E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003445 |
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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 efficacy of satavaptan on top of conventional treatment in the treatment of clinically evident ascites in patients with cirrhosis of the liver. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the tolerability and safety of satavaptan over a 52-week treatment period in patients with cirrhosis of the liver and ascites. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
- Patients with cirrhosis of the liver confirmed by histology and/or a combination of either ultrasound, CT or endoscopic examination with laboratory evidence (e.g. low platelet count, low serum albumin, elevated total serum bilirubin or elevated INR). -Patients with clinically evident ascites primarily managed by diet and/or diuretics o Patients should have a physical exam compatible with diagnosis of ascites (e.g. abdominal distension with confirmation of ascites by presence of at least one of the following signs: fluid wave, shifting dullness, bulging flanks lying supine, tympany at the top of the abdominal curve while supine, or presence of Puddle sign) or confirmation of ascites by ultrasound or by diagnostic paracentesis -Stable treatment of ascites for at least the previous 2 weeks without paracentesis - Patients may have undergone either • no therapeutic paracentesis, or • only one therapeutic paracentesis, or • in the case of more than one therapeutic paracentesis in the previous 6 months, the interval between the last 2 paracenteses must be >3 months. |
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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 each). Sepsis or spontaneous bacterial peritonitis currently or in the 10 days before randomisation. Current hepatic encephalopathy (>grade 1 by the West Haven criteria, Appendix B) evaluated by clinical features 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 >143 mmol/l Serum potassium <3.5 mmol/l or >=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 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 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 E: - Aprepitant, atazanavir, chloramphenicol, clarithromycin, cremophor EL, cyclosporine, 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) |
The primary endpoint is the proportion of patients with ascites worsening at 12 weeks. This endpoint will be defined by any of the following criteria occurring during the first 12 weeks of the study:
Therapeutic paracentesis is defined as - Removal of >=1 litres of ascitic fluid by paracentesis OR - Weight increase of >=2 kg since the baseline measurement on Day 1 before the first intake of study medication (including the weight of any ascitic fluid removed by paracentesis)
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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 | Information not present in EudraCT |
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.8.3 |
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 | 7 |
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 | Information not present in EudraCT |
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
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End of the trial is the post-treatment follow-up visit 2 weeks after the end of treatment (Week 54). |
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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 | |
E.8.9.1 | In the Member State concerned months | 26 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 26 |