Peter Fickert1, Gideon M Hirschfield2, Gerald Denk3, Hanns-Ulrich Marschall4, Istvan Altorjay5, Martti Färkkilä6, Christoph Schramm7, Ulrich Spengler8, Roger Chapman9, Annika Bergquist10, Erik Schrumpf11, Frederik Nevens12, Palak Trivedi2, Florian P Reiter3, Istvan Tornai5, Emina Halilbasic13, Roland Greinwald14, Markus Pröls14, Michael P Manns15, Michael Trauner16. 1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. 2. Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, United Kingdom. 3. Department of Medicine II, Liver Center Munich, Ludwig Maximilians University (LMU), Munich, Germany. 4. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. 5. Department of Gastroenterology, School of Medicine, Debrecen University, Debrecen, Hungary. 6. University of Helsinki and Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland. 7. 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 8. Department of Internal Medicine 1, Rheinische Friedrich-Wilhelm's University Bonn, Bonn, Germany. 9. Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, United Kingdom. 10. Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institute, Huddinge, Stockholm, Sweden. 11. Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway. 12. Hepatology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium. 13. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. 14. Dr. Falk Pharma GmBH, Freiburg, Germany. 15. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 16. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.
Abstract
BACKGROUND & AIM: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. METHODS:One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. RESULTS: norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. CONCLUSIONS: norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.
RCT Entities:
BACKGROUND & AIM: Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease, currently lacking effective medical therapy. 24-norursodeoxycholic acid (norUDCA) is a side chain-shortened C23 homologue of UDCA and has shown potent anti-cholestatic, anti-inflammatory and anti-fibrotic properties in a preclinical PSC mouse model. A randomized controlled trial, including 38 centers from 12 European countries, evaluated the safety and efficacy of three doses of oral norUDCA (500mg/d, 1,000mg/d or 1,500mg/d) compared with placebo in patients with PSC. METHODS: One hundred sixty-one PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for a 12-week treatment followed by a 4-week follow-up. The primary efficacy endpoint was the mean relative change in ALP levels between baseline and end of treatment visit. RESULTS:norUDCA reduced ALP levels by -12.3%, -17.3%, and -26.0% in the 500, 1,000, and 1,500mg/d groups (p=0.029, p=0.003, and p<0.0001 when compared to placebo), respectively, while a +1.2% increase was observed in the placebo group. Similar dose-dependent results were found for secondary endpoints, such as ALT, AST, γ-GT, or the rate of patients achieving ALP levels <1.5× ULN. Serious adverse events occurred in seven patients in the 500mg/d, five patients in the 1,000mg/d, two patients in the 1500mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. CONCLUSIONS:norUDCA significantly reduced ALP values dose-dependently in all treatment arms. The safety profile of norUDCA was excellent and comparable to placebo. Consequently, these results justify a phase III trial of norUDCA in PSC patients. Lay summary: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed. In this phase II clinical study in PSC patients, a side chain-shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA), significantly reduced serum alkaline phosphatase levels in a dose-dependent manner during a 12-week treatment. Importantly, norUDCA showed a favorable safety profile, which was similar to placebo. The use of norUDCA in PSC patients is promising and will be further evaluated in a phase III clinical study. ClinicalTrials.gov number: NCT01755507.
Authors: John E Eaton; Kevin M Nelson; Andrea A Gossard; Elizabeth J Carey; James H Tabibian; Keith D Lindor; Nicholas F LaRusso Journal: Scand J Gastroenterol Date: 2019-05-26 Impact factor: 2.423
Authors: Jorge A Bezerra; Rebecca G Wells; Cara L Mack; Saul J Karpen; Jay H Hoofnagle; Edward Doo; Ronald J Sokol Journal: Hepatology Date: 2018-09 Impact factor: 17.425