following an adverse event * Patient's decision / Personal consultee decision * Termination of the trial by a regulatory authority or by study sponsor * Any other reason for withdrawal that the trial physician or patient feels is in the best interest of the patient |
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |