Dose Response Study of GSK2330672 for the Treatment of Pruritus in Participants With Primary Biliary Cholangitis
Condition: Cholestasis
MeSH terms: Cholangitis; Cholestasis; Liver Cirrhosis, Biliary; Pruritus
Intervention: Placebo; GSK2330672
Intervention description: GSK2330672 matching placebo will be supplied as white film-coated tablets.; GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 147.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: linerixibat; PBC; itch; GSK2330672; GLIMMER; primary biliary cholangitis; pruritus

Summary:

      This study is being conducted to evaluate the efficacy, safety and tolerability of GSK2330672
      administration for the treatment of pruritus (itch) in participants with primary biliary
      cholangitis (PBC). Participants will receive either placebo or one of the 4 dose regimens of
      GSK2330672 (20 milligram [mg], 90 mg or 180 mg taken once daily or 90 mg twice daily).
      Participants on GSK2330672 will also receive placebo tablets to maintain blinding. The study
      has a prospectively defined adaptive design that will utilize interim data to further inform
      and potentially optimize the doses under investigation. Hence, additional dose regimen may be
      added during study. The total duration of a participant in the study will be up to 45 days of
      screening and 24 weeks of study including follow-up.
    

Eligibility criteria:

        Inclusion Criteria

          -  Participant must be 18 to 80 years of age inclusive, at the time of signing the
             informed consent.

          -  Participants who have proven PBC, as demonstrated by having at least 2 of the
             following: History of sustained increased ALP levels >ULN first recognized at least 6
             months prior to the Screening Visit (Sustained ALP elevations at the time of Screening
             is not required, recognizing that the ALP may have decreased after institution of
             ursodeoxycholic acid (UDCA) therapy as described in inclusion number 4). Documented
             positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or
             M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear
             antibodies (antinuclear dot and/or nuclear rim positive). Liver biopsy (at any time in
             the past) consistent with PBC.

          -  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.

          -  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. No changes or discontinuation is
             permitted until completion of the Main Study Period.

          -  Male and/or female: Female participants- A female participant is eligible to
             participate if she is not pregnant, not breastfeeding, and at least one of the
             following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP
             who agrees to follow the contraceptive guidance during the treatment period and until
             at least 4 weeks after the last dose of study treatment.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in this
             protocol.

        Exclusion Criteria

          -  Screening total bilirubin >2x ULN. Total bilirubin >2x ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35 percent (%).

          -  Screening ALT or AST >6x ULN.

          -  Screening eGFR <45 milliliter (mL)/minute/1.73 square meter (m^2) based on the
             CKD-EPI.

          -  History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy
             or ascites).

          -  Presence of actively replicating viral hepatitis due to hepatitis B or C virus (HBV,
             HCV) infection, and/or confirmed hepatocellular carcinoma or biliary cancer. 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 investigator's opinion.

          -  Current diarrhea.

          -  Current symptomatic cholelithiasis or inflammatory gall bladder disease. Participants
             with history of cholecystectomy >=3 months before screening may be eligible for
             enrolment.

          -  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.

          -  Initiation or increase in dose of colchicine, methotrexate, azathioprine, or systemic
             corticosteroids in the 2 months prior to screening. If a change in dose in any of
             these medications is anticipated during the course of the study, the participant
             should be excluded.

          -  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.

          -  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.

          -  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.

          -  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.

          -  Administration of any other Inhibitor of the Human Ileal Bile Acid Transporter (IBAT)
             in the 3 months prior to screening.

          -  Current enrolment or participation within the 8 weeks before start of the Initial
             Study Period, in any other clinical study involving an investigational study
             treatment.

          -  QT interval corrected for heart rate QTc >480 millisecond (msec).

          -  History of sensitivity to the study treatment or components thereof or a history of
             drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline
             (GSK) Medical Monitor, contraindicates their participation in the study.

          -  History of regular alcohol consumption within 6 months of the study defined as an
             average weekly intake of >21 units for males or >14 units for females. One unit is
             equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass
             (125 mL) of wine or 1 measure (25 mL) of spirits.