Abstract
Medically refractory, severe, cholestasis-induced pruritus in Alagille syndrome may be improved by surgical interruption of the enterohepatic circulation. This multicenter trial (NCT02057692) tested the hypothesis that the intestinal bile acid transport inhibitor maralixibat would similarly reduce pruritus in Alagille syndrome. Thirty-seven children with Alagille syndrome were randomly assigned to double-blinded administration of placebo, 70, 140, or 280 µg/kg/day of maralixibat for 13 weeks. Pruritus was assessed by caregiver (itch-reported outcome instrument [ItchRO]) and clinician report (range, 0-4 [severe]). Liver chemistries and serum bile acids were measured. The primary outcome was the change from baseline to week 13 in ItchRO relative to placebo. In the a priori first analysis of the primary efficacy endpoint, the mean adjusted difference between participants receiving 140 or 280 µg/kg/day and placebo was –0.47 (95% confidence interval [CI], –1.14, 0.20; P = 0.16). Statistically significant decreases were observed with doses of 70 and 140 µg/kg/day (mean adjusted difference, –0.89; 95% CI, –1.70, –0.08; P = 0.032; and mean adjusted difference, –0.91; 95% CI, –1.62, –0.19; P = 0.014) but not 280 µg/kg/day (mean adjusted difference, –0.04; 95% CI, –0.94, 0.86; P = 0.44) or all doses combined (mean adjusted difference, –0.61; 95% CI, –1.24, 0.20; P = 0.055). A 1-point reduction in pruritus was more common in maralixibat-treated versus placebo-treated participants (caregiver ItchRO, 65% versus 25%; P = 0.06; clinician score, 76% versus 25%; P = 0.01). There were no significant changes in liver chemistries or bile acids relative to placebo. Adverse and serious adverse events were similar between maralixibat and placebo. Conclusion: Although the prespecified primary analyses of ItchRO were not all statistically significant, the data suggest that maralixibat is safe and may reduce pruritus in Alagille syndrome.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1184-1198 |
| Number of pages | 15 |
| Journal | Hepatology Communications |
| Volume | 2 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2018 |
Funding
Funding Supported by U01 grants from the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases: (U01DK103149 to B.L.S. & D.H.L.); (U01DK103135, U01DK062456-13, U01DK062456-15 to B.K.); (U01DK062456 to C.S. & J.C.M.); (U01DK062436 to L.M.B.); (U01DK062497 to K.D.S. & A.M.); (U01DK084536 to J.P.M.); (U01DK062466 to R.H.S.); (U01DK084575 to K.F.M.); (U01DK062481 to K.M.L.); (U01DK062500 to P.R.); (U01DK062470 to S.J.K.); (U01DK103140 to S.L.G.); (U01DK084538 to D.T.); (U01DK062453 to C.L.M. & R.J.S.); also supported (in part or in full) by the National Center for Advancing Translational Sciences of the NIH under the following Clinical and Translational Science Award grants: Cincinnati Children’s Hospital Medical Center (DK 62497, UL1TR0000777 to K.D.S. & A.M.), Children’s Healthcare of Atlanta (DK 62470, UL1TR002378 to S.J.K.), Children’s Hospital of Philadelphia (DK 62481, UL1TR001878 to K.M.L.), University of Michigan (DK 62456 to C.S. & J.C.M.), Riley Hospital for Children (DK 84536, UL1TR001108 to J.P.M.), Seattle Children’s Hospital (DK 84575, UL1TR000423 to K.F.M.), University of California San Francisco Children’s Hospital (DK 62500, UL1TR001872 to P.R.), Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center (DK 62503, UL1TR000005 to R.H.S.), Children’s Hospital Colorado (DK 62453, UL1TR001082 to C.L.M. & R.J.S.), Children’s Hospital Los Angeles (DK 62452, UL1TR000130 to D.T.), Ann and Robert H. Lurie Children’s Hospital of Chicago (DK 62436, UL1TR001422 to L.M.B.), Texas Children’s Hospital (DK103149 to B.L.S. & D.H.L.), Hospital for Sick Children (DK103135, DK062456-13, DK062456-15 to B.M.K.), and University of Utah (DK103140, UL1TR001067 to S.L.G.). See Supporting Table S3 for full listing of sites, principal investigators, and grant numbers. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Clinical trials registration number NCT02057692. Potential conflict of interest: Dr. Kamath consults for Retrophin. Dr. Murray received grants from Gilead and Shire and owns stock in Merck. Dr. Miethke consults and received grants from Shire. Dr. Molleston consults for Lilly and received grants from AbbVie, Gilead, and Shire. Dr. Spino consults for Albireo. Dr. Leung consults for Merck and received grants from Bristol-Myers Squibb, Gilead, AbbVie, and Roche. Dr. Rosenthal consults and is on the speakers’ bureau for Retrophin; he consults for Gilead, AbbVie, Intercept, Alexion, Albireo, and Audentes and received grants from Gilead, AbbVie, Bristol-Myers Squibb, and Roche. Dr. Karpen consults for Intercept, Albireo, and Retrophin. Dr. Setchell consults for Retrophin and received grants from Retrophin and Shire; he owns stock in Asklepion. Dr. Sokol consults for Shire, Retrophin, Albireo, and Alexion. The other authors have nothing to report. Heather Van Doren, M.F.A., senior medical editor with Arbor Research Collaborative for Health, provided editorial assistance on this manuscript. Peter F. Whitington, M.D., who retired prior to submission of this manuscript, contributed to the development, execution, and interpretation of this study.
ASJC Scopus subject areas
- Hepatology