norUrsodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis
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norUrsodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis. / Fickert, Peter; Hirschfield, Gideon M; Denk, Gerald; Marschall, Hanns-Ulrich; Altorjay, Istvan; Färkkilä, Martti; Schramm, Christoph; Spengler, Ulrich; Chapman, Roger W; Bergquist, Annika; Schrumpf, Erik; Nevens, Frederik; Trivedi, Palak J; Reiter, Florian P; Tornai, Istvan; Halilbasic, Emina; Greinwald, Roland; Pröls, Markus; Manns, Michael P; Trauner, Michael; European PSC norUDCA Study Group.
In: J HEPATOL, Vol. 67, No. 3, 09.2017, p. 549-558.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - norUrsodeoxycholic Acid Improves Cholestasis in Primary Sclerosing Cholangitis
AU - Fickert, Peter
AU - Hirschfield, Gideon M
AU - Denk, Gerald
AU - Marschall, Hanns-Ulrich
AU - Altorjay, Istvan
AU - Färkkilä, Martti
AU - Schramm, Christoph
AU - Spengler, Ulrich
AU - Chapman, Roger W
AU - Bergquist, Annika
AU - Schrumpf, Erik
AU - Nevens, Frederik
AU - Trivedi, Palak J
AU - Reiter, Florian P
AU - Tornai, Istvan
AU - Halilbasic, Emina
AU - Greinwald, Roland
AU - Pröls, Markus
AU - Manns, Michael P
AU - Trauner, Michael
AU - European PSC norUDCA Study Group
N1 - Copyright © 2017. Published by Elsevier B.V.
PY - 2017/9
Y1 - 2017/9
N2 - Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease 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.AIM: To evaluate the safety and efficacy of 3 doses of oral norUDCA (500mg/d, 1000mg/d or 1500 mg/d) compared with placebo in PSC in a RCT including 38centers from 12European countries.METHODS: 161 PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for 12-weeks treatment followed by a 4-weeks follow-up. 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, 1000, and 1500 mg/d groups (p=0.029, =0.003, and <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 <1.5x ULN. Serious adverse events occurred in 7 in the 500mg/d-, 5 in the 1000mg/d-, 2 in the 1500 mg/d-group, and 3 in the placebo group, respectively. There was no difference in reported pruritus between treatment and placebo groups.CONCLUSIONS: norUDCA significantly reduced ALP values dose dependently in all treatment arms. Safety profile of norUDCA was excellent and comparable to placebo. Consequently, a phase-3 trial of norUDCA in PSC appears justified. CLINICALTRIALS.GOV NUMBER: NCT01755507 LAY SUMMARY: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed.In this phase II clinical study, a side chain shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA) significantly reduced serum alkaline phosphatase levels within 12 weeks as important surrogate marker in PSC in a dose-dependent manner. 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.
AB - Primary sclerosing cholangitis (PSC) represents a devastating bile duct disease 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.AIM: To evaluate the safety and efficacy of 3 doses of oral norUDCA (500mg/d, 1000mg/d or 1500 mg/d) compared with placebo in PSC in a RCT including 38centers from 12European countries.METHODS: 161 PSC patients without concomitant UDCA therapy and with elevated serum alkaline phosphatase (ALP) levels were randomized for 12-weeks treatment followed by a 4-weeks follow-up. 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, 1000, and 1500 mg/d groups (p=0.029, =0.003, and <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 <1.5x ULN. Serious adverse events occurred in 7 in the 500mg/d-, 5 in the 1000mg/d-, 2 in the 1500 mg/d-group, and 3 in the placebo group, respectively. There was no difference in reported pruritus between treatment and placebo groups.CONCLUSIONS: norUDCA significantly reduced ALP values dose dependently in all treatment arms. Safety profile of norUDCA was excellent and comparable to placebo. Consequently, a phase-3 trial of norUDCA in PSC appears justified. CLINICALTRIALS.GOV NUMBER: NCT01755507 LAY SUMMARY: Effective medical therapy for primary sclerosing cholangitis (PSC) is urgently needed.In this phase II clinical study, a side chain shortened derivative of ursodeoxycholic acid, norursodeoxycholic acid (norUDCA) significantly reduced serum alkaline phosphatase levels within 12 weeks as important surrogate marker in PSC in a dose-dependent manner. 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.
KW - Journal Article
U2 - 10.1016/j.jhep.2017.05.009
DO - 10.1016/j.jhep.2017.05.009
M3 - SCORING: Journal article
C2 - 28529147
VL - 67
SP - 549
EP - 558
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 3
ER -
