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A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Repeat Doses of GSK2330672 Administration in Subjects With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01899703
First received: July 3, 2013
Last updated: July 14, 2017
Last verified: July 2017
  Purpose
This will be a randomized, double-blind, placebo-controlled study to assess safety and tolerability of GSK2330672 administration in subjects with primary biliary cirrhosis (PBC) and symptoms of pruritus. It is a double-blind, crossover study with subjects receiving placebo or GSK23306772 in random order during two 14-day treatment periods. Additionally, the study will determine GSK2330672 exposure and interactions with ursodeoxycholic acid (UDCA). The total duration of subject participation will be 14 weeks for screening (45 days) and the treatment period. Subjects who are eligible for enrolment will participate in a 2-week placebo run-in period. Subjects will be randomized in a crossover fashion (Sequence 1 / Sequence 2) to receive placebo or GSK2330672 treatment during two consecutive 2-week study periods. Subjects will then participate in a 2-week placebo dosing period ending in follow-up assessments. Study results will be utilized to form a benefit: risk profile for GSK2330672 in PBC that will determine plans for progression to exploratory efficacy trials

Condition Intervention Phase
Cholestasis, Intrahepatic Drug: GSK2330672 Drug: Placebo Drug: Ursodeoxycholic acid Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Participant, Investigator
Primary Purpose: Treatment
Official Title: A Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Repeat Doses of GSK2330672 Administration in Patients With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline to Day 56 [ Time Frame: Up to Day 56 ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect, important medical events which may require medical or surgical interventions.

  • Change from Baseline in white blood cell count (WBC), total neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet counts at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    White blood cell, total neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet counts were measured at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). Change from baseline is summarized for these parameters. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the baseline visit, the last pre-dose value at the baseline visit was considered as baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Hemoglobin and MCHC were measured at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). Change from baseline is summarized for these parameters. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the baseline visit, the last pre-dose value at the baseline visit was considered as baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in mean corpuscle volume (MCV) at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Hematology parameters were measured at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). Change from baseline in MCV is summarized. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the baseline visit, the last pre-dose value at the baseline visit was considered as baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in hematocrit at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Hematology parameters were measured at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). Change from baseline in hematocrit is summarized. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the baseline visit, the last pre-dose value at the baseline visit was considered as baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in red blood cells (RBC) and reticulocytes at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    White and red blood cell, reticulocytes, total neutrophil, lymphocyte, monocyte, eosinophil, basophil, and platelet counts, hematocrit, hemoglobin, mean corpuscle hemoglobin concentration, mean corpuscle volume were measured at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). Change from baseline for these parameters is summarized. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the baseline visit, the last pre-dose value at the baseline visit was considered as baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in alkaline phopshatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) at Day 28, Day 42 and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Blood samples were collected for the measurement of ALP, ALT, AST, and GGT at Baseline, Day 28 (D28), Day 42 (D42) and Follow-up (Day 56). The Baseline value was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in direct and total bilirubin, creatinine, and uric acid at Day 28, Day 42 and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Blood samples were collected for the measurement of direct and total bilirubin, creatinine, and uric acid at Baseline, Day 28 (D28), Day 42 (D42), and Follow-up (F/U) (Day 56). The Baseline value was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in calcium, chloride, carbon dioxide (CO2) content/bicarbonate, glucose, potassium, sodium, and urea/blood urea nitrogen (BUN) at Day 28, Day 42 and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42 and Follow-up (Day 56) ]
    Blood samples were collected for the measurement of calcium, chloride, carbon dioxide content/bicarbonate, glucose, potassium, sodium, and urea/BUN at Baseline, Day 28 (D28), Day 42 (D42), and Follow-up (D56). The Baseline value was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in albumin and total protein at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42, and Follow-up (Day 56) ]
    Blood samples were collected for the measurement of albumin and total protein at Baseline, Day 28 (D28), Day 42 (D42), and Follow-up (Day 56). The Baseline value was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in urine pH at Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 28, Day 42, and Follow-up (Day 56) ]
    Urine samples were collected at Baseline, Day 28 (D28), Day 42 (D42), and Follow-up (Day 56). The Baseline value was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from baseline was calculated as Post-Baseline Visit value minus Baseline values.

