Dose response study of GSK2330672 for the treatment of pruritus in patients with primary biliary cholangitis – The GLIMMER Study

Phase 1

Conditions: Primary biliary cholangitis (PBC)
MedDRA version: 20.0Level: PTClassification code 10008604Term: CholangitisSystem Organ Class: 10019805 - Hepatobiliary disorders
MedDRA version: 20.0Level: PTClassification code 10037087Term: PruritusSystem Organ Class: 10040785 - Skin and subcutaneous tissue disorders
Therapeutic area: Body processes [G] - Metabolic Phenomena [G03]

Registration Number: EUCTR2016-002416-41-GB

Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 150

Inclusion Criteria

Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Participants who have proven PBC, as demonstrated by having at least 2 of the following:
• History of sustained increased ALP levels >upper limit of normal (ULN) first recognized at least 6 months prior to the Screening Visit (Note: Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after institution of UDCA therapy as described in inclusion number 4).
• Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by ELISA) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive).
• Liver biopsy (at any time in the past) consistent with PBC.
3. Participants must rate their itch severity as being =4 on a 0 to 10 point scale for the majority of time (at least half the days, as recalled by the participant) during the 8 weeks prior to the Screening Visit. Periods of low itch or no itch are acceptable as long as the worst daily itch score is =4 on the majority of days.
4. Participants who are currently taking UDCA should be on stable doses of UDCA for >8 weeks at time of screening. Participants not taking UDCA due to intolerance may be enrolled 8 weeks after their last dose of UDCA.
Note: no changes or discontinuation is permitted until completion of the Main Study Period.
Sex
5. Male and/or female:
a. Female participants:
A female participant is eligible to participate if she is not pregnant (see Appendix 2 of study protocol), not breastfeeding, and at least one of the following conditions applies:
(i) Not a woman of childbearing potential (WOCBP) as defined in Appendix 2 of study protocol
OR
(ii) A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 of study protocol during the treatment period and until at least 4 weeks after the last dose of study treatment.
Informed Consent
6. Capable of giving signed informed consent as described in Appendix 3 of study protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 130
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 20

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Screening total bilirubin >2x ULN. Isolated bilirubin >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.
2. Screening ALT or aspartate aminotransferase (AST) >6x ULN.
3. Screening estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
4. History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites).
5. Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection and/or confirmed hepatocellular carcinoma or biliary cancer. Note: Other hepatic conditions (e.g., primary sclerosing cholangitis (PSC), alcoholic liver disease, autoimmune hepatitis, non-alcoholic steatohepatitis (NASH) are permitted if PBC is the dominant liver injury in the investigators opinion.
6. Current diarrhea.
7. Current symptomatic cholelithiasis or inflammatory gall bladder disease. Participants with history of cholecystectomy =3 months before screening may be eligible for enrollment.
8. Any current medical condition (e.g. psychiatric disorder, senility or dementia), which may affect the participant’s ability to comply with the protocol specified procedures.
Prior/Concomitant Therapy
9. Initiation or increase in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 2 months prior to screening. Note: If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded. [Rationale: Limited evidence indicates these drugs may alter disease progression in some PBC patients.
10. Initiation or increase in dose of bezafibrate or fenofibrate at any time during the 3 months prior to screening. Participants may join the study on stable doses of these medications, but no change or discontinuation is permitted until completion of the Main Study Period.
11. Initiation or increase in dose of any of the following in the 8 weeks prior to screening: rifampicin, naltrexone, naloxone, nalfurafine, or sertraline. Participants may join the study on stable or decreased doses of these medications, but no change in dose is permitted until completion of the Main Study Period.
12. Bile acid binding resin use: a participant must discontinue use of cholestyramine, colesevelam, colestipol or colestimide prior to the start of the Initial Study Period (no later than Day -2). Note: these drugs may be administered after completion of the Main Study Period, if clinically indicated.
13. Obeticholic acid use: a participant must discontinue use of obeticholic acid at least 8 weeks prior to the start of the Initial Study Period and may not restart until after the end of the study.
14. Administration of any other IBAT inhibitor in the 3 months prior to screening. [Rationale: Effects of another IBAT inhibitor may influence pruritus.]
Prior/Concurrent Clinical Study Experience
15. Current enrollment or participation within the 8 weeks before start of the Initial Study Period, in any other clinical study involving an investigational study treatment.
Diagnostic assessments
16. QTc >480 msec
NOTES:
- The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Fridericia’s formula (QTcF), and/or another method. It is either machine-read or manually over-read.
- The specific formula used to determine

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: ? To investigate the dose response of oral GSK2330672 on itch in PBC patients with moderate to severe pruritus at Baseline.;Secondary Objective: Key Secondary Objectives:<br>? To characterize the effects of GSK2330672 compared to placebo on impact of symptoms and quality of life in PBC patients with moderate to severe pruritus at Baseline.<br>?To evaluate the effects of GSK2330672 compared to placebo on markers of disease among participants at high risk of PBC progression (i.e., those with serum ALP concentrations <1.67xULN and/or total bilirubin concentrations >ULN at Day 1).<br>(Please refer to study protocol 201000 for other Secondary Objectives);Primary end point(s): Mean change from Baseline at Week 16 in the Mean Worst Daily Itch Score.;Timepoint(s) of evaluation of this end point: Week 16

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): ? Mean change from Baseline at Week 16 in PBC-40 Scale.<br>In participants meeting the criteria for high risk of PBC progression:<br>? Mean change from Baseline at Week 16 in serum ALP concentrations.<br>? Proportion of participants having serum ALP concentrations <1.67x ULN and total bilirubin concentrations =ULN at Week 16.<br>? Mean change from Baseline at Week 16 in serum ALT, AST, GGT, total bilirubin and albumin concentrations and PT/INR.;Timepoint(s) of evaluation of this end point: Week 16

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