Show simple item record

dc.contributor.authorJones, D
dc.contributor.authorBoudes, PF
dc.contributor.authorSwain, MG
dc.contributor.authorBowlus, CL
dc.contributor.authorGalambos, MR
dc.contributor.authorBacon, BR
dc.contributor.authorDoerffel, Y
dc.contributor.authorGitlin, N
dc.contributor.authorGordon, SC
dc.contributor.authorOdin, JA
dc.contributor.authorSheridan, David
dc.contributor.authorWörns, M-A
dc.contributor.authorClark, V
dc.contributor.authorCorless, L
dc.contributor.authorHartmann, H
dc.contributor.authorJonas, ME
dc.contributor.authorKremer, AE
dc.contributor.authorMells, GF
dc.contributor.authorBuggisch, P
dc.contributor.authorFreilich, BL
dc.contributor.authorLevy, C
dc.contributor.authorVierling, JM
dc.contributor.authorBernstein, DE
dc.contributor.authorHartleb, M
dc.contributor.authorJanczewska, E
dc.contributor.authorRochling, F
dc.contributor.authorShah, H
dc.contributor.authorShiffman, ML
dc.contributor.authorSmith, JH
dc.contributor.authorChoi, Y-J
dc.contributor.authorSteinberg, A
dc.contributor.authorVarga, M
dc.contributor.authorChera, H
dc.contributor.authorMartin, R
dc.contributor.authorMcWherter, CA
dc.contributor.authorHirschfield, GM
dc.date.accessioned2017-08-25T11:17:03Z
dc.date.available2017-08-25T11:17:03Z
dc.date.issued2017-08-14
dc.identifier.issn2468-1253
dc.identifier.issn2468-1253
dc.identifier.urihttp://hdl.handle.net/10026.1/9859
dc.description.abstract

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0·0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.

dc.format.extent716-726
dc.format.mediumPrint-Electronic
dc.languageen
dc.language.isoen
dc.publisherElsevier BV
dc.subjectAcetates
dc.subjectAdult
dc.subjectAged
dc.subjectAlanine Transaminase
dc.subjectCholangitis
dc.subjectDiarrhea
dc.subjectDouble-Blind Method
dc.subjectDrug Administration Schedule
dc.subjectFemale
dc.subjectHumans
dc.subjectLiver
dc.subjectMale
dc.subjectMiddle Aged
dc.subjectNausea
dc.subjectPPAR delta
dc.subjectPruritus
dc.subjectTreatment Outcome
dc.subjectTriazoles
dc.subjectUrsodeoxycholic Acid
dc.titleSeladelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study.
dc.typejournal-article
dc.typeClinical Trial, Phase II
dc.typeJournal Article
dc.typeMulticenter Study
dc.typeRandomized Controlled Trial
dc.typeResearch Support, Non-U.S. Gov't
plymouth.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/28818518
plymouth.issue10
plymouth.volume2
plymouth.publication-statusPublished online
plymouth.journalLancet Gastroenterology & Hepatology
dc.identifier.doi10.1016/S2468-1253(17)30246-7
plymouth.organisational-group/Plymouth
plymouth.organisational-group/Plymouth/Faculty of Health
plymouth.organisational-group/Plymouth/Faculty of Health/Peninsula Medical School
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA
plymouth.organisational-group/Plymouth/REF 2021 Researchers by UoA/UoA01 Clinical Medicine
plymouth.organisational-group/Plymouth/Users by role
plymouth.organisational-group/Plymouth/Users by role/Academics
dc.publisher.placeNetherlands
dcterms.dateAccepted2017-07-10
dc.rights.embargodate2018-2-14
dc.identifier.eissn2468-1253
dc.rights.embargoperiodNot known
rioxxterms.versionofrecord10.1016/S2468-1253(17)30246-7
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-08-14
rioxxterms.typeJournal Article/Review


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record


All items in PEARL are protected by copyright law.
Author manuscripts deposited to comply with open access mandates are made available in accordance with publisher policies. Please cite only the published version using the details provided on the item record or document. In the absence of an open licence (e.g. Creative Commons), permissions for further reuse of content should be sought from the publisher or author.
Theme by 
Atmire NV