  • Change from Baseline in electrocardiogram (ECG) parameters at Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56) ]
    A 12-lead ECG measurement was obtained following 10 minutes rest in semi-supine position at Baseline, Day 1 and Day 14 (Run-in period), Day 28, Day 42, and Follow-up (Day 56). Parameters included: PR interval, QRS interval, Corrected QT (QTc) and uncorrected QT intervals were analyzed. Baseline is the average of the triplicate readings taken pre-dose for the first dose. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in heart rate (HR) at Day 14, Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56) ]
    HR was measured at the following time points: Baseline, Day 14 (D14, Run-in Period), Day 28 (D28, Period 1), Day 42 (D42, Period 2) and Follow-up (Day 56). Heart rate was obtained in a semi-supine position, after 10 minutes of rest. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Change from Baseline in diastolic blood pressure (DBP) and systolic blood pressure (SBP) at Day 14, Day 28, Day 42, and Follow-up (Day 56) [ Time Frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56) ]
    Diastolic blood pressure and systolic blood pressure were measured at Baseline, Day 14 (D14; Run-in Period), Day 28 (D28; Period 1), Day 42 (D42; Period 2) and Follow-up (Day 56). All measurements were made in semi-supine position, after a 10-minute rest. Baseline was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit were considered as Baseline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

  • Summary of responses to gastrointestinal symptom response system (GSRS) by dimension at Day 1, Day 13, Day 27, Day 41, and Follow-up (Day 56) [ Time Frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2), and Follow-up (Day 56) ]
    Gastrointestinal symptom response system is a rating scale was used to assess participant-reported symptoms over the preceding 5 to 7 days. Baseline was considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit were considered as Baseline.

  • Fecal Occult blood testing on Day 14, Day 28, Day 42 and Follow-up (Day 56) [ Time Frame: Day 14, Day 28, Day 42 and Follow-up (Day 56) ]
    Fecal occult blood monitoring was done on Day 14, Day 28, Day 42 and Follow-up (Day 56). It was a monitoring system (in form of a card) to detect symptomatic or visible gastrotintestinal bleeding or asymptomatic occult bleeding in participants. Baseline is considered to be the participant's last non-missing assessment prior to dosing. If assessments were performed more than once at the Baseline visit, the last pre-dose value at the Baseline visit was considered as Baseline.


Secondary Outcome Measures:
  • Area under curve (AUC) of serum profiles of total bile acid concentrations (T-bile acid) at Day 14, Day 28, and Day 42 [ Time Frame: Pre-dose, and at 2 and 5 hour (h) post-dose on Days 14, 28 and 42 ]
    Serum samples were collected on Days 14, 28 and 42 for T bile acid. Area under the curve (AUC) over the given time interval was obtained using the repeated measures Analysis of covariance (ANCOVA) analysis.

  • AUC of serum profiles of 7-alpha hydroxy 4-cholesten-3-one (C4) at Day 14, Day 28, and Day 42 [ Time Frame: Pre-dose, and at 2 and 5 hr post-dose on Days 14, 28 and 42 ]
    Serum samples were collected on Days 14, 28 and 42 for C4. AUC over the given time interval was obtained using the repeated measures ANCOVA analysis.

  • Summary of derived trimmed mean participant-reported itch Scores on the Pruritus 0-10 point scale (Itch type: Worst, Intensity, Bothersome and Interference) [ Time Frame: From Day 1 to Day 56 ]
    A 0 to 10 point scale was implemented to measure symptoms of itching as well as other associated symptoms twice daily in the morning and evening (approximately the time of drug dosing). Participants were provided with a paper or electronic diary and were asked to score the severity of their itching symptoms from "0" for no itching to "10" for the worst possible itching. Itch type Worst, Intensity, Bothersome and Interference are reported.

  • Summary of Participant-reported Itch scores on the 5-D Itch scale (Domain=Degree, Direction, Disability, Distribution, Duration and Overall) on Day 1, Day 13, Day 27, Day 41 and Follow-up (Day 56) [ Time Frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56) ]
    The 5-D itch scale covers five dimensions of itching experienced by participants including duration, degree, direction, disability and distribution. It was reported on Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56). The scores of each of the five domains were achieved separately and then summed together to obtain a total 5-D score. 5-D scores potentially ranged between 5 (no pruritus) and 25 (most severe pruritus).

  • Participant reported outcome for primary biliary cirrhosis (PBC)-40 Quality of life (QOL) scale (Domain=Symptoms) on Day 1, Day 13, Day 27, Day 41 and Follow-up (Day 56) [ Time Frame: Day 1 and Day 13 (Run-in period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56) ]
    PBC-40 scale includes 6 domains (cognitive, itch, fatigue, social, emotional, and other). Symptoms with individual questions were scored between 1 to 5, a higher score indicating greater symptom and worse quality of life. The PBC-40 scale was validated for use with a 4 week recall, however, for the purposes of this study it was administered every 2 weeks on Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56).

  • Dose-normalized area under the concentration-time curve (DNAUC[0-24hr]) for UDCA and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) on Day 14, Day 28, and Day 42 [ Time Frame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 h on Days 14, 28 and 42 ]
    DNAUC(0-24hr) was estimated for assessment of UDCA and its metabolites TUDCA and GUDCA. ANCOVA was used and data presented were log transformed. Blood samples were collected at following time points: pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 h on Days 14, 28 and 42.

  • Dose-normalized maximum plasma concentration (DNCmax) for UDCA and its metabolites TUDCA and GUDCA on Day 14, Day 28, and Day 42 [ Time Frame: Pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours on Days 14, 28 and 42 ]
    DNCmax was estimated for assessment of UDCA and its metabolites TUDCA and GUDCA. An analysis of variance (ANCOVA) was used and data presented were log transformed. Blood samples were collected at following time points: pre-dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours on Days 14, 28 and 42.

  • Plasma pharmacokinetics for GSK2330672 on Day 14, Day 28, and Day 42 [ Time Frame: Pre-dose and post-dose 2, 10, 12 hours on Days 14, 28 and 42 ]
    Plasma samples were collected at following time points: pre-dose and post-dose 2, 10, 12 hr on Days 14, 28 and 42. Pharmacokinetic analysis of plasma concentration-time data for these analytes were conducted using non-compartmental Model 200.

  • Steady state maximum plasma concentration (Cmax) for ursodeoxycholic acid (UDCA) and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) [ Time Frame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). ]
    Approximately 2 mL of whole blood was collected for UDCA and it's metabolites PK analysis at Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). Blood sampling for UDCA and it's metabolites PK analysis was only performed in participants who were administering UDCA.

  • Steady state time to Cmax (Tmax) for UDCA, TUDCA, and GUDCA [ Time Frame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). ]
    Approximately 2 mL of whole blood was collected for UDCA and it's metabolites PK analysis at Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). Blood sampling for UDCA and it's metabolites PK analysis was only performed in participants who were administering UDCA.

  • Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and GUDCA. [ Time Frame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2) ]
    Approximately 2 mL of whole blood was collected for UDCA and it's metabolites PK analysis at Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). Blood sampling for UDCA and it's metabolites PK analysis was only performed in participants who were administering UDCA.

  • Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA) [ Time Frame: Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). ]
    Approximately 2 mL of whole blood was collected for UDCA and it's metabolites PK analysis at Pre-dose (0.0, of first dose of the day), 6.0, 12.0 (Pre-dose of second dose of the day), 12.5, 13.0, 14.0, 15.0, 17.0, 19.0, 21.0 and 24.0 hr on Day 14 (end of Run-in period), 28 (end of Period 1), and 42 (end of Period 2). Blood sampling for UDCA and it's metabolites PK analysis was only performed in participants who were administering UDCA.


