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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
22
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.
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. .
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.
GSK Investigational Site
Birmingham, West Midlands, United Kingdom
GSK Investigational Site
Cambridge, United Kingdom
GSK Investigational Site
Newcastle upon Tyne, United Kingdom
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.
Time frame: Up to Day 56
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42, and Follow-up (Day 56)
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.
Time frame: Baseline, Day 28, Day 42, and Follow-up (Day 56)
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.
Time frame: Baseline, Day 1, Day 14, Day 28, Day 42, and Follow-up (Day 56)
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.
Time frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)
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.
Time frame: Baseline, Day 14 (Run-in Period), Day 28 (Period 1), Day 42 (Period 2), and Follow-up (Day 56)
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.
Time frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2), and Follow-up (Day 56)
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.
Time frame: Day 14, Day 28, Day 42 and Follow-up (Day 56)
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.
Time frame: Pre-dose, and at 2 and 5 hour (h) post-dose on Days 14, 28 and 42
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.
Time frame: Pre-dose, and at 2 and 5 hr post-dose on Days 14, 28 and 42
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.
Time frame: From Day 1 to Day 56
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).
Time frame: Day 1 and Day 13 (Run-in Period), Day 27 (Period 1), Day 41 (Period 2) and Follow-up (Day 56)
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)
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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).
Time frame: 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.
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
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.
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
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.
Time frame: Pre-dose and post-dose 2, 10, 12 hours on Days 14, 28 and 42
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.
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).
Steady state time to Cmax (Tmax) for UDCA, TUDCA, and 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.
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).
Areas under the plasma concentration-time curve(AUC)0-24hr UDCA, TUDCA and 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.
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)
Molar Ratio of AUC(0-24) between metabolites (TUDCA and GUDCA) and parent (UDCA)
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.
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).