Clinical Trial: 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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 B

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 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

Detailed Summary:
Sponsor: GlaxoSmithKline

Current Primary Outcome:

• Safety and tolerability assessment following repeat doses of GSK2330672 [ Time Frame: From Baseline up to Day 56 ]
  GSK2330672 will be administered twice daily (BID) to assess safety and tolerability including clinical hematology, clinical chemistry, urinalysis, 12-lead electrocardiograms (ECGs),vital sign measurements including systolic and diastolic blood pressure (BP) and pulse rate.
• Tolerability assessment using Gastrointestinal Symptom Rating Scale (GSRS). [ Time Frame: From Day 1 up to Day 56 ]
  Subjects will be asked to complete a validated scale. The scale will be used to assess symptoms experienced by subject over the preceding 5 to 7 days
• Fecal occult blood testing [ Time Frame: Up to Day 56 ]
  Fecal occult blood monitoring for symptomatic or visible gastrointestinal bleeding or asymptomatic occult bleeding

Original Primary Outcome:

• Safety and tolerability assessment following repeat doses of GSK2330672 [ Time Frame: From Baseline up to Day 56 ]
  GSK2330672 will be administered twice daily (BID) to assess safety and tolerability including clinical hematology, clinical chemistry, urinalysis, single 12-lead electrocardiograms (ECGs),vital sign measurements including systolic and diastolic blood pressure (BP) and pulse rate.
• Tolerability assessment using Gastrointestinal Symptom Rating Scale (GSRS). [ Time Frame: From Day 1 up to Day 56 ]
  Subjects will be asked to complete a validated scale. The scale will be used to assess symptoms experienced by subject over the preceding 5 to 7 days
• Fecal occult blood testing [ Time Frame: Up to Day 56 ]
  Fecal occult blood monitoring for symptomatic or visible gastrointestinal bleeding or asymptomatic occult bleeding

Current Secondary Outcome:

• Steady-state PK assessment of UDCA and its taurine and glycine conjugates taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) [ Time Frame: Pre dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours (Hrs) post dose on Days 14, 28 and 42 ]
  Blood sample will be collected only for the subjects who are taking UDCA for the measurements of steady state PK parameters of UDCA and its metabolites including maximum observed plasma concentration (Cmax), time to Cmax (tmax), AUC(0-24hours), and terminal phase half-life (t1/2)
• Plasma GSK2330672 PK assessment [ Time Frame: Pre dose and post dose 2, 10, 12 Hrs on Days 14, 28 and 42 ]
  Blood sample will be collected for measurements of GSK2330672 PK parameters
• Measurement of serum profiles of total bile acid concentrations and 7-alpha hydroxy-4-cholesten-3-one (C4) [ Time Frame: Pre dose, and at 2 and 5 hrs post dose (total bile acids), pre dose only (C4) on Days 14, 28 and 42 ]
  Blood sample was collected for measurement of serum profiles of total bile acid concentrations and C4. C4 is the first committed step of bile acid synthesis from cholesterol
• Subject reported outcomes - daily pruritus 0 to 10 pt scale. [ Time Frame: From Day 1 Up to Day 56 ]
  A 0 to 10 point Scale will be 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). The severity of itching symptoms from "0" (no itching) to "10" (worst possible itching) will be recorded
• Subject reported outcomes - 5D-itch scale [ Time Frame: From Day 1 Up to Day 56 ]
  The 5-D itch scale covers five dimensions of itching experienced by subjects including duration, degree, direction, disability and distribution. The scores of each of the five domains are achieved separately and then summed together to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus).
• Patient reported outcomes PBC-40 quality of life (QoL) scale. [ Time Frame: From Day 1 Up to Day 56 ]
  The PBC-40 QoL scale has six domains; cognitive, itch, fatigue, social, emotional and (other) symptoms with individual questions scored in the range 1to 5 (with high scores denoting greater symptom impact and worse QoL).

Original Secondary Outcome:

• Steady-state PK assessment of UDCA and its taurine and glycine conjugates taurodeoxycholic acid (TUDCA) and glycoursodeoxcholic acid (GUDCA) [ Time Frame: Pre dose and at 6, 12, 12.5, 13, 14, 15, 17, 19, 21 and 24 hours (Hrs) post dose on Days 14, 28 and 42 ]
  Blood sample will be collected for measurements of steady state PK parameters of UDCA and its metabolites including maximum observed plasma concentration (Cmax), time to Cmax (tmax), AUC(0-24hours), and terminal phase half-life (t1/2)
• Plasma GSK2330672 PK assessment [ Time Frame: Pre dose and post dose 2, 10, 12 Hrs on Days 14, 28 and 42 ]
  Blood sample will be collected for measurements of GSK2330672 PK parameters
• Measurement of serum profiles of total bile acid concentrations and 7-alpha hydroxy-4-cholesten-3-one (C4) [ Time Frame: Pre dose, and at 2 and 5 hrs post dose (total bile acids), pre dose only (C4) on Days 14, 28 and 42 ]
  Blood sample was collected for measurement of serum profiles of total bile acid concentrations and C4. C4 is the first committed step of bile acid synthesis from cholesterol
• Subject reported outcomes - daily pruritus 0 to 10 pt scale. [ Time Frame: From Day 1 Up to Day 56 ]
  A 0 to 10 point Scale will be 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). The severity of itching symptoms from "0" (no itching) to "10" (worst possible itching) will be recorded
• Subject reported outcomes - 5D-itch scale [ Time Frame: From Day 1 Up to Day 56 ]
  The 5-D itch scale covers five dimensions of itching experienced by subjects including duration, degree, direction, disability and distribution. The scores of each of the five domains are achieved separately and then summed together to obtain a total 5-D score. 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus).
• Patient reported outcomes PBC-40 quality of life (QoL) scale. [ Time Frame: From Day 1 Up to Day 56 ]
  The PBC-40 QoL scale has six domains; cognitive, itch, fatigue, social, emotional and (other) symptoms with individual questions scored in the range 1to 5 (with high scores denoting greater symptom impact and worse QoL).

Information By: GlaxoSmithKline

Dates:
Date Received: July 3, 2013
Date Started: March 2014
Date Completion:
Last Updated: February 4, 2016
Last Verified: February 2016