Enrollment: 22
Actual Study Start Date: March 10, 2014
Study Completion Date: October 7, 2015
Primary Completion Date: October 7, 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2330672
Subject will receive GSK2330672 45 mg BID from Day 1 to 3 and 90 mg BID from Day 4 to 14 of one of the two treatment periods.
Drug: GSK2330672
GSK2330672 oral preserved solution 1.5mg/g will be supplied in amber glass bottles and as per randomization schedule subject will receive 45 mg BID from Day 1 to 3 and 90 mg BID from Day 4 to 14 of one of the two treatment periods.
Drug: Ursodeoxycholic acid
UDCA 250 mg will be supplied in capsule form. The subjects, who are taking UDCA at the time of Run-in-period, will be continued on the same total daily dose of drug but converted to a standardized formulation and a standardized dosing regimen administering the entire daily dose once daily in the evening before bedtime. Once daily dosing of UDCA will continue for the duration of the study.
Experimental: Placebo
Subject will receive placebo BID from Day 1 to 14 of one of the two treatment periods.
Drug: Placebo
Placebo oral preserved solution will be supplied in amber glass bottles and as per randomization schedule subject will receive placebo BID from Day 1 to 14 of one of the two treatment periods. .
Drug: Ursodeoxycholic acid
UDCA 250 mg will be supplied in capsule form. The subjects, who are taking UDCA at the time of Run-in-period, will be continued on the same total daily dose of drug but converted to a standardized formulation and a standardized dosing regimen administering the entire daily dose once daily in the evening before bedtime. Once daily dosing of UDCA will continue for the duration of the study.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female aged between 18 and 75 years of age inclusive, at the time of signing the informed consent.
  • Proven or likely PBC, as demonstrated by the subject presenting with at least 2 of the following: history of sustained increased alkaline phosphatise (AP) levels first recognized at least 6 months prior to Day 1; positive antimitochondrial antibodies (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay [ELISA]) or PBC-specific antinuclear antibodies (antinuclear dot and nuclear rim positive); liver biopsy consistent with PBC.
  • Screening AP value between <=10 × upper limit of normal (ULN).
  • Subjects should be on stable doses of UDCA for >8 weeks at time of screening. Subjects not taking UDCA due to intolerance may be enrolled into this study following agreement by the GSK medical monitor.
  • Symptoms of pruritus as follows (one of the following): PBC subjects with severe symptoms of pruritus that significantly impact daily life and have proven refractory after at least one previous therapy has been discontinued due to inadequate clinical response, poor tolerability or adverse events. Temporary response to cooling, 1% menthol in aqueous cream, nasobiliary drainage or molecular adsorbent recirculating system (MARS) therapy is still compatible with refractory itch; PBC subjects with unresolved symptoms with use of a single antipruritic agent who can tolerate washout of current therapy for the duration of the trial; PBC subjects seeking treatment for pruritus that is newly diagnosed or previously untreated.
  • A female subject is eligible to participate if she is not pregnant, as confirmed by a negative serum human chorionic gonadotrophin (hCG) test or at least one of the following conditions applies: Non-reproductive potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli-international units per milliliter and estradiol <40 picograms per milliliter (<147 picomole per liter) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods along with either a second form of highly effective contraception or barrier protection (condoms with spermicide) if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment; Reproductive potential and agrees to follow one of the contraception options methods for the specified duration of time.
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

  • Screening total bilirubin >1.5x ULN. Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%.
  • Screening alanine aminotransferase or aspartate aminotransferase >4x ULN.
  • Screening serum creatinine >2.5 milligrams per decilitre (221 micromole/liter).
  • History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy, or poorly controlled ascites).
  • History or presence of other concomitant liver diseases including hepatitis due to hepatitis B or C virus (HCV, HBV) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease, definite autoimmune hepatitis or biopsy proven nonalcoholic steatohepatitis (NASH).
  • Administration of the following drugs at any time during the 3 months prior to screening for the study: colchicine, methotrexate, azathioprine, or systemic corticosteroids.
  • Current or chronic history of inflammatory bowel disease, chronic diarrhea, Crohn's disease or diarrhea related to malabsorption syndromes.
  • Fecal occult blood positive test at screening.
  • Based on averaged corrected QT interval (QTc) values of triplicate ECGs obtained at least 5 minutes apart: QTc >=450 milliseconds (msec); or QTc >=480 msec in subjects with Bundle Branch Block.
  • History of sensitivity to heparin or heparin-induced thrombocytopenia.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.
  • 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 g of alcohol: a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
  • A positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and benzodiazepines
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
  • The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01899703

Locations
United Kingdom
GSK Investigational Site
Birmingham, West Midlands, United Kingdom, B15 2WB
GSK Investigational Site
Cambridge, United Kingdom
GSK Investigational Site
Newcastle upon Tyne, United Kingdom, NE1 4LP
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 117213
For additional information about this study please refer to the GSK Clinical Study Register

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01899703     History of Changes
Other Study ID Numbers: 117213
Study First Received: July 3, 2013
Last Updated: July 14, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
Intestinal bile acid transport inhibitor
Pruritus
Primary biliary cirrhosis
Ursodeoxycholic acid
GSK2330672
Pharmacokinetics

Additional relevant MeSH terms:
Fibrosis
Liver Cirrhosis
Pruritus
Cholestasis
Liver Cirrhosis, Biliary
Cholestasis, Intrahepatic
Pathologic Processes
Liver Diseases
Digestive System Diseases
Skin Diseases
Skin Manifestations
Signs and Symptoms
Bile Duct Diseases
Biliary Tract Diseases
Ursodeoxycholic Acid
Cholagogues and Choleretics
Gastrointestinal Agents

ClinicalTrials.gov processed this record on July 25, 2017