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    Summary
    EudraCT Number:2021-000007-21
    Sponsor's Protocol Code Number:212620
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-05-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGreece - EOF
    A.2EudraCT number2021-000007-21
    A.3Full title of the trial
    A two-part, randomized, placebo controlled, double blind, multicenter, Phase 3 study to evaluate the efficacy and safety of linerixibat for the treatment of cholestatic pruritus in participants with primary biliary cholangitis (PBC).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Global Linerixibat Itch STudy of Efficacy and Safety iN PBC (GLISTEN)
    A.3.2Name or abbreviated title of the trial where available
    PH3a,linerixibat vsPBO,efficacy&safety,itch study for the treatment of cholestatic pruritus in PBC
    A.4.1Sponsor's protocol code number212620
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGlaxoSmithKline Research & Development Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGlaxoSmithKline, Research and Development Ltd
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGlaxoSmithKline Research & Development Ltd
    B.5.2Functional name of contact pointClinical Trials Helpdesk Support
    B.5.3 Address:
    B.5.3.1Street Address980 Great West Road
    B.5.3.2Town/ cityBrentford, Middlesex
    B.5.3.3Post codeTW8 9GS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 0800 783 9733
    B.5.6E-mailGSKClinicalSupportHD@gsk.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGSK2330672/linerixibat 40 mg
    D.3.2Product code GSK2330672/linerixibat 40 mg
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLinerixibat
    D.3.9.1CAS number 1345982-69-5
    D.3.9.2Current sponsor codeGSK2330672
    D.3.9.3Other descriptive name3-({[(3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl]methyl}amino)pentanedioic acid
    D.3.9.4EV Substance CodeSUB194569
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Moderate to severe Cholestatic pruritus with primary biliary cholangitis (PBC).
    E.1.1.1Medical condition in easily understood language
    Moderate to Severe itch (Pruritus) in patients with primary biliary cholangitis (PBC)
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 24.1
    E.1.2Level PT
    E.1.2Classification code 10064190
    E.1.2Term Cholestatic pruritus
    E.1.2System Organ Class 10040785 - Skin and subcutaneous tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10080429
    E.1.2Term Primary biliary cholangitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate the effect of treatment with oral linerixibat compared with placebo on itch in PBC patients with cholestatic pruritus over 24 weeks (Part A)
    E.2.2Secondary objectives of the trial
    To evaluate the early effects of oral linerixibat compared to placebo on itch in PBC patients with cholestatic pruritus (Part A)
    To characterize the effects of treatment with oral linerixibat compared with placebo on health related QoL(Part A)
    To evaluate the effects of 24 weeks of treatment with oral linerixibat compared to placebo on itch response rates in PBC patients with cholestatic pruritus (Part A)
    To investigate the treatment effect of oral linerixibat compared with placebo on Patient’s Global Impression of Severity (PGI-S) and Patient’s Global Impression of Change (PGI-C) throughout the treatment period (Part A)
    To evaluate the effects of treatment with linerixibat on markers of PBC disease activity and progression (Part A )

    Safety
    To evaluate the safety of oral linerixibat compared with placebo (Part A and Part B)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants are eligible to be included in the study only if all of the following criteria apply:
    Sex and Age
    1. Male and female participants must be between 18 to 80 years of age inclusive, at the time of signing the informed consent.
    Note: if country/site age requirements for consent differ, the more stringent (e.g., higher age) restriction will be required for that country/site.
    Type of Participant and Disease Characteristics
    2. Participants who have proven PBC, as demonstrated by historically having at least 2 of the following:
    • Documented history of sustained increased ALP levels greater than ULN first recognized at least 6 months prior to the Screening Visit (Note: Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after initiation of UDCA therapy).
    • Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA]) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive).
    • Liver biopsy (documented at any time in the past) consistent with PBC.
    3. Participants who, during the Screening period, record their daily itch score by entering at least 40 of the 56 required itch entries, with an entry on at least 4 days in each week, during the 4-week period immediately preceding Randomization at Day 1 and have a Monthly Itch Score of ≥4 (i.e., at least 1 of the 4 weekly Mean Worst Daily Itch Scores must be ≥4), and no Mean Worst Daily Itch Score can be <3 for any other week.
    Contraceptive/Barrier Requirements
    4. Contraceptive/Barrier Requirements (applicable for female participants only): A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
    -Is a woman of non-childbearing potential (WONCBP)
    OR
    -Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method as described in Section 10.4 during the study intervention period (at a minimum until 4 weeks after the last dose of study intervention).
    The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention.
    • A WOCBP must have a negative highly sensitive urine pregnancy test (or serum as required by local regulations) within 7 days before the first dose of study intervention, see Section 8.2.5 Pregnancy Testing.
    • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.2.5.
    • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
    Note: Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
    • Full requirements for pregnancy testing during and after study intervention are located in Section 10.4 Appendix 4.
    Informed Consent
    5. Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    E.4Principal exclusion criteria
    Participants are excluded from the study if any of the following criteria apply:
    Medical Conditions
    1. Participants with recent positive COVID-19 test results, symptoms suggestive of active COVID-19 infection (e.g. fever, loss of taste or smell, cough, shortness of breath) and/or contact within the past 14 days with someone with COVID-19 are excluded for a minimum of 14 days from the test results or time of exposure, respectively, and must be symptom free before Screening procedures may begin. If a participant tests positive for COVID-19 during the Screening period, the participant should be considered a screen failure and may be re-screened 14 days after the positive test result and after participant is symptom free.
    2. Total bilirubin >2.0 x ULN using the average of two baseline measures. Note: Total bilirubin > 2x ULN but < 3x ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%
    3. Screening ALT > 6x ULN in a single baseline measure or ALT > 5x ULN using the average of two baseline measures.
    4. Participants with abnormal liver biochemistry (ALT, aspartate aminotransferase [AST], ALP, or total bilirubin) during the Screening period (at Visit 1 or Visit 2) and the variance between these two samples for the abnormal parameter is >40%. Note: Variance will be calculated as the absolute value of [(Sample 1- Sample 2)/average of Sample 1 and Sample 2) x100] If variance of >40% is seen between Visit 1 and 2 samples, an additional sample may be taken and the variance between the additional sample (third sample) and the Screening (Visit 1) sample must be ≤ 40%
    5. Screening estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
    6. History or presence of hepatic decompensation (e.g., variceal bleeding, hepatic encephalopathy or ascites).
    7. Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease and/or confirmed hepatocellular carcinoma or biliary cancer.
    8. Infection with human immunodeficiency virus (HIV)
    9. Current clinically significant diarrhea in the Investigator’s medical opinion.
    10. Active inflammatory ileal disease according to Investigator´s clinical judgment.
    11. Current symptomatic cholelithiasis or cholecystitis. (Participants with history of cholecystectomy ≥12 weeks before screening may be eligible for enrolment at the discretion of the investigator.)
    12. Current diagnosis of primary skin disorders with itch symptoms (e.g., atopic dermatitis, psoriasis).
    13. Primary sleep disorders such as but are not limited to sleep apnea, narcolepsy, hypersomnia
    14. Any current malignancies (including hematologic and solid malignancies).
    15. Current/previous diagnosis of colorectal cancer.
    16. History of bariatric surgery with ileal bypass at any time, or any bariatric surgery performed in the past 3 years
    17. Any current uncontrolled psychiatric condition
    18. Any current medical condition (e.g. senility or dementia), which may affect the participant’s ability to comply with the protocol specified procedures.
    Prior/Concomitant Therapy
    19. Initiation, discontinuation or change in dose of UDCA in the 8 weeks prior to Screening. (Participants may join the study on stable doses of UDCA, but no initiation, discontinuation, or change in dose is permitted until completion of the Treatment Periods.)
    20. Use of obeticholic acid: within 8 weeks prior to Screening. (Participants may not initiate or restart during the study, please see Section 6.8.2)
    21. Initiation, discontinuation or change in dose of bezafibrate or fenofibrate at any time during the 8 weeks prior to Screening. (Participants may join the study on stable doses of these medications, but no initiation, discontinuation, or change in dose is permitted until completion of the Treatment Periods.)
    22. Initiation, discontinuation, or change in dose of any of the following in the 8 weeks prior to Screening: bile acid binding resins, rifampicin, naltrexone, naloxone, nalfurafine, pregabalin, gabapentin, sertraline or other SSRIs. (Participants may join the study on stable doses of these medications, but no change in dose nor addition of new treatment for cholestatic pruritus is permitted during the study.) Note: Dosing of linerixibat and bile acid binding resins should be staggered by at least 4 hours.
    23. Initiation, discontinuation or change in dose of opioids, regardless of indication, in the 8 weeks prior to Screening. (Participants may join the study on stable doses of these medications)
    24. Initiation, discontinuation or change in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 8 weeks prior to Screening Note: If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded.
    Refer Protocol Page No. 45 to 48 for other Exclusion Criteria.
    E.5 End points
    E.5.1Primary end point(s)
    • Change from Baseline in Monthly Itch Scores over 24 weeks using a 0-10 numerical rating scale (NRS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Itch data will be collected daily from Screening through Week 32
    E.5.2Secondary end point(s)
    • Change from baseline in Mean Worst Daily Itch score at Week 2
    • Change from Baseline in Monthly Sleep Score as measured by 0-10 NRS over 24 weeks
    • Change from Baseline in PBC-40 domain scores at Week 24
    • Responder defined as achieving a ≥2-point reduction from Baseline in the Monthly Itch score at Week 24.
    • Responder defined as achieving a ≥3-point reduction from Baseline in the Monthly Itch score at Week 24.
    • Responder defined as achieving a ≥4-point reduction from Baseline in the Monthly Itch score at Week 24.
    • Change from baseline in Patient's Global Impression of Severity (PGI-S) over 24 weeks
    • PGI-C over 24 weeks
    Change from baseline in ALP at Week 24
    • Change from baseline in bilirubin at Week 24
    • Clinical assessments including, but not limited to:
    • Adverse Events (AEs) and Serious Adverse
    Events (SAEs)
    • Vital signs
    • 12-lead Electrocardiogram (ECG) Clinical laboratory evaluation (including liver chemistry panel and fasting lipids)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Sleep data will be collected daily from Screening through Week 32. PBC-40, PGI-S, PGI-C, and lab parameters (ALP, bilirubin) will be collected at monthly clinic visits
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Brazil
    Canada
    China
    Israel
    Japan
    Mexico
    United States
    France
    Poland
    Bulgaria
    Switzerland
    Czechia
    Germany
    Greece
    Italy
    Belgium
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study is defined as the date of the last visit of the last participant in the study in the trial globally. A participant is considered to have completed the study if he/she has completed all phases of the study including the last visit. For participants that will enroll into a follow on study this last visit is Week 32. If the participant will not enrolled in a follow-on study, this would include completion of the follow-up phone call as shown in the SoA (Section 1.3) of protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 175
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 67
    F.4.2.2In the whole clinical trial 230
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Participants who complete treatment in Part A and Part B will be offered the opportunity to take part in a separate long-term follow-on study, where linerixibat will be provided in an open-label manner. Participants who do not enter the follow-on study will have a follow up phone call approximately 7-14 days after the last dose of study drug.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-06-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-06-17
    P. End of Trial
    P.End of Trial StatusOngoing
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