Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study

Summary Background Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primar...

Full description

Saved in:
Bibliographic Details
Published in:The Lancet (British edition) 2017-03, Vol.389 (10074), p.1114-1123
Main Authors: Hegade, Vinod S, Dr, Kendrick, Stuart F W, PhD, Dobbins, Robert L, MD, Miller, Sam R, MSc, Thompson, Douglas, PhD, Richards, Duncan, FRCP, Storey, James, PhD, Dukes, George E, PharmD, Corrigan, Margaret, MRCP, Oude Elferink, Ronald P J, PhD, Beuers, Ulrich, Prof, Hirschfield, Gideon M, Prof, Jones, David E, Prof
Format: Article
Language:English
Subjects:
Abdomen
Acids
Adult
Bile
Biomedical research
Carrier Proteins - antagonists & inhibitors
Cholangitis - complications
Clinical trials
Cross-Over Studies
Double-Blind Method
Drug dosages
Drug therapy
Fatigue
Female
Gallbladder diseases
Humans
Ileum
Internal Medicine
Licenses
Liver Cirrhosis, Biliary - complications
Liver diseases
Male
Membrane Glycoproteins - antagonists & inhibitors
Methylamines - therapeutic use
Middle Aged
Narcotics
Patients
Pharmacokinetics
Pruritus
Pruritus - drug therapy
Pruritus - etiology
Rodents
Studies
Thiazepines - therapeutic use
Treatment Outcome
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Summary Background Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. Methods We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov , number NCT01899703. Findings Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were −57% (95% CI −73 to −42, p
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(17)30319-7