E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cirrhotic ascites / ascitis cirrótica. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003445 |
E.1.2 | Term | Ascites |
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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 |
To evaluate the long term safety and tolerability up to 2 years of treatment with satavaptan in patients with cirrhosis of the liver previously treated for 52 weeks with satavaptan in any of the phase III studies |
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E.2.2 | Secondary objectives of the trial |
Number and time (from randomization in the previous phase III EFC studies) of therapeutic paracentesis, defined as the removal of ≥ 2 liters of ascitic fluid by paracentesis. Increase in ascites measured by body weight and volume of ascites removed by paracentesis ( to be expressed as increase per unit of time to avoid any bias due to withdrawl). Diuretics regimen at each scheduled visit according to a predefined classification.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Only patients that have been previously randomized and have completed the 52 weeks treatment period plus the 2 weeks post treatment follow up in any of the following studies: EFC4492; EFC4493 or EFC6682 Patients must agree to participate and sign a new inform consent specific for this study LTS10036 Patients must not have a treatment discontinuation longer than 18 days from the phases III studies treatment completion
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E.4 | Principal exclusion criteria |
Age <18 years
No written informed consent
Inability to follow verbal and written instructions.
Patients with an existing functional Transjugular Intrahepatic Portosystemic Shunt (TIPS) or other shunt designed to transfer blood from the portal system to the systemic circulation bypassing the liver.
Budd-Chiari syndrome
Patients with positive Hepatitis B virus (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 each).
Sepsis or spontaneous bacterial peritonitis currently or in the 10 days before randomisation.
Current hepatic encephalopathy (>grade 1 by the West Haven criteria, evaluated by clinical features
Known gastrointestinal bleeding currently or in the 10 days before randomisation.
QTcF interval on an ECG ³480 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.
Related to satavaptan Haemodynamic insufficiency (systolic arterial pressure <80 mmHg or symptomatic orthostatic hypotension)
Serum sodium >142 mmol/l
Serum potassium < 3.5 mmol/l or ³ 5.0 mmol/l
Serum Magnesium < 0.65 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 more than one month prior to enrollment and a negative pregnancy test
Intrauterine device in combination with a secondary barrier (e.g. diaphragm, condom or spermicide) and a negative pregnancy test Hormonal 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 within the two weeks prior to study start of the following CYP3A inhibitors, which may significantly increase exposure to the study drug. These are listed below and in Appendix C
Aprepitant, 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)
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E.5 End points |
E.5.1 | Primary end point(s) |
Survival, adverse events, laboratory data, vital signs, and ECG for long term safety evaluation. |
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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 | 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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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 | 9 |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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Last visit of last 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 | 1 |
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 | 1 |