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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

Primary Purpose

Cholestasis, Intrahepatic

Status

Completed

Phase

Phase 2

Locations

United Kingdom

Study Type

Interventional

Intervention

GSK2330672

Placebo

Ursodeoxycholic acid

About this trial

This is an interventional treatment trial for Cholestasis, Intrahepatic focused on measuring Intestinal bile acid transport inhibitor, Pruritus, Primary biliary cirrhosis, Ursodeoxycholic acid, GSK2330672, Pharmacokinetics

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

GSK Investigational Site
GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

GSK2330672

Placebo

Arm Description

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. Patients were randomized to one of two sequences receiving either (i) GSK2330672 followed by placebo; OR (ii) placebo followed by GSK2330672.

Subject will receive placebo BID from Day 1 to 14 of one of the two treatment periods. Patients were randomized to one of two sequences receiving either GSK2330672 followed by placebo; OR placebo followed by GSK2330672.

Outcomes

Primary Outcome Measures

Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline 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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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

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

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)

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)

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)

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

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

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

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)

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

Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and GUDCA.

Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA)

Full Information

NCT ID

NCT01899703

First Posted

July 3, 2013

Last Updated

July 31, 2017

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT01899703

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2017

Overall Recruitment Status

Completed

Study Start Date

March 10, 2014 (Actual)

Primary Completion Date

October 7, 2015 (Actual)

Study Completion Date

October 7, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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 follow-up period ending in final 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cholestasis, Intrahepatic

Keywords

Intestinal bile acid transport inhibitor, Pruritus, Primary biliary cirrhosis, Ursodeoxycholic acid, GSK2330672, Pharmacokinetics

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Crossover Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

22 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GSK2330672

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

GSK2330672

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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. .

Intervention Type

Drug

Intervention Name(s)

Ursodeoxycholic acid

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of participants with any on-treatment adverse event (AE) or serious adverse event (SAE) from Baseline to Day 56

Description

Time Frame

Up to Day 56

Title

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)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in hemoglobin and mean corpuscle hemoglobin concentration (MCHC) at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in mean corpuscle volume (MCV) at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in hematocrit at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in red blood cells (RBC) and reticulocytes at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

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)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in direct and total bilirubin, creatinine, and uric acid at Day 28, Day 42 and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

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)

Description

Time Frame

Baseline, Day 28, Day 42 and Follow-up (Day 56)

Title

Change from Baseline in albumin and total protein at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42, and Follow-up (Day 56)

Title

Change from Baseline in urine pH at Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 28, Day 42, and Follow-up (Day 56)

Title

Change from Baseline in electrocardiogram (ECG) parameters at Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)

Title

Change from Baseline in heart rate (HR) at Day 14, Day 28, Day 42, and Follow-up (Day 56)

Description

Time Frame

Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)

Title

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)

Description

Time Frame

Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)

Title

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)

Description

Time Frame

Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2), and Follow-up (Day 56)

Title

Fecal Occult blood testing on Day 14, Day 28, Day 42 and Follow-up (Day 56)

Description

Time Frame

Day 14, Day 28, Day 42 and Follow-up (Day 56)

Secondary Outcome Measure Information:

Title

Area under curve (AUC) of serum profiles of total bile acid concentrations (T-bile acid) at Day 14, Day 28, and Day 42

Description

Time Frame

Pre-dose, and at 2 and 5 hour (h) post-dose on Days 14, 28 and 42

Title

AUC of serum profiles of 7-alpha hydroxy 4-cholesten-3-one (C4) at Day 14, Day 28, and Day 42

Description

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.

Time Frame

Pre-dose, and at 2 and 5 hr post-dose on Days 14, 28 and 42

Title

Summary of derived trimmed mean participant-reported itch Scores on the Pruritus 0-10 point scale (Itch type: Worst, Intensity, Bothersome and Interference)

Description

Time Frame

From Day 1 to Day 56

Title

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)

Description

Time Frame

Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)

Title

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)

Description

Time Frame

Day 1 and Day 13 (Run-in period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)

Title

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

Description

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

Title

Dose-normalized maximum plasma concentration (DNCmax) for UDCA and its metabolites TUDCA and GUDCA on Day 14, Day 28, and Day 42

Description

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

Title

Plasma pharmacokinetics for GSK2330672 on Day 14, Day 28, and Day 42

Description

Time Frame

Pre-dose and post-dose 2, 10, 12 hours on Days 14, 28 and 42

Title

Steady state maximum plasma concentration (Cmax) for ursodeoxycholic acid (UDCA) and its metabolites taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA)

Description

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).

Title

Steady state time to Cmax (Tmax) for UDCA, TUDCA, and GUDCA

Description

Time Frame

Title

Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and GUDCA.

Description

Time Frame

Title

Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA)

Description

Time Frame

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Birmingham

State/Province

West Midlands

ZIP/Postal Code

B15 2WB

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Cambridge

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Newcastle upon Tyne

ZIP/Postal Code

NE1 4LP

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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.

Citations:

PubMed Identifier

28187915

Citation

Hegade VS, Kendrick SF, Dobbins RL, Miller SR, Thompson D, Richards D, Storey J, Dukes GE, Corrigan M, Oude Elferink RP, Beuers U, Hirschfield GM, Jones DE. Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study. Lancet. 2017 Mar 18;389(10074):1114-1123. doi: 10.1016/S0140-6736(17)30319-7. Epub 2017 Feb 8.

Results Reference

derived

PubMed Identifier

27431238

Citation

Hegade VS, Kendrick SF, Dobbins RL, Miller SR, Richards D, Storey J, Dukes G, Gilchrist K, Vallow S, Alexander GJ, Corrigan M, Hirschfield GM, Jones DE. BAT117213: Ileal bile acid transporter (IBAT) inhibition as a treatment for pruritus in primary biliary cirrhosis: study protocol for a randomised controlled trial. BMC Gastroenterol. 2016 Jul 19;16(1):71. doi: 10.1186/s12876-016-0481-9.

Results Reference

derived

Links:

URL

https://www.clinicalstudydatarequest.com

Description

Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Available IPD and Supporting Information:

Available IPD/Information Type

Dataset Specification

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Study Protocol

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Annotated Case Report Form

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Statistical Analysis Plan

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Clinical Study Report

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Individual Participant Data Set

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

Available IPD/Information Type

Informed Consent Form

Available IPD/Information URL

https://www.clinicalstudydatarequest.com

Available IPD/Information Identifier

117213

Available IPD/Information Comments

For additional information about this study please refer to the GSK Clinical Study Register

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