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), signs of systemic inflammation and urinary infection, pneumonia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection will be included |
Pazienti con cirrosi avanzata, un’infezione batterica diversa dalla peritonite batterica spontanea e segni di infiammazione sistemica |
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E.1.1.1 | Medical condition in easily understood language |
Patients with advanced cirrhosis, signs of systemic inflammation and urinary infection, pneumonia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection will be included |
Pazienti con cirrosi avanzata,infezione batterica diversa dalla peritonite batterica spontanea e segni di infiammazione sistemica (febbre, alterazioni di parametri vitali o dei globuli bianchi). |
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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 | 16.1 |
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 | 16.1 |
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 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
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 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
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 | 16.1 |
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 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
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 and 28-day mortality reduction in patients with advance cirrhosis, infection other than spontaneous bacterial peritonitis and high risk mortality |
Effetto della somministrazione di albumina nella sopravvivenza intraospedaliera e a 28 giorni. |
|
E.2.2 | Secondary objectives of the trial |
- 90-day survival - 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 in both treatment arms - Changes in serum levels of IL-6, TNF-alpha and NOX and in plasma levels of vWF:Ag in both treatment arms -Changes in blood leukocyte count and serum CRP levels during treatment of infection in both treatment arms -Changes in CLIF-SOFA, CLIF-Consortium, CHILD-PUGH and MELD scores in both treatment arms - Incidence of new individual organ failures during hospitalization in both treatment arms - Incidence of ACLF (type 1, 2 and 3 according to the Canonic Study) during hospitalization in both treatment arms -Risk factors of HRS and ACLF in both treatment arms - Risk factors of short-term mortality in both treatment arms - Causes of death in both treatment arms - Length of hospital stay |
• Sopravvivenza a 90 giorni • Incidenza di disfunzione renale e di sindrome epatorenale (HRS) di tipo 1 e 2 durante il ricovero • Funzione circolatoria (variazioni dei livelli plasmatici di renina e di noradrenalina,livelli sierici di lattato • Variazioni dei livelli sierici di interleuchina-6 (IL-6), fattore di necrosi tumorale alfa (TNF-alfa) e ossido nitrico (NOX) e sui livelli plasmatici di fattore di von Willebrand (vWF: Ag) • Variazioni della conta dei leucociti nel sangue e sui livelli sierici di proteina C-reattiva (PCR) • Sviluppo di insufficienza di altri organi • Sviluppo di insufficienza epatica acuta-su-cronica (ACLF di tipo 1, 2 e 3, secondo lo studio CANONIC), score CLIF-SOFA, score CLIF-Consortium, score di Child-Pugh e MELD • Valutazione dei fattori predittivi per lo sviluppo di HRS e di ACLF nelle infezioni diverse dalla peritonite batterica spontanea • Fattori di rischio di mortalità a breve termine • Cause di morte • Durata della degenza ospedaliera |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age between 18 and 79 years.
- Diagnosis of liver cirrhosis established by histology or by the combination of clinical, analytical and ultrasonographic data.
- Clinical data of systemic inflammation indicated by the presence of at least 1 diagnostic criterion of SIRS and high serum CRP levels (? 2 mg/dL or 20 mg/L).
- Diagnosis of urinary infection, pneumonia, skin/soft tissue infection, acute cholangitis or suspected bacterial infection at hospital admission or during hospitalization. Diagnostic criteria at inclusion will be the following: (a) urinary infections: more than 10 leukocytes per high-power field in urine or a positive reagent strip; (b) pneumonia: presence of new infiltrates on chest x-ray; (c) skin/soft tissue infection: physical exam findings of swelling, erythema, heat and tenderness in the skin; (d) acute cholangitis: cholestasis, compatible symptoms (right upper quadrant pain and jaundice) and radiological data of biliary obstruction and (e) suspected bacterial infection: signs of infection but no identifiable origin of this infection (polymorphonuclear cells in ascitic and pleural fluid < 250/mm3, normal urine sediment and chest X-ray).
- 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 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. |
Pazienti cirrotici con età compresa tra i 18 ed i 79 anni
Segni di infiammazione sistemica: almeno 1 criterio diagnostico di sindrome da risposta infiammatoria sistemica (SIRS) e livelli sierici di PCR ≥ 2 mg/dl. Questo valore di cut-off ha una sensibilità dell'82% e una specificità del 70% per la diagnosi di infezione batterica nei pazienti con cirrosi avanzata
Infezione delle vie urinarie, polmonite, infezione della pelle/dei tessuti molli o sospetta infezione
Evidenza bioumorale di disfunzione renale e/o epatica (creatinina sierica ≥ 1,2 mg/dl, sodiemia ≤ 130 mEq/l, bilirubina sierica ≥ 4 mg/dl). I pazienti con polmonite richiederanno la presenza di almeno uno di questi criteri di analisi per essere inclusi nello studio. Pazienti con infezione delle vie urinarie, della pelle/tessuti molli o sospetta infezione richiederanno 2 o più criteri di inclusione |
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E.4 | Principal exclusion criteria |
- > 48h 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
- 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).
- Acute respiratory distress syndrome [PaO2/Fi02 ?200 or a pulse oximetric saturation (SpO2) to FiO2 ratio ?214].
- Gastrointestinal bleeding in the last 5 days.
- Biopsy proven severe acute alcoholic hepatitis requiring specific treatment.
- Type-1 HRS (IAC criteria: serum creatinine ? 2.5 mg/dl).
- Type-3 ACLF.
- Intrinsic nephropathy (proteinuria, hematuria or abnormal findings on renal ultrasonography) with renal failure (serum creatinine chronically ? 1.5 mg/dl).
- Renal replacement therapy.
- Arterial hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg).
- Evidence of current malignancy (except for hepatocellular carcinoma within Milan criteria or non-melanocytic skin cancer),
- Moderate or severe chronic heart (NYHA class II, III or IV).
- Severe pulmonary disease (GOLD III or IV).
- Severe psychiatric disorders.
- Any immunosuppressive drug.
- HIV infection.
- Contraindications to albumin (allergy, signs of pulmonary edema)
- Administration of any dose of IV albumin or albumin dialysis in the last 10 days
- Clinical indication for albumin use at inclusion (spontaneous bacterial peritonitis coinfection, large volume paracentesis)
- 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. |
Tempo trascorso dalla diagnosi di infezione > 48 h
Donne in pre-menopausa (data ultime mestruazioni ≤12 mesi precedenti all’arruolamento), donne in allattamento o incinte o in età fertile che non facciano uso di metodi contraccettivi accettabili.
Insufficienza epatica acuta o subacuta senza cirrosi sottostante
Shock settico
Sindrome da distress respiratorio acuto
Sanguinamento gastrointestinale negli ultimi 5 giorni
Grave epatite alcolica acuta comprovata con biopsia che richieda un trattamento specifico
ACLF di Grado 3 (definito secondo i criteri del Canonci Study)
HRS di tipo 1 (definiti secondo criteri IAC)
Nefropatia intrinseca con insufficienza renale (creatinina sierica ≥ 1,5 mg/dl)
Emodialisi
Ipertensione arteriosa (pressione arteriosa sistolica>160 mmHg e/o pressione diastolica>90 mHg)
Presenza di neoplasia (ad eccezione del carcinoma epatocellulare entro i criteri di Milano o neoplasie della pelle diverse dela melanoma)
Insufficienza cardiaca cronica moderata o grave (classe NYHA II, III o IV) o di malattia polmonare (Stadio GOLD III o IV)
Gravi disturbi psichiatrici
Assunzione di farmaci immunosoppressori
Infezione da HIV
Controindicazioni all'albumina,
Assunzione del farmaco o dialisi con albumina nei 10 giorni precedenti
Indicazione all'albumina al momento dell'inclusione
Rifiuto di partecipare al protocollo
Incapacità/impossibilità a rilasciare un consenso informato, assenza di un legale rappresentante del paziente, stato psico-fisico che rende improbabile che il paziente possa riacquistare coscienza o capacità sufficiente per fornire il consenso informato in un secondo momento
Indisponibilità di terapia intensiva se necessaria |
|
E.5 End points |
E.5.1 | Primary end point(s) |
-To evaluate the effect of albumin administration on hospital and 28-day survival |
Valutare sopravvivenza intraospedaliera e a 28 giorni |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
day 3, day of infection resolution (or day 7 and every 7 days) and 28 day |
al giorno 3, alla risoluzione dell'infezione (o al giorno 7 e ogni 7 giorni) e al giorno 28 |
|
E.5.2 | Secondary end point(s) |
-Effect of albumin administration on 90-day survival.
-Effect of albumin infusion on the incidence of 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 infusion on the development of other individual organ failures (renal, liver, cerebral, circulatory, coagulation and respiratory) during hospitalization.
-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. |
Effetto della somministrazione di albumina sulla sopravvivenza a 90 giorni.
- Effetto della somministrazione di albumina sull’incidenza di disfunzione renale e di sindrome epatorenale (HRS) di tipo 1 e 2 durante il ricovero.
- Effetto della somministrazione di albumina sulla funzione circolatoria stimata dalle variazioni dei livelli plasmatici di renina e di noradrenalina e dei livelli sierici di lattato tra la diagnosi di infezione, il giorno 3 e al momento della risoluzione dell'infezione.
- Effetto della somministrazione di albumina sui livelli sierici di interleuchina-6 (IL-6), fattore di necrosi tumorale alfa (TNF-alfa) e ossido nitrico (NOX) e sui livelli plasmatici di fattore di von Willebrand (vWF: Ag) alla diagnosi e al momento della risoluzione dell'infezione .
- Effetto della somministrazione di albumina sulla conta dei leucociti nel sangue e sui livelli sierici di proteina C-reattiva (PCR) durante l'infezione.
- Effetto della somministrazione di albumina riguardo lo sviluppo di insufficienza di altri organi (insufficienza renale, epatica, cerebrale, circolatoria, respiratoria e coagulativa), insufficienza epatica acuta-su-cronica (ACLF di tipo 1, 2 e 3, secondo lo studio CANONIC), score CLIF-SOFA, score CLIF-Consortium, Child-Pugh e MELD score durante il ricovero.
- Valutazione dei fattori predittivi per lo sviluppo di HRS e di ACLF nelle infezioni diverse dalla peritonite batterica spontanea.
- Campioni ( sangue, plasma , siero e nelle urine ) saranno ottenuti e conservati per analisi di genomica , proteomica e indagini biochimiche standard in studi futuri ancillari. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
day 3, day of infection resolution (or day 7 and every 7 days) day 28 and day 90 |
Al momento della diagnosi di infezione, al giorno 3 e alla risoluzione dell'infezione (o ogni 7 giorni fino a dimissione o fino alla morte se il paziente non risolve l'infezione) |
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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 |
standard antibiotic treatment without albumin |
lack of treatment |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 | 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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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
?? Termination of the trial by a regulatory authority
?? Any other reason for withdrawal that the trial physician or patient feels is in the best interest of the patient |
|
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 |