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

Primary Purpose

Cholestasis

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Placebo

GSK2330672

About this trial

This is an interventional treatment trial for Cholestasis focused on measuring linerixibat, PBC, itch, GSK2330672, GLIMMER, primary biliary cholangitis, pruritus

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
Participants who have proven PBC, as demonstrated by having at least 2 of the following: History of sustained increased ALP levels >ULN first recognized at least 6 months prior to the Screening Visit (Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after institution of ursodeoxycholic acid (UDCA) therapy as described in inclusion number 4). Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive). Liver biopsy (at any time in the past) consistent with PBC.
Participants must rate their itch severity as being >=4 on a 0 to 10 point scale for the majority of time (at least half the days, as recalled by the participant) during the 8 weeks prior to the Screening Visit. Periods of low itch or no itch are acceptable as long as the worst daily itch score is >=4 on the majority of days.
Participants who are currently taking UDCA should be on stable doses of UDCA for >8 weeks at time of screening. Participants not taking UDCA due to intolerance may be enrolled 8 weeks after their last dose of UDCA. No changes or discontinuation is permitted until completion of the Main Study Period.
Male and/or female: Female participants- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and until at least 4 weeks after the last dose of study treatment.
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria

Screening total bilirubin >2x ULN. Total bilirubin >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent (%).
Screening ALT or AST >6x ULN.
Screening eGFR <45 milliliter (mL)/minute/1.73 square meter (m^2) based on the CKD-EPI.
History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites).
Presence of actively replicating viral hepatitis due to hepatitis B or C virus (HBV, HCV) infection, and/or confirmed hepatocellular carcinoma or biliary cancer. Other hepatic conditions ( e.g., primary sclerosing cholangitis [PSC], alcoholic liver disease, autoimmune hepatitis, non-alcoholic steatohepatitis [NASH] ) are permitted if PBC is the dominant liver injury in the investigator's opinion.
Current diarrhea.
Current symptomatic cholelithiasis or inflammatory gall bladder disease. Participants with history of cholecystectomy >=3 months before screening may be eligible for enrolment.
Any current medical condition (e.g. psychiatric disorder, senility or dementia), which may affect the participant's ability to comply with the protocol specified procedures.
Initiation or increase in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 2 months prior to screening. If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded.
Initiation or increase in dose of bezafibrate or fenofibrate at any time during the 3 months prior to screening. Participants may join the study on stable doses of these medications, but no change or discontinuation is permitted until completion of the Main Study Period.
Initiation or increase in dose of any of the following in the 8 weeks prior to screening: rifampicin, naltrexone, naloxone, nalfurafine, or sertraline. Participants may join the study on stable or decreased doses of these medications, but no change in dose is permitted until completion of the Main Study Period.
Bile acid binding resin use: a participant must discontinue use of cholestyramine, colesevelam, colestipol or colestimide prior to the start of the Initial Study Period (no later than Day-2). Note: these drugs may be administered after completion of the Main Study Period, if clinically indicated.
Obeticholic acid use: a participant must discontinue use of obeticholic acid at least 8 weeks prior to the start of the Initial Study Period and may not restart until after the end of the study.
Administration of any other Inhibitor of the Human Ileal Bile Acid Transporter (IBAT) in the 3 months prior to screening.
Current enrolment or participation within the 8 weeks before start of the Initial Study Period, in any other clinical study involving an investigational study treatment.
QT interval corrected for heart rate QTc >480 millisecond (msec).
History of sensitivity to the study treatment or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation in the study.
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 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 measure (25 mL) of spirits.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

GSK2330672 20 mg once daily

GSK2330672 90 mg once daily

GSK2330672 180 mg once daily

GSK2330672 40 mg twice daily

GSK2330672 90 mg twice daily

Arm Description

Participants will receive matching placebo

Participants will receive GSK2330672 and matching placebo to maintain blind

Outcomes

Primary Outcome Measures

Mean Change From Baseline at Week 16 in the Mean Worst Daily Itch Score

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

Mean Change From Baseline at Week 16 in Primary Biliary Cholangitis-40 (PBC-40) Scale

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

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

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 Alanine Aminotransferase (ALT) Among Those With a High Risk of PBC Progression

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 Aspartate Aminotransferase (AST) Among Those With a High Risk of PBC Progression

Mean Change From Baseline at Week 16 in Serum Gamma Glutamyl Transferase (GGT), Among Those With a High Risk of PBC Progression

Mean Change From Baseline at Week 16 in Total Bilirubin Concentration, Among Those With a High Risk of PBC Progression

Mean Change From Baseline at Week 16 in Albumin Concentration, Among Those With a High Risk of PBC Progression

Mean Change From Baseline at Week 16 in Prothrombin International Normalized Ratio (INR), Among Those With a High Risk of PBC Progression

Mean Change From Baseline at Week 16 in Prothrombin Time, Among Those With a High Risk of PBC Progression

Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) -Main Study Period

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

Number of Participants With Non-SAEs and SAEs - Follow-up Period

Number of Participants With Clinical Chemistry Data of Potential Clinical Importance

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

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

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)

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

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

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

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.

Number of Participants With Improvement of >= 30 Percent (%) in the Mean Worst Daily Itch Score at Week 16 From Baseline

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.

Number of Participants With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline

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.

Percentage of Responder Days With Worst Daily Itch Score of <4

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.

Percentage of Responder Days With Improvement of >= 30% in the Mean Worst Daily Itch Score at Week 16 From Baseline

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

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

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

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.

Change From Baseline in the Five-Dimensional (5-D) Itch Scale 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.

Mean Change From Baseline at Week 16 in Serum Total Bile Acid Concentration

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)

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

Blood samples were collected for measurement of plasma GSK2330672 concentration.

Full Information

NCT ID

NCT02966834

First Posted

November 15, 2016

Last Updated

April 8, 2021

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT02966834

Brief Title

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

Official Title

A Randomized, Double-blind, Multi-dose, Placebo-controlled Study to Evaluate the Efficacy, Safety and Tolerability of GSK2330672 Administration for the Treatment of Pruritus in Patients With Primary Biliary Cholangitis (GLIMMER: GSK2330672 triaL of IBAT Inhibition With Multidose Measurement for Evaluation of Response)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

January 11, 2017 (Actual)

Primary Completion Date

April 15, 2020 (Actual)

Study Completion Date

April 15, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

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

Cholestasis

Keywords

linerixibat, PBC, itch, GSK2330672, GLIMMER, primary biliary cholangitis, pruritus

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

147 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Participants will receive matching placebo

Arm Title

GSK2330672 20 mg once daily

Arm Type

Experimental

Arm Description

Participants will receive GSK2330672 and matching placebo to maintain blind

Arm Title

GSK2330672 90 mg once daily

Arm Type

Experimental

Arm Description

Participants will receive GSK2330672 and matching placebo to maintain blind

Arm Title

GSK2330672 180 mg once daily

Arm Type

Experimental

Arm Description

Participants will receive GSK2330672 and matching placebo to maintain blind

Arm Title

GSK2330672 40 mg twice daily

Arm Type

Experimental

Arm Description

Participants will receive GSK2330672 and matching placebo to maintain blind

Arm Title

GSK2330672 90 mg twice daily

Arm Type

Experimental

Arm Description

Participants will receive GSK2330672 and matching placebo to maintain blind

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

GSK2330672 matching placebo will be supplied as white film-coated tablets.

Intervention Type

Drug

Intervention Name(s)

GSK2330672

Intervention Description

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

Primary Outcome Measure Information:

Title

Mean Change From Baseline at Week 16 in the Mean Worst Daily Itch Score

Description

Time Frame

Baseline and Week 16

Secondary Outcome Measure Information:

Title

Mean Change From Baseline at Week 16 in Primary Biliary Cholangitis-40 (PBC-40) Scale

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Serum Alkaline Phosphatase (ALP) Concentrations, in Participants With High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

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

Description

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.

Time Frame

At Week 16

Title

Mean Change From Baseline at Week 16 in Serum Alanine Aminotransferase (ALT) Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Serum Aspartate Aminotransferase (AST) Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Serum Gamma Glutamyl Transferase (GGT), Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Total Bilirubin Concentration, Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Albumin Concentration, Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Prothrombin International Normalized Ratio (INR), Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Prothrombin Time, Among Those With a High Risk of PBC Progression

Description

Time Frame

Baseline and at Week 16

Title

Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) -Main Study Period

Description

Time Frame

Up to 12 weeks

Title

Number of Participants With Non-SAEs and SAEs -Final Study Period

Description

Time Frame

Up to 4 weeks

Title

Number of Participants With Non-SAEs and SAEs - Follow-up Period

Description

Time Frame

Up to 4 weeks

Title

Number of Participants With Clinical Chemistry Data of Potential Clinical Importance

