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Lack of efficacy of an inhibitor of PDE4 in phase 1 and 2 trials of patients with nonalcoholic steatohepatitis
V. Ratziu, P. Bedossa, SM. Francque, D. Larrey, GP. Aithal, L. Serfaty, M. Voiculescu, L. Preotescu, F. Nevens, V. De Lédinghen, GI. Kirchner, P. Trunecka, SD. Ryder, CP. Day, J. Takeda, K. Traudtner,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu klinické zkoušky, fáze I, klinické zkoušky, fáze II, časopisecké články, randomizované kontrolované studie, práce podpořená grantem
- MeSH
- alanintransaminasa krev MeSH
- aspartátaminotransferasy krev MeSH
- dospělí MeSH
- inhibitory fosfodiesterasy 4 aplikace a dávkování škodlivé účinky MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nealkoholová steatóza jater farmakoterapie patologie MeSH
- placeba aplikace a dávkování MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND & AIMS: ASP9831 is a phosphodiesterase-4 inhibitor developed to treat nonalcoholic steatohepatitis (NASH); it showed potent anti-inflammatory and antifibrotic effects in preclinical studies. We evaluated the efficacy and safety of ASP9831 in patients with NASH. METHODS: In a phase 1 trial, we determined the optimal therapeutic window of ASP9831 in healthy volunteers and evaluated 2 doses (50 and 100 mg) in patients with NASH. Based on the positive outcomes of the phase 1 study, we performed a phase 2 trial to compare the biochemical effects of ASP9831 vs placebo. Patients with NASH were assigned randomly to groups given either 50 mg (n = 33) or 100 mg (n = 33) ASP9831 twice daily, or placebo (n = 30), for 12 weeks. The primary end point was the mean percentage change, from baseline to the end of ASP9831 administration, in serum level of alanine aminotransferase (ALT); secondary outcomes included changes in aspartate aminotransferase (AST) levels, ratio of AST:ALT, and various biomarkers of NASH. RESULTS: After 12 weeks of administration, there was no significant change in mean serum levels of ALT (P = .42) or AST (P = .20) or other biomarkers in any group, and no significant differences were observed among groups. Most adverse events were mild; gastrointestinal disorders occurred more frequently in the ASP9831 groups than the placebo group. CONCLUSIONS: Despite a relevant mechanism of action, ASP9831 did not significantly alter the biochemical markers of NASH, compared with placebo, in a clinical trial. This highlights the difficulties of developing therapeutics for NASH and the need for more extensive preclinical testing of mechanisms of potential drug candidates. Clinicaltrialsregister.eu: 2005-001687-31; EudraCT numbers: 2007-002114-19.
Astellas Pharma Europe BV Leiden The Netherlands
Astellas Pharma Inc Tokyo Japan
Department of Hepatology University Hospitals KU Leuven Leuven Belgium
Department of Internal Medicine 1 University Hospital of Regensburg Regensburg Germany
Department of Internal Medicine and Nephrology Fundeni Clinical Institute Bucharest Romania
Hôpital Beaujon INSERM U773 Université Paris Diderot Paris France
INSERM U1053 Université Bordeaux Segalen Bordeaux France
Institute of Cellular Medicine Faculty of Medical Sciences Newcastle University United Kingdom
Matei Balş National Institute for Infectious Diseases Bucharest Romania
Service d'Hépato Gastro Entérologie Hôpital Haut Lévêque Pessac France
Citace poskytuje Crossref.org
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