norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis
<strong>Background & Aim</strong> 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-cholestat...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2017
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| _version_ | 1797080673841840128 |
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| author | Fickert, P Hirschfield, G Denk, G Marschall, H Altorjay, I Färkkilä, M Schramm, C Spengler, U Chapman, R Bergquist, A Schrumpf, E Nevens, F Trivedi, P Reiter, F Tornai, I Halilbasic, E Greinwald, R Pröls, M Manns, M Trauner, M European Psc Norudca Study Group |
| author_facet | Fickert, P Hirschfield, G Denk, G Marschall, H Altorjay, I Färkkilä, M Schramm, C Spengler, U Chapman, R Bergquist, A Schrumpf, E Nevens, F Trivedi, P Reiter, F Tornai, I Halilbasic, E Greinwald, R Pröls, M Manns, M Trauner, M European Psc Norudca Study Group |
| author_sort | Fickert, P |
| collection | OXFORD |
| description | <strong>Background & Aim</strong> 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. <strong>Methods</strong> 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. <strong>Results</strong> norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. <strong>Conclusions</strong> 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. |
| first_indexed | 2024-03-07T01:03:28Z |
| format | Journal article |
| id | oxford-uuid:8a82ad46-7070-46f2-bf70-23d149e84a68 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:03:28Z |
| publishDate | 2017 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:8a82ad46-7070-46f2-bf70-23d149e84a682022-03-26T22:32:05ZnorUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8a82ad46-7070-46f2-bf70-23d149e84a68EnglishSymplectic Elements at OxfordElsevier2017Fickert, PHirschfield, GDenk, GMarschall, HAltorjay, IFärkkilä, MSchramm, CSpengler, UChapman, RBergquist, ASchrumpf, ENevens, FTrivedi, PReiter, FTornai, IHalilbasic, EGreinwald, RPröls, MManns, MTrauner, MEuropean Psc Norudca Study Group<strong>Background & Aim</strong> 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 (500 mg/d, 1,000 mg/d or 1,500 mg/d) compared with placebo in patients with PSC. <strong>Methods</strong> 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. <strong>Results</strong> norUDCA reduced ALP levels by −12.3%, −17.3%, and −26.0% in the 500, 1,000, and 1,500 mg/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 500 mg/d, five patients in the 1,000 mg/d, two patients in the 1500 mg/d group, and three in the placebo group. There was no difference in reported pruritus between treatment and placebo groups. <strong>Conclusions</strong> 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. |
| spellingShingle | Fickert, P Hirschfield, G Denk, G Marschall, H Altorjay, I Färkkilä, M Schramm, C Spengler, U Chapman, R Bergquist, A Schrumpf, E Nevens, F Trivedi, P Reiter, F Tornai, I Halilbasic, E Greinwald, R Pröls, M Manns, M Trauner, M European Psc Norudca Study Group norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title | norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title_full | norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title_fullStr | norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title_full_unstemmed | norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title_short | norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
| title_sort | norursodeoxycholic acid improves cholestasis in primary sclerosing cholangitis |
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