Description

Time Frame

At Weeks 8, 12, 16 and 20

Title

Number of Participants With Hematology Data of Potential Clinical Importance

Description

Time Frame

At Weeks 8, 12, 16 and 20

Title

Number of Participants With Abnormal 12-Lead Electrocardiogram (ECG) Parameters

Description

Time Frame

At Weeks 8, 12, 16 and 20

Title

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Description

Time Frame

Baseline and Week 20

Title

Change From Baseline in Pulse Rate

Description

Time Frame

Baseline and Week 20

Title

Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Assessment

Description

Time Frame

Baseline and Week 20

Title

Number of Participants With Mean Worst Daily Itch Score of <4 at Week 16

Description

Time Frame

At Week 16

Title

Number of Participants With Improvement of >= 30 Percent (%) in the Mean Worst Daily Itch Score at Week 16 From Baseline

Description

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.

Time Frame

Baseline and At Week 16

Title

Number of Participants With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline

Description

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.

Time Frame

Baseline and At Week 16

Title

Percentage of Responder Days With Worst Daily Itch Score of <4

Description

Time Frame

Up to Week 16

Title

Percentage of Responder Days With Improvement of >= 30% in the Mean Worst Daily Itch Score at Week 16 From Baseline

Description

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..

Time Frame

Baseline and at Week 16

Title

Percentage of Responder Days With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline

Description

Time Frame

Baseline and at Week 16

Title

Change From Baseline in the Mean Daily Sleep Score at Week 16

Description

Time Frame

Baseline and at Week 16

Title

Change From Baseline in the Mean Daily Fatigue Score at Week 16

Description

Time Frame

Baseline and at Week 16

Title

Change From Baseline in the Five-Dimensional (5-D) Itch Scale at Week 16

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Serum Total Bile Acid Concentration

Description

Time Frame

Baseline and at Week 16

Title

Mean Change From Baseline at Week 16 in Serum 7-alpha Hydroxy-4-cholesten-3-one (C4)

Description

Time Frame

Baseline and at Week 16

Title

Plasma Concentration of GSK2330672 After Sparse Sampling

Description

Blood samples were collected for measurement of plasma GSK2330672 concentration.

Time Frame

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)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent. Participants who have proven PBC, as demonstrated by having at least 2 of the following: History of sustained increased ALP levels >ULN first recognized at least 6 months prior to the Screening Visit (Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after institution of ursodeoxycholic acid (UDCA) therapy as described in inclusion number 4). Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive). Liver biopsy (at any time in the past) consistent with PBC. Participants must rate their itch severity as being >=4 on a 0 to 10 point scale for the majority of time (at least half the days, as recalled by the participant) during the 8 weeks prior to the Screening Visit. Periods of low itch or no itch are acceptable as long as the worst daily itch score is >=4 on the majority of days. Participants who are currently taking UDCA should be on stable doses of UDCA for >8 weeks at time of screening. Participants not taking UDCA due to intolerance may be enrolled 8 weeks after their last dose of UDCA. No changes or discontinuation is permitted until completion of the Main Study Period. Male and/or female: Female participants- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive guidance during the treatment period and until at least 4 weeks after the last dose of study treatment. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria Screening total bilirubin >2x ULN. Total bilirubin >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent (%). Screening ALT or AST >6x ULN. Screening eGFR <45 milliliter (mL)/minute/1.73 square meter (m^2) based on the CKD-EPI. History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites). Presence of actively replicating viral hepatitis due to hepatitis B or C virus (HBV, HCV) infection, and/or confirmed hepatocellular carcinoma or biliary cancer. Other hepatic conditions ( e.g., primary sclerosing cholangitis [PSC], alcoholic liver disease, autoimmune hepatitis, non-alcoholic steatohepatitis [NASH] ) are permitted if PBC is the dominant liver injury in the investigator's opinion. Current diarrhea. Current symptomatic cholelithiasis or inflammatory gall bladder disease. Participants with history of cholecystectomy >=3 months before screening may be eligible for enrolment. Any current medical condition (e.g. psychiatric disorder, senility or dementia), which may affect the participant's ability to comply with the protocol specified procedures. Initiation or increase in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 2 months prior to screening. If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded. Initiation or increase in dose of bezafibrate or fenofibrate at any time during the 3 months prior to screening. Participants may join the study on stable doses of these medications, but no change or discontinuation is permitted until completion of the Main Study Period. Initiation or increase in dose of any of the following in the 8 weeks prior to screening: rifampicin, naltrexone, naloxone, nalfurafine, or sertraline. Participants may join the study on stable or decreased doses of these medications, but no change in dose is permitted until completion of the Main Study Period. Bile acid binding resin use: a participant must discontinue use of cholestyramine, colesevelam, colestipol or colestimide prior to the start of the Initial Study Period (no later than Day-2). Note: these drugs may be administered after completion of the Main Study Period, if clinically indicated. Obeticholic acid use: a participant must discontinue use of obeticholic acid at least 8 weeks prior to the start of the Initial Study Period and may not restart until after the end of the study. Administration of any other Inhibitor of the Human Ileal Bile Acid Transporter (IBAT) in the 3 months prior to screening. Current enrolment or participation within the 8 weeks before start of the Initial Study Period, in any other clinical study involving an investigational study treatment. QT interval corrected for heart rate QTc >480 millisecond (msec). History of sensitivity to the study treatment or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation in the study. 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 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 measure (25 mL) of spirits.

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

Phoenix

State/Province

Arizona

ZIP/Postal Code

85054

Country

United States

Facility Name

GSK Investigational Site

City

Sacramento

State/Province

California

ZIP/Postal Code

95817

Country

United States

Facility Name

GSK Investigational Site

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

GSK Investigational Site

City

Novi

State/Province

Michigan

ZIP/Postal Code

48377

Country

United States

Facility Name

GSK Investigational Site

City

Manhasset

State/Province

New Jersey

ZIP/Postal Code

11030

Country

United States

Facility Name

GSK Investigational Site

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

GSK Investigational Site

City

Allentown

State/Province

Pennsylvania

ZIP/Postal Code

18104

Country

United States

Facility Name

GSK Investigational Site

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390-8887

Country

United States

Facility Name

GSK Investigational Site

City

Seattle

State/Province

Washington

ZIP/Postal Code

981104

Country

United States

Facility Name

GSK Investigational Site

City

Camperdown

State/Province

New South Wales

ZIP/Postal Code

2050

Country

Australia

Facility Name

GSK Investigational Site

City

Herston

State/Province

Queensland

ZIP/Postal Code

4029

Country

Australia

Facility Name

GSK Investigational Site

City

Prahran

State/Province

Victoria

ZIP/Postal Code

3181

Country

Australia

Facility Name

GSK Investigational Site

City

Nedlands

State/Province

Western Australia

ZIP/Postal Code

6009

Country

Australia

Facility Name

GSK Investigational Site

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T2N 4Z6

Country

Canada

Facility Name

GSK Investigational Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 2C8

Country

Canada

Facility Name

GSK Investigational Site

City

Winnipeg

State/Province

Manitoba

ZIP/Postal Code

R3E 3P4

Country

Canada

Facility Name

GSK Investigational Site

City

London

State/Province

Ontario

ZIP/Postal Code

N6A 5A5

Country

Canada

Facility Name

GSK Investigational Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2C4

Country

Canada

Facility Name

GSK Investigational Site

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H2X 0A9

Country

Canada

Facility Name

GSK Investigational Site

City

Clermont-Ferrand

ZIP/Postal Code

63003

Country

France

Facility Name

GSK Investigational Site

City

Grenoble Cedex 9

ZIP/Postal Code

38043

Country

France

Facility Name

GSK Investigational Site

City

Lille cedex

ZIP/Postal Code

59037

Country

France

Facility Name

GSK Investigational Site

City

Paris cedex 12

ZIP/Postal Code

75571

Country

France

Facility Name

GSK Investigational Site

City

Pessac cedex

ZIP/Postal Code

33604

Country

France

Facility Name

GSK Investigational Site

City

Erlangen

State/Province

Bayern

ZIP/Postal Code

91054

Country

Germany

Facility Name

GSK Investigational Site

City

Homburg

State/Province

Saarland

ZIP/Postal Code

66421

Country

Germany

Facility Name

GSK Investigational Site

City

Hamburg

ZIP/Postal Code

20246

Country

Germany

Facility Name

GSK Investigational Site

City

Bologna

State/Province

Emilia-Romagna

ZIP/Postal Code

40138

Country

Italy

Facility Name

GSK Investigational Site

City

Milano

State/Province

Lombardia

ZIP/Postal Code

20142

Country

Italy

Facility Name

GSK Investigational Site

City

Monza (MB)

