TY - JOUR
T1 - A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis
AU - Mayo, Marlyn J.
AU - Pockros, Paul J.
AU - Jones, David
AU - Bowlus, Christopher L.
AU - Levy, Cynthia
AU - Patanwala, Imran
AU - Bacon, Bruce
AU - Luketic, Velimir
AU - Vuppalanchi, Raj
AU - Medendorp, Sharon
AU - Dorenbaum, Alejandro
AU - Kennedy, Ciara
AU - Novak, Patricia
AU - Gu, Joan
AU - Apostol, George
AU - Hirschfield, Gideon M.
N1 - Funding Information:
Dr. David Gothard and Dr. Elizabeth Gandhi, employees of Oxford PharmaGenesis, Oxford, United Kingdom, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis, with funding provided by Shire International GmBH. Jürgen Wiehn and Thomas Jaecklin from Shire International GmbH also reviewed and edited the manuscript for scientific accuracy. Jana Steinmetz from Premier Research was the study statistician. Trial recruitment in Birmingham, United Kingdom, used the National Institute for Health Research clinical research facilities.
Publisher Copyright:
© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
PY - 2019/3
Y1 - 2019/3
N2 - Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% confidence interval [CI], –31.8, –21.2) and placebo (–23.4; 95% CI, –30.3, –16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.
AB - Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium-dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% confidence interval [CI], –31.8, –21.2) and placebo (–23.4; 95% CI, –30.3, –16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.
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U2 - 10.1002/hep4.1305
DO - 10.1002/hep4.1305
M3 - Article
C2 - 30859149
AN - SCOPUS:85069938073
SN - 2471-254X
VL - 3
SP - 365
EP - 381
JO - Hepatology Communications
JF - Hepatology Communications
IS - 3
ER -