title: BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial.
abstract: BACKGROUND
  Pruritus (itch) is a symptom commonly experienced by patients with cholestatic liver diseases such as primary biliary cholangitis (PBC, previously referred to as primary biliary cirrhosis). Bile acids (BAs) have been proposed as potential pruritogens in PBC. The ileal bile acid transporter (IBAT) protein expressed in the distal ileum plays a key role in the enterohepatic circulation of BAs. Pharmacological inhibition of IBAT with GSK2330672 may reduce BA levels in the systemic circulation and improve pruritus.
  
  
  METHODS
  This clinical study (BAT117213 study) is sponsored by GlaxoSmithKline (GSK) with associated exploratory studies supported by the National Institute for Health Research (NIHR). It is a phase 2a, multi-centre, randomised, double bind, placebo controlled, cross-over trial for PBC patients with pruritus. The primary objective is to investigate the safety and tolerability of repeat doses of GSK2330672, and explore whether GSK2330672 administration for 14 days improves pruritus compared with placebo. The key outcomes include improvement in pruritus scores evaluated on a numerical rating scale and other PBC symptoms in an electronic diary completed twice daily by the patients. The secondary outcomes include the evaluation of the effect of GSK2330672 on total serum bile acid (BA) concentrations, serum markers of BA synthesis and steady-state pharmacokinetics of ursodeoxycholic acid (UDCA).
  
  
  CONCLUSIONS
  BAT117213 study is the first randomised controlled crossover trial of ileal bile acid transporter inhibitor, a novel class of drug to treat pruritus in PBC. The main strengths of the trial are utility of a novel, study specific, electronic symptom diary as patient reported outcome to measure the treatment response objectively and the crossover design that allows estimating the treatment effect in a smaller number of patients. The outcome of this trial will inform the trial design of future development phase of the IBAT inhibitor drug. The trial will also provide opportunity to conduct metabonomic and gut microbiome studies as explorative and mechanistic research in patients with cholestatic pruritus.
  
  
  BACKGROUND
  EudraCT number: 2012-005531-84, ClinicalTrials.gov Identifier: NCT01899703 , registered on 3(rd) July 2013.
authors.affiliation: NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. Vinod.Hegade@ncl.ac.uk.|Institute of Cellular Medicine, William Leech Building, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Vinod.Hegade@ncl.ac.uk.
authors.forename: Vinod S
authors.initials: VS
authors.lastname: Hegade
authors.affiliation: NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.|GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, UK.
authors.forename: Stuart F W
authors.initials: SF
authors.lastname: Kendrick
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dobbins
authors.affiliation: GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, UK.
authors.forename: Sam R
authors.initials: SR
authors.lastname: Miller
authors.affiliation: GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, UK.
authors.forename: Duncan
authors.initials: D
authors.lastname: Richards
authors.affiliation: GlaxoSmithKline Research and Development, Medicines Research Centre, Stevenage, UK.
authors.forename: James
authors.initials: J
authors.lastname: Storey
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: George
authors.initials: G
authors.lastname: Dukes
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Gilchrist
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Vallow
authors.affiliation: Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust Cambridge, Cambridge, UK.
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Alexander
authors.affiliation: Centre for Liver Research, University of Birmingham and NIHR Birmingham Liver Biomedical Research Unit, Birmingham, UK.
authors.forename: Margaret
authors.initials: M
authors.lastname: Corrigan
authors.affiliation: Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust Cambridge, Cambridge, UK.
authors.forename: Gideon M
authors.initials: GM
authors.lastname: Hirschfield
authors.affiliation: NIHR Newcastle Biomedical Research Centre and Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: David E J
authors.initials: DE
authors.lastname: Jones
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002756:Cholagogues and Choleretics / Q000493:pharmacokinetics / Q000627:therapeutic use; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000150:complications*; D008297:Male; D008744:Methylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D011537:Pruritus / Q000188:drug therapy* / Q000209:etiology; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D013841:Thiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014580:Ursodeoxycholic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
chemical_list: C583160:3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid; D001647:Bile Acids and Salts; D015415:Biomarkers; D002756:Cholagogues and Choleretics; D008744:Methylamines; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D013841:Thiazepines; C071908:sodium-bile acid cotransporter; D014580:Ursodeoxycholic Acid
keywords: IBAT; Ileal bile acid transporter; PBC; Primary biliary cholangitis; Pruritus