State/Province

Lombardia

ZIP/Postal Code

20900

Country

Italy

Facility Name

GSK Investigational Site

City

Firenze

State/Province

Toscana

ZIP/Postal Code

50134

Country

Italy

Facility Name

GSK Investigational Site

City

Padova

State/Province

Veneto

ZIP/Postal Code

35128

Country

Italy

Facility Name

GSK Investigational Site

City

Chiba

ZIP/Postal Code

270-1694

Country

Japan

Facility Name

GSK Investigational Site

City

Fukui

ZIP/Postal Code

918-8503

Country

Japan

Facility Name

GSK Investigational Site

City

Gunma

ZIP/Postal Code

371-8511

Country

Japan

Facility Name

GSK Investigational Site

City

Hiroshima

ZIP/Postal Code

730-8619

Country

Japan

Facility Name

GSK Investigational Site

City

Hokkaido

ZIP/Postal Code

006-8555

Country

Japan

Facility Name

GSK Investigational Site

City

Kagawa

ZIP/Postal Code

760-8557

Country

Japan

Facility Name

GSK Investigational Site

City

Kanagawa

ZIP/Postal Code

252-0375

Country

Japan

Facility Name

GSK Investigational Site

City

Nagasaki

ZIP/Postal Code

856-8562

Country

Japan

Facility Name

GSK Investigational Site

City

Osaka

ZIP/Postal Code

545-8586

Country

Japan

Facility Name

GSK Investigational Site

City

Osaka

ZIP/Postal Code

591-8025

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

105-8471

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

173-8606

Country

Japan

Facility Name

GSK Investigational Site

City

Tokyo

ZIP/Postal Code

181-8611

Country

Japan

Facility Name

GSK Investigational Site

City

Czestochowa

ZIP/Postal Code

42-217

Country

Poland

Facility Name

GSK Investigational Site

City

Katowice

ZIP/Postal Code

40-506

Country

Poland

Facility Name

GSK Investigational Site

City

Myslowice

ZIP/Postal Code

41-400

Country

Poland

Facility Name

GSK Investigational Site

City

Warszawa

ZIP/Postal Code

00-332

Country

Poland

Facility Name

GSK Investigational Site

City

Wroclaw

ZIP/Postal Code

50-349

Country

Poland

Facility Name

GSK Investigational Site

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

GSK Investigational Site

City

Madrid

ZIP/Postal Code

28007

Country

Spain

Facility Name

GSK Investigational Site

City

Madrid

ZIP/Postal Code

28034

Country

Spain

Facility Name

GSK Investigational Site

City

Sevilla

ZIP/Postal Code

41013

Country

Spain

Facility Name

GSK Investigational Site

City

Valencia

ZIP/Postal Code

46026

Country

Spain

Facility Name

GSK Investigational Site

City

Basingstoke

ZIP/Postal Code

RG24 9NA

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Edgbaston

ZIP/Postal Code

B15 2GW

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Glasgow

ZIP/Postal Code

G31 2ER

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Liverpool.

ZIP/Postal Code

L7 8XP

Country

United Kingdom

Facility Name

GSK Investigational Site

City

London

ZIP/Postal Code

NW3 2QG

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Manchester

ZIP/Postal Code

M13 9WU

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Middlesbrough

ZIP/Postal Code

TS4 3BW

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Newcastle-upon-Tyne

ZIP/Postal Code

NE1 4LP

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Nottingham

ZIP/Postal Code

NG7 2UH

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Plymouth

ZIP/Postal Code

PL6 8DH

Country

United Kingdom

Facility Name

GSK Investigational Site

City

Sheffield

ZIP/Postal Code

S5 7AU

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

IPD for this study will be made available via the Clinical Study Data Request site.

IPD Sharing Time Frame

IPD will be made available within 6 months of publishing the results of the primary endpoints, key secondary endpoints and safety data of the study.

IPD Sharing Access Criteria

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

IPD Sharing URL

http://clinicalstudydatarequest.com

Citations:

PubMed Identifier

36343847

Citation

Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, Mayo MJ, Haque N, von Maltzahn R, Allinder M, Swift B, McLaughlin MM, Hirschfield GM; GLIMMER Study Group. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol. 2023 Jul;21(7):1902-1912.e13. doi: 10.1016/j.cgh.2022.10.032. Epub 2022 Nov 4.

Results Reference

derived

Learn more about this trial

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

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

Cholestasis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial