E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
cirrhotic ascites |
ascite cirrotica |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10003445 |
E.1.2 | Term | Ascites |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
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 |
To evaluate the efficacy of satavaptan on top of diuretic drugs in reducing the recurrence of ascites |
Valutare l'efficacia e la sicurezza di satavaptan, in concomitanza con terapia diuretica, nella riduzione delle recidive dell'ascite. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate the tolerability and safety of satavaptan on top of diuretic drugs over a 52-week treatment period in patients with cirrhosis of the liver and recurrent ascites |
Valutare la tollerabilita' e la sicurezza di satavaptan,in concomitanza con terapia diuretica,nella riduzione delle recidive dell'ascite durante il periodo di trattamento di 52 settimane. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with cirrhosis of the liver confirmed by histology and/or a combination of either ultrasound or endoscopic examination with laboratory evidence (e.g. low platelet count, low serum albumin, elevated total serum bilirubin or elevated INR). - Patients with recurrent ascites having undergone both of the following: . therapeutic paracentesis for the removal of ascites in the previous 24 hours with the removal of >= 4 litres of fluid, . at least one other therapeutic paracentesis in the previous 3 months |
·I pazienti dovranno avere una diagnosi di cirrosi epatica confermata da istologia e/o ecografia o endoscopia supportate da evidenze di laboratorio (i.e. bassi valori di conta piastrinica, di albumina sierica oppure valori elevati di bilirubina o INR). ·Pazienti con ascite ricorrente, che siano stati sottoposti a paracentesi-Nelle precedenti 24 ore, con rimozione di > 4 litri di fluido ascitico-e almeno in un'altra occasione nei 3 mesi precedenti. |
|
E.4 | Principal exclusion criteria |
1)Related to study methodology: Age <18 years; no written informed consent; inability to follow verbal and written instructions; patients with an existing functional TIPS (transjugular intrahepatic portosystemic shunt) or other shunt designed to transfer blood from the portal system to the systemic circulation bypassing the liver; Budd-Chiari syndrome; patients with positive HBV DNA who have started antiviral treatment in the previous 4 weeks or in whom such treatment is planned to start during the next 12 weeks; previous liver transplantation; known hepatocellular carcinoma (unless only one lesion <5 cm diameter or no more than 3 nodules of <3 cm); sepsis or spontaneous bacterial peritonitis currently or in the 10 days before randomisation; current hepatic encephalopathy (>grade 1 by the West Haven criteria, known gastrointestinal bleeding currently or in the 10 days before randomisation; QTcF interval on an ECG >= 480 ms; patients with ascites of cardiac origin or due to peritoneal infection (e.g. tuberculosis) or peritoneal carcinoma Serum bilirubin >150 µmol/l INR >3.0, neutrophils <1 000/mm3, platelets <30 000/mm3; patients previously exposed to satavaptan in the past 12 months 2) Related to satavaptan Haemodynamic insufficiency (systolic arterial pressure <80 mmHg or symptomatic orthostatic hypotension); serum sodium >142 mmol/l; serum potassium >= 5.0 mmol/l; significant renal impairment with serum creatinine >150 µmol/l; positive pregnancy test; females of child-bearing potential are excluded unless they meet one of the following criteria: . Post-menopausal for 6 months or more, and if post-menopausal for less than 2 years, a negative pregnancy test . Surgical sterilisation for more than one month duration and a negative pregnancy test . Intrauterine device in combination with a secondary barrier (e.g. diaphragm, condom or spermicide) and a negative pregnancy test . Oral contraceptive in combination with a secondary barrier (e.g. diaphragm, condom or spermicide) and a negative pregnancy test; known hypersensitivity to satavaptan Administration of inducers of CYP3A listed below within the two weeks prior to study drug administration: . carbamazepine, phenobarbital, phenytoin, rifampicin (rifampin), Saint John's Wort; administration of potent and selected moderate inhibitors of CYP3A, which may significantly increase exposure to the study drug within the two weeks prior to study drug administration. These are listed below and in Appendix F: . Aprepitant, atazanavir, chloramphenicol, clarithromycin, cremophor EL, cyclosporin, diltiazem, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, verapamil; patients taking other drugs known to increase the risk of hyperkalaemia in addition to spironolactone, potassium canrenoate or eplerenone may not be included in the study in order to avoid an additive effect on serum potassium concentrations (e.g. angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists). |
-Criteri di esclusione relativi alla metodologia di studio: oEta' < 18 anni; oConsenso informato non firmato; oIncapacita' a seguire istruzioni scritte o verbali; o pazienti con TIPS o altri shunt atti a trasferire il sangue dalla circolazione portale a quella sistemica bypassando il fegato; o sindrome di Budd-Chiari; o pazienti con test positivo per il DNA del virus dell'epatite B, che abbiano iniziato un trattamento antivirale nelle precedenti 4 settimane o che abbiano in programma di iniziarlo nelle successive 12 settimane; o precedente trapianto di fegato; o carcinoma epatocellulare (a meno che non sia presente una sola lesione con diametro < 5 cm o non piu' di tre noduli con diametro < 3 cm); o sepsi o peritonite batterica spontanea nei dieci giorni precedenti; o encefalopatia epatica > grado 1 in atto, valutata clinicamente; o sanguinamento gastrointestinale in corso o nei 10 giorni precedenti; o QTcF > 480 msec; o Ascite di origine cardiaca, o causata da infezione (i.e. tubercolosi) o carcinosi peritoneale; o Bilirubina sierica > 150 mmol/l; o INR > 3.0, neutrofili < 1.000/mm3, piastrine < 30.000/mm3 o trattamento con satavaptan nei 12 mesi precedenti ·Criteri di esclusione relativi a satavaptan: o scompenso emodinamico (pressione arteriosa sistolica <80mmHg o ipotensione ortostatica sintomatica); o Sodio sierico > 142 mmol/l; o Potassio sierico > 5.0 mmol/l; o insufficienza renale significativa, con creatinina sierica > 150mol/l; o test di gravidanza positivo; o donne in eta' fertile, a meno che non sia rispettato uno dei seguenti criteri: - in menopausa da 6 mesi o piu', e se in menopausa da meno di due anni, test di gravidanza negativo; - sterilizzazione chirurgica da piu' di un mese e test di gravidanza negativo; - spirale in combinazione con un metodo di barriera (diaframma, preservativo o crema spermicida) e test di gravidanza negativo; - contraccettivo orale in combinazione con un metodo di barriera (diaframma, preservativo o crema spermicida) e test di gravidanza negativo; o Ipersensibilita' nota a satavaptan; o Somministrazione di induttori di CYP3A (carbamazepina, fenobarbital, fenitoina, rifampicina, iperico) o Somministrazione di inibitori da moderati a potenti di CYP3A, che possono aumentare l'effetto del farmaco in studio, nelle due settimane precedenti la somministrazione dello farmaco in studio (atanazavir, cloramfenicolo, claritromicina, ciclosporina, diltiazem, eritromicina, fluconazolo, succo di pompelmo, itraconazolo, chetoconazolo, nefazodone, nelfinavir, ritonavir, saquinavir, telitromicina, troleandomicina, verapamil); o Pazienti che stiano assumendo altri farmaci noti per aumentare il rischio di iperpotassiemia in aggiunta a spironolattone, potassio canrenoato o eplerenone non potranno essere inclusi nello studio, in modo da evitare un effetto additivo sulle concentrazioni sieriche di potassio (i.e. ACE-inibitori e antagonisti del recettore II dell'angiotensina). |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the number and time (from randomisation) of recurrences of therapeutic paracenteses occurring during the first 12 weeks of the double blind period of the study. Therapeutic paracentesis will be defined as the removal of >= 2 litres of ascitic fluid by paracentesis |
·Numero di paracentesi terapeutiche (con rimozione di liquido > 2 litri) ed intervallo di tempo intercorrente tra paracentesi terapeutiche (a partire dalla randomizzazione) |
|
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 | 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) | 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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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 | Yes |
E.8.2.3 | Other | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | No |
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 | Information not present in EudraCT |
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
| |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 26 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 26 |
E.8.9.2 | In all countries concerned by the trial days | 0 |