E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Portal hypertension, liver cirrhosis |
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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 | 10036200 |
E.1.2 | Term | Portal hypertension |
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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 | 10024667 |
E.1.2 | Term | Liver cirrhosis |
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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 assess the optimal dose of udenafil tablets for treatment of portal hypertension in patients with liver cirrhosis.
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E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of a dose range of udenafil 12.5 to 75 mg/day administered for portal hypertension in patients with liver cirrhosis.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent. 2. Man or woman between 18 and 70 years of age. 3. Compensated liver cirrhosis as proven by clinical findings, laboratory tests, and ultrasound. 4. Liver cirrhosis as proven by histology (histology within 5 years prior to Baseline visit) or FibroScan (facultative) or by unequivocal clinical, radiological and laboratory signs. 5. Clinically significant portal hypertension defined as HVPG ≥ 12 mm Hg. 6. Low risk of bleeding characterized by no or small (< 5 mm in diameter) oesophageal varices proven by endoscopy (previous full variceal banding ligation or obliterative sclerotherapy as primary or secondary prophylaxis for variceal haemorrhage allowed). 7. Women of child-bearing potential have to apply double barrier methods of contraception (e.g. oral contraception with condom). The investigator is responsible for determining whether the patient has adequate birth control for study participation.
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E.4 | Principal exclusion criteria |
1. Child-Pugh C. 2. Existing transjugular intrahepatic portosystemic shunt (TIPS) or surgical shunt. 3. Splenic or portal vein thrombosis by Doppler ultrasonography, magnetic resonance imaging. 4. Gastric/duodenal varices with bleeding stigmata (red colour sign or clot) or gastric/duodenal varices with history of bleeding. 5. Large oesophageal varices (≥ 5 mm in diameter). 6. Alcoholic hepatitis. 7. Hepatic encephalopathy ≥ stage 2. 8. Ascites present at Baseline visit. 9. Total Bilirubin > 3 mg/dl. 10. Bleeding disorder, INR > 2. 11. Active peptic ulceration. 12. Open-label pilot phase only: Positive Hepatitis B or C serology 13. Positive HIV serology 14. Anatomical deformation of the penis or penile implants. 15. Predisposing priapism, sickle cell anaemia or trait, thrombocythaemia, polycythaemia, prone to venous thrombosis (immobility, surgery of pelvis, abdomen, hip, thrombophilia, history of thrombosis etc.), hyperviscosity syndrome (increased blood viscosity in particular due to polymers typical in multiple myeloma, polycythemia vera, Raynaud’s phenomenon, Waldenström’s macroglobulinemia). 16. Known hereditary degenerative retinal disorders, including retinitis pigmentosa. 17. Previous episode of NAION. 18. Renal failure (GFR < 60 ml/min/1.73 m²). 19. QTc prolongation (QTc>440 ms) or treatment with QTc interval-increasing medications. 20. Heart failure (NYHA II-IV). 21. Angina pectoris. 22. History of myocardial infarction, stroke or life-threatening arrhythmia. 23. Aortic stenosis. 24. Resting hypotension (systolic blood pressure [SBP]/diastolic blood pressure [DBP] < 90/60 mm Hg), uncontrolled hypertension (SBP/DBP > 170/100 mm Hg). 25. Symptomatic hypotension (e.g. fainting) following alpha-blocker administration. 26. Bacterial infection (positive blood, urine or ascites cultures; or ascites with leucocytes ≥ 500/µl or PMN ≥ 250/µl) within 2 weeks prior to Baseline visit. 27. Drugs that may have an effect on splanchnic haemodynamics/portal pressure, e.g. β-blockers, clonidine, prazosin, nitrates, and any other antihypertensive treatment within 2 weeks prior to Baseline visit (Exception: losartan within 4 weeks prior to Baseline visit). 28. Concomitant treatment with β-blockers, calcium channel blockers, clonidine, prazosin, nitrates, molsidomine, any antihypertensive treatment and any drug which may have an effect on splanchnic haemodynamics/portal pressure. 29. Concomitant treatment with vasopressin or somatostatin and their derivatives and analogues. 30. Concomitant treatment with platelet aggregation inhibitors, e.g. aspirin, heparin. 31. Concomitant treatment with other PDE-5 inhibitors, e.g. sildenafil, tadalafil or vardenafil. 32. Treatment with ketoconazole or other CYP3A inhibitors or inducers, consumption of grapefruit juice. 33. Active hepatocellular cancer or a history of hepatocellular cancer (to be excluded by ultrasound and tumour markers). 34. Active malignancy other than hepatocellular cancer or treatment with anticancer drugs during the last 5 years. Patients with a history of cancer other than hepatocellular cancer and at least five years of uneventful follow up and no signs of recurrence may be eligible. 35. Severe co-morbidity substantially reducing life expectancy. 36. Known intolerance/hypersensitivity/resistance to study drug or drugs of similar chemical structure or pharmacological profile. 37. Doubt about the patient’s cooperation, e.g. because of addiction to alcohol or drugs. 38. Existing or intended pregnancy or breast-feeding. 39. Participation in another clinical study within the last 30 days, simultaneous participation in another clinical study, or previous participation in this study
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E.5 End points |
E.5.1 | Primary end point(s) |
Hepatic venous pressure gradient (HVPG): Rate of response defined as final HVPG reduction to ≤ 12 mm Hg or by ≥ 20% compared to Baseline. HVPG (measurements to be performed in triplicate) determined pre-dose and one hour post-dose at Baseline, after one week, i.e. last day of pilot phase and after 1-week of treatment in the double-blind phase, and at the final/withdrawal visit of the double-blind phase.
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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 | 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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Different Doses of Udenafil (12.5 mg; 25 mg; 50 mg; 75 mg) |
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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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 | 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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |