Dose Response Study of GSK2330672 for the Treatment of Pruritus in Participants With Primary Biliary Cholangitis

Phase 2

Completed

• Conditions: Cholestasis
• Interventions: Drug: Placebo; Drug: GSK2330672

• Registration Number: NCT02966834
• Lead Sponsor: GlaxoSmithKline

Brief Summary

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

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-11-15
• Study First Submitted QC: 2016-11-15
• Study First Posted: 2016-11-17
• Study Start: 2017-01-11
• Primary Completion: 2020-04-15
• Study Completion: 2020-04-15
• Status Verified: 2021-04
• Results First Submitted: 2021-04-08
• Results First Submitted QC: 2021-04-08
• Last Update Submitted: 2021-04-08
• Results First Posted: 2021-05-04
• Last Update Posted: 2021-05-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 147

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GSK2330672 90 mg twice daily	Placebo	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 90 mg once daily	Placebo	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 90 mg once daily	GSK2330672	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 20 mg once daily	Placebo	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 180 mg once daily	Placebo	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 20 mg once daily	GSK2330672	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 180 mg once daily	GSK2330672	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 40 mg twice daily	Placebo	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 40 mg twice daily	GSK2330672	Participants will receive GSK2330672 and matching placebo to maintain blind
GSK2330672 90 mg twice daily	GSK2330672	Participants will receive GSK2330672 and matching placebo to maintain blind
Placebo	Placebo	Participants will receive matching placebo

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline at Week 16 in the Mean Worst Daily Itch Score	Baseline and Week 16	Participants were required to score the severity of their itching using a 0-10 numerical rating scale (NRS) where 0 represents no itching and 10 indicates the worst imaginable itching. The Worst Daily Itch Score is the most severe (highest) NRS recorded on a given day. Mean Worst Daily Itch score was calculated as the average of the worst daily itch scores provided in the 7 days prior to the Week 16 visit. Baseline is the average of the scores in the 7 days prior to the Week 4 (Visit 3 \[V3\]). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was done using Analysis of covariance (ANCOVA) including treatment group and centered Mean Worst Daily Itch score at Baseline.

Secondary Outcome Measures

Name	Time	Method
Mean Change From Baseline at Week 16 in Primary Biliary Cholangitis-40 (PBC-40) Scale	Baseline and at Week 16	PBC-40 is a disease-specific health-related quality of life (HRQoL) questionnaire for use in PBC participants. It consists of 40 questions arranged in 6 domains with 3 to 11 questions in each domain. Each question is scored from 1 (least impact) to 5 (greatest impact). All questions within a domain are summed to obtain individual domain score. Domains were: Symptoms (7 questions) with score range 7-35, Itch (3 questions) with score range 3-15, Fatigue (11 questions) with score range 11-55, Cognitive (6 questions) with score range 6-30, Emotional (3 questions) with score range 3-15, and Social (10 questions) with score range 10-50. Higher scores for individual domains represent a poor quality of life. Baseline is the assessment performed at Week 4 (V3) which is conducted prior to first dosing of randomized medication that evening. Change from Baseline was calculated as post-Baseline value minus Baseline value. Analysis was performed using ANCOVA including treatment group and Baseline.
Mean Change From Baseline at Week 16 in Serum Alkaline Phosphatase (ALP) Concentrations, in Participants With High Risk of PBC Progression	Baseline and at Week 16	Criteria for high risk of PBC progression is defined as serum ALP concentrations more than or equal to (\>=)1.67 times upper limit of normal (ULN) range and/or total bilirubin concentrations more than (\>)ULN at Day 1. Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 (Day 1) or Visit 1 (Screening), excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA including treatment group and Baseline.
Number of Participants With Serum ALP Concentrations Less Than (<)1.67 Times ULN and Total Bilirubin Concentrations Less Than or Equal to (<=) ULN at Week 16	At Week 16	Number of participants with ALP \< 1.67 times ULN and total bilirubin \<= ULN at Week 16 is presented. The endpoint was analyzed in Restricted High Risk Population.
Mean Change From Baseline at Week 16 in Serum Aspartate Aminotransferase (AST) Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including Treatment group and Baseline.
Mean Change From Baseline at Week 16 in Serum Gamma Glutamyl Transferase (GGT), Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including treatment group and Baseline.
Mean Change From Baseline at Week 16 in Total Bilirubin Concentration, Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA including treatment group and Baseline.
Mean Change From Baseline at Week 16 in Serum Alanine Aminotransferase (ALT) Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including Treatment group and Baseline.
Mean Change From Baseline at Week 16 in Albumin Concentration, Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA including treatment group and Baseline.
Mean Change From Baseline at Week 16 in Prothrombin International Normalized Ratio (INR), Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including treatment group and Baseline.
Mean Change From Baseline at Week 16 in Prothrombin Time, Among Those With a High Risk of PBC Progression	Baseline and at Week 16	Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including treatment group and Baseline.
Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) -Main Study Period	Up to 12 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persisting disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Number of Participants With Non-SAEs and SAEs -Final Study Period	Up to 4 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persisting disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Number of Participants With Non-SAEs and SAEs - Follow-up Period	Up to 4 weeks	An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any untoward event resulting in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persisting disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Number of Participants With Clinical Chemistry Data of Potential Clinical Importance	At Weeks 8, 12, 16 and 20	Blood samples were collected to measure analyze the following parameters: albumin, calcium, Glomerular filtration rate (GFR) from creatinine, glucose, potassium and sodium. Participants were counted in the worst case category that their value changes to (low, within range \[w/in\] or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (for example \[e.g.\], high to high), or whose value became within range, were recorded in the "To w/in Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100 percent (%). Only "To Low" and/or "To High" categories with potential clinical importance data have been presented.
Number of Participants With Hematology Data of Potential Clinical Importance	At Weeks 8, 12, 16 and 20	Blood samples were collected to analyze the following parameters: hematocrit, hemoglobin, leukocytes, lymphocytes, neutrophils and platelets. Participants were counted in the worst case category that their value changes to (low, w/in or no change, or high), unless there is no change in their category. Participants whose laboratory value category was unchanged (e.g., high to high), or whose value became within range, were recorded in the "To w/in Range or No Change" category. Participants were counted twice if the participant had values that changed "To Low" and "To High", so the percentages may not add to 100%. Only "To Low" and/or "To High" categories with potential clinical importance data have been presented.
Number of Participants With Abnormal 12-Lead Electrocardiogram (ECG) Parameters	At Weeks 8, 12, 16 and 20	A 12-lead ECG was recorded with the participant in a semi-supine position. 12-lead ECGs were obtained by using an automated ECG machine. Data for abnormal, not clinically significant (NCS) and clinically significant (CS) ECG findings are presented. CS abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition.
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Baseline and Week 20	SBP and DBP were measured in the semi-supine position with a completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Change From Baseline in Pulse Rate	Baseline and Week 20	Pulse rate was measured in a semi-supine position after 5 minutes of rest. Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Assessment	Baseline and Week 20	GSRS is a validated scale used to assess gastrointestinal symptoms experienced by participants over the preceding 5 to 7 days. GSRS was measured for all 5 domains: Average Diarrhea Syndrome Score, Average Indigestion Syndrome Score, Average Constipation Syndrome Score, Average Abdominal Pain Syndrome Score, Average Reflux Syndrome Score. All individual domains are scored on a 7-point Likert scale ranging from 1(not at all) to 7(extremely). Higher score indicate more severe symptoms. The Average Total GSRS score was mean of these 5 domains and ranges from 1 to 7. Higher score indicates worst possible degree of symptoms. The responses summarized at each visit are those given during the week prior to the visit, with exception of Day 1. Baseline is the most recent assessment completed by participant prior to randomization. Change from Baseline was calculated as post-Baseline value minus the Baseline value. Data has been presented for each domain along with the average Total GSRS score.
Number of Participants With Mean Worst Daily Itch Score of <4 at Week 16	At Week 16	Participants were required to score the severity of their itching using a 0-10 NRS where 0 represents no itching and 10 indicates the worst imaginable itching. The Worst Daily Itch Score is the most severe (highest) NRS recorded on a given day. Mean Worst Daily Itch score was calculated as the average of the worst daily itch scores provided in the 7 days prior to the Week 16 visit. Number of participants with Mean Worst Daily Itch Score of \<4 at Week 16 is presented.
Mean Change From Baseline at Week 16 in Serum Total Bile Acid Concentration	Baseline and at Week 16	Blood samples were collected for evaluating total bile acid concentration as a biomarker of PBC. Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Mean Change From Baseline at Week 16 in Serum 7-alpha Hydroxy-4-cholesten-3-one (C4)	Baseline and at Week 16	Blood samples were collected for evaluating C4 concentration as a marker of bile acid synthesis. Baseline is the assessment performed at Week 4 (V3), or if missing then Visit 2 or Visit 1, excluding unscheduled visits. Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Plasma Concentration of GSK2330672 After Sparse Sampling	At Week 4 (between 1 and 3 hours post-dose) and At Weeks 8, 12 and 16 (between 1 and 3 hours post-dose, and between 5 and 8 hours post-dose)	Blood samples were collected for measurement of plasma GSK2330672 concentration.
Number of Participants With Improvement of >= 30 Percent (%) in the Mean Worst Daily Itch Score at Week 16 From Baseline	Baseline and At Week 16	Participants were required to score the severity of their itching using a 0-10 NRS where 0 represents no itching and 10 indicates the worst imaginable itching. The Worst Daily Itch Score is the most severe (highest) NRS recorded on a given day. Mean Worst Daily Itch score was calculated as the average of the worst daily itch scores provided in the 7 days prior to the Week 16 visit. Baseline is the most recent assessment completed by the participant prior to randomization. Number of participants with improvement of \>= 30% in the Mean Worst Daily Itch Score at Week 16 from Baseline is presented.
Percentage of Responder Days With Worst Daily Itch Score of <4	Up to Week 16	Percentage of Responder Days with Worst Daily Itch score was calculated as: (number of days response from Visit 3+1 to Visit 6-1 divided by number of days from Visit 3+1 to Visit 6-1 with worst daily itch scores available) times 100. Days for which no worst daily itch score was available did not contribute to either the numerator or the denominator. Analysis was performed using ANCOVA model including treatment group. Percentage of responder days with Worst Daily Itch Score of \<4 is presented.
Number of Participants With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline	Baseline and At Week 16	Participants were required to score the severity of their itching using a 0-10 NRS where 0 represents no itching and 10 indicates the worst imaginable itching. The Worst Daily Itch Score is the most severe (highest) NRS recorded on a given day. Mean Worst Daily Itch score was calculated as the average of the worst daily itch scores provided in the 7 days prior to the Week 16 visit. Baseline is the most recent assessment completed by the participant prior to randomization. Number of participants with improvement of \>=2 in the Mean Worst Daily Itch Score at Week 16 from Baseline is presented.
Change From Baseline in the Five-Dimensional (5-D) Itch Scale at Week 16	Baseline and at Week 16	The 5-D itch scale had been developed as a brief, single page, instrument for the multidimensional quantification of itch that is sensitive to change over time. It has data to support its validity in a population of participants with pruritus and covers five dimensions of itch experienced by participants: duration, degree, direction, disability and distribution. Each domain was scored on a 5-point scale, ranging from 1 (Not present/resolved/never) to 5 (unbearable/getting worse/always), higher scores indicates worst itching. The scores of each of five domains were achieved separately and then summed together to obtain a total 5-D score. A total 5-D scores potentially ranged between 5 (no pruritus) and 25 (most severe pruritus) where higher score indicates worse possible itching. Baseline is assessment performed at Week 4 (V3) which is conducted prior to first dosing of randomized medication that evening. Change from Baseline was calculated as post-Baseline value minus Baseline value.
Percentage of Responder Days With Improvement of >= 30% in the Mean Worst Daily Itch Score at Week 16 From Baseline	Baseline and at Week 16	Percentage of Responder Days with Worst Daily Itch score was calculated as: (number of days response from Visit 3+1 to Visit 6-1 divided by number of days from Visit 3+1 to Visit 6-1 with worst daily itch scores available) times 100. Days for which no worst daily itch score was available did not contribute to either the numerator or the denominator. Analysis was performed using ANCOVA model including treatment group. Baseline is the most recent assessment completed by the participant prior to randomization. Percentage of responder days with improvement of \>= 30% in the Mean Worst Daily Itch Score at Week 16 from Baseline is presented..
Percentage of Responder Days With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline	Baseline and at Week 16	Percentage of Responder Days with Worst Daily Itch was calculated as: (number of days response from Visit 3+1 to Visit 6-1 divided by number of days from Visit 3+1 to Visit 6-1 with worst daily itch scores available) times 100. Days for which no worst daily itch score was available did not contribute to either the numerator or the denominator. Analysis was performed using ANCOVA model including treatment group. Baseline is the most recent assessment completed by the participant prior to randomization. Percentage of responder days with improvement of \>=2 in the Mean Worst Daily Itch Score at Week 16 from Baseline is presented.
Change From Baseline in the Mean Daily Sleep Score at Week 16	Baseline and at Week 16	Mean Daily Sleep Score is defined as the average of the daily sleep scores provided in the 7 days prior to the relevant visit. Participants sleep quality was recorded in an electronic diary each morning using a 0-10 NRS in which 0: good sleep to 10:worst possible sleep. Higher score indicates worse possible sleep. Baseline is the average of the scores in the 7 days prior to the Week 4 (V3) visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA including treatment group and Baseline.
Change From Baseline in the Mean Daily Fatigue Score at Week 16	Baseline and at Week 16	Mean Daily Fatigue Score is defined as the average of the daily fatigue scores provided in the 7 days prior to the relevant visit. Participants fatigue level was recorded in an electronic diary each evening using a 0-10 NRS in which 0: no fatigue to 10:worst possible fatigue. Higher score indicates worse possible fatigue. Baseline is the average of the scores in the 7 days prior to the Week 4 (V3) visit. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Analysis was performed using ANCOVA model including treatment group and Baseline.

Trial Locations

Locations (1)

GSK Investigational Site; 🇬🇧 Sheffield, United Kingdom