E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Fibrotic alcoholic liver disease is in early stages often completely asymptomatic. Fully developed cirrhosis affect a wide range of physiological conditions. Eksamples are portal hypertension and following ascites and oesofagus varices. Serious sequelae of liver failure, in the form of hepatic encephalopathy and impaired synthesis of albumin and clotting factors are also seen. The prognosis is at this stage of disease progression extremely poor. |
Fibrotisk leversygdom på alkoholisk basis i præcirrotiske stadier giver i reglen ikke anledning til symptomer. Ved fuldt udviklet cirrose påvirkes en lang række fysiologiske forhold. Et Eksempel herpå er portal hypertension med ascites og oesofagusvaricer til følge. Desuden ses alvorlige følgetilstande til leversvigt, i form af hepatisk encephalopati og nedsat syntese af albumin og koagulationsfaktorer. Prognosen er på dette tidspunkt i sygdomsudviklingen særdeles dårlig. |
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E.1.1.1 | Medical condition in easily understood language |
Incipient cirrhosis due to overuse of alcohol usually gives no symptoms. By developing disease bloodcirculation and liver function are affected. The prognosis is at this time very poor. |
Begyndende skrumpelever på grund af overforbrug af alkohol giver oftest ikke symptomer. Ved udviklet sygdom påvirkes kredsløb og leverfunktion. Prognosen er på dette tidspunkt særdeles dårlig. |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001627 |
E.1.2 | Term | Alcoholic liver disease |
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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001626 |
E.1.2 | Term | Alcoholic liver damage, unspecified |
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 |
Fibrotic liver disease traditionally seen as an irreversible condition. Angiotensin II receptor antagonists in animal studies has been shown to have an inhibitory effect on the development of liver fibrosis and these findings are backed up in small human studies. Molecular biological studies, animal studies and small human studies support the hypothesis that Angiotensin II receptor inhibitors in therapeutic doses has a antifibrotisk potential in patients with precirrhotic alcoholic liver disease.
The main purpose of this study is to investigate whether losartan at therapeutic dose after 12 months has a antifibrotic effect on pin patients with precirrhotic alcoholic liver fibrosis. |
Fibrotisk leversygdom opfattes traditionelt som en irreversibel tilstand. Angiotensin II receptorantagonister har i dyreforsøg vist sig at have en hæmmende effekt på udviklingen af leverfibrose og disse fund bakkes op i mindre humane studier. Molekylærbiologiske studier, dyreforsøg samt mindre humane studier støtter den hypotese, at AT-II receptorhæmmere i terapeutisk dosis har et antifibrotisk potentiale hos patienter med præcirrotisk leversygdom på alkoholisk basis.
Det primære formål med dette studium er at undersøge, om losartan i terapeutisk dosis efter 12 måneder har antifibrotisk effekt på præcirrotiske patienter med leverfibrose på alkoholisk basis.
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E.2.2 | Secondary objectives of the trial |
There is no established secondary objective of this study. |
Der er ikke opstillet sekundære formål med dette forsøg. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Men and women aged 18 to 75 years.
- Alcoholconsumption corresponding to an assumed average alcohol intake of ≥ 40 g alcohol daily for more than 3 years.
- Presence of significant or advanced fibrotic liver disease (Metavir F2 / F3) diagnosed by liver biopsy or elastiometric ultrasound with cut-off ≥ 8 kPa.
- Women of childbearing potential must agree to use adequate contraception. |
- Mænd og kvinder i alderen 18 – 75 år.
- Alkoholanamnese svarende til et formodet gennemsnitligt alkoholindtag på ≥ 40 gram alkohol dagligt (ca. 3½ genstand) i mere end 3 år.
- Forekomst af signifikant eller avanceret fibrotisk leversygdom (Metavir F2 / F3) diagnostiseret ved leverbiopsi ELLER elastografisk ultralydsskanning med cut off ≥ 8 kPa.
- Fertile kvinder skal acceptere anvendelse af sikker antikonception: P-piller, implantat (P-stav), transdermal depotplastre, vaginalring eller depotinjektion. Steril fast partner eller brug af dobbeltbarriere (kondom OG pessar) er også acceptabelt. |
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E.4 | Principal exclusion criteria |
- Known cirrhosis confirmed by biopsy
- Clinically decompensated cirrhosis determined by the presence of ascites (former or known by elastiographic ultrasoundinvestigation) or eusofagusvariser.
- Elastiographic value (stiffness) <8 kPa.
- Pregnancy
- Co-morbidity in the form of viral hepatitis (HBV or HCV), HIV, BMI > 30
- Unwillingness or inability to accept participation in the trial
- Current treatment with an ACE inhibitor or Angiotensin II antagonists
- Previous allergic reaction to Angiotensin II antagonists. Specific questioning of angioedema.
- Hypotension with clinical symptoms, where it is deemed medically irresponsible to intervene with antihypertensive medication. |
- Kendt cirrose verificeret ved biopsi
- Klinisk inkompenseret cirrose bestemt ved tilstedeværelse af ascites (tidligere eller erkendt ved elastiografi) eller eusofagusvariser.
- Elastiografisk værdi (hårdhedsgrad) < 8 kPa.
- Graviditet
- Comorbiditet i form af Viral hepatitis (HBV eller HCV), HIV, BMI > 30
- Manglende vilje eller evne til at acceptere deltagelse i forsøget
- Aktuel behandling med ACE-hæmmer eller Angiotensin II-antagonister
- Tidligere allergisk reaktion over for Angiotensin II antagonister. Specifik udspørgen til angioødem.
- Hypotension med kliniske symptomer, hvor det lægeligt skønnes uforsvarligt at intervenere med antihypertensiv medicin.
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E.5 End points |
E.5.1 | Primary end point(s) |
Significant difference in grade of fibrosis in liver biopsies and by elastiometric ultrasoundinvestigation before and after 12 months of treatment with losartan 50 mg x 1 daily. |
Signifikant forskel i fibrosegrad målt ved leverbiopsi og elastiometri før og efter 12 måneders behandling med 50 mg losartan x 1 dagligt. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Significant difference in the frequency of upper gastrointestinal bleeding episodes. Bleeding Episode is defined by:
--- Significant or unexplained hemoglobin decrease
--- Verified by gastroscopy (objective signs of active or new bleeding.
Significant difference in the incidence of ascites. A distinction is made between:
Grade 0: Neither clinical or ultrasound demonstrated ascites
Grade 1: No clinical ascites, but ascites easily seen by ultrasound.
Grade 2: Ascites can be recognized by basic clinical examination.
Grade 3: Visible ascites. |
- Signifikant forskel i antallet af øvre gastrointestinale blødningsepisoder. Blødningsepisode defineres ved:
--- Signifikant eller uforklaret hæmoglobinfald
--- Verificering ved gastroskopi, hvor der findes tegn til aktiv blødning og/eller blødningsstigmata.
Signifikant forskel i forekomsten af ascites. Der skelnes mellem:
Grad 0: Hverken klinisk eller ultralyds påvist ascites
Grad 1: Ikke klinisk ascites, men let ascites set ved ultralydsscanning.
Grad 2: Ascites kan erkendes ved udperkutering, hvor dæmpning i flankerne ændres ved lejeskifte.
Grad 3: Synlig ascites.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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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LVLS |
Undersøgelsen gøres op efter den sidste forsøgspersons sidste besøg. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |