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    Summary
    EudraCT Number:2016-004599-23
    Sponsor's Protocol Code Number:GSN000300
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-10
    Trial results View 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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2016-004599-23
    A.3Full title of the trial
    A Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Assess the Efficacy and Safety of Oral GKT137831 in Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase
    Een dubbelblinde, gerandomiseerde, placebogecontroleerde klinische studie ter beoordeling van de werkzaamheid en veiligheid van oraal GKT137831 bij patiënten met primaire biliaire cholangitis met een aanhoudend verhoogde alkalische fosfatasewaarde die ursodeoxycholzuur krijgen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study assessing the efficacy and safety of GKT137831 in Patients with Primary Biliary Cholangitis Receiving Ursodeoxycholic Acid and with Persistently Elevated Alkaline Phosphatase
    A.4.1Sponsor's protocol code numberGSN000300
    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 SponsorGenkyotex SA
    B.1.3.4CountryFrance
    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 supportGenkyotex Innovation SA
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenkyotex Innovation SA
    B.5.2Functional name of contact pointAgnes Gruber
    B.5.3 Address:
    B.5.3.1Street Address218 avenue Marie Curie, Forum 2 – Archamps Techonopole,
    B.5.3.2Town/ citySaint Julien en Genevois, Cedex
    B.5.3.3Post code74166
    B.5.3.4CountryFrance
    B.5.4Telephone number+3345644 81 13
    B.5.6E-mailagnes.gruber@genkyotex.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.3.2Product code GKT137831
    D.3.4Pharmaceutical form Capsule
    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 INNGKT137831
    D.3.9.1CAS number 1218942-37-0
    D.3.9.3Other descriptive nameGKT137831
    D.3.9.4EV Substance CodeSUB57852
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboCapsule
    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
    Primary Biliary Cholangitis
    E.1.1.1Medical condition in easily understood language
    Primary Biliary Cholangitis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10036680
    E.1.2Term Primary biliary cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of oral GKT137831 in comparison with placebo, in subjects with PBC receiving UDCA and with persistently elevated Alkaline Phosphatase (ALP).
    E.2.2Secondary objectives of the trial
    - To evaluate the safety of oral GKT137831 in comparison with placebo, in subjects with PBC.
    - To estimate the population pharmacokinetics (PK) of GKT137831 and explore any potential Pharmacokinetics-Pharmacodynamics (PK-PD) relationships in this subject population.
    - To explore any relationship between genetic parameters and therapeutic responses in a subset of subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria:
    1. Male or female aged 18 to 80 years, inclusive.
    2. Willing and able to give written informed consent and to comply with the requirements of the study.
    3. PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:
    o History of elevated ALP levels (> ULN) for at least 6 months
    o Positive anti-mitochondrial antibody (AMA) titer or if AMA negative or in low titer (< 1:80) PBC-specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex])
    o Liver biopsy consistent with PBC (based on historic liver biopsy), including non-suppurative, destructive cholangitis affecting mainly the interlobular and septal bile ducts.
    4. Serum ALP ≥ 1.5 x ULN.
    5. Serum GGT ≥ 1.5 x ULN.
    6. UDCA treatment for at least 6 months and stable dose for at least 3 months prior to Visit 1.
    7. Subjects being treated for pruritus with colestyramine must be on a stable dose of colestyramine for at least 8 weeks prior to baseline/Day 1 (Visit 2). Subjects must be willing and able to take colestyramine at least 2 hours before or after study medication.
    8. Female subjects of childbearing potential must use a highly effective method of contraception to prevent pregnancy for 4 weeks before randomization and must agree to continue strict contraception for up to 90 days after last administration of investigational medicinal product (IMP). Male participants with female partners of childbearing potential must be willing to use a condom and require their partner to use an additional form of adequate contraception as approved by the Investigator. This requirement begins at the time of informed consent and ends 90 days after the last administration of IMP. Male study participants must also not donate sperm from baseline until 90 days after the last administration of IMP.
    E.4Principal exclusion criteria
    1. A positive pregnancy test or breast-feeding for female subjects.
    2. Any hepatic decompensation, defined as a past or current history of hepatic encephalopathy, gastrointestinal tract bleeding due to esophageal varices, or ascites
    3. International normalized ratio (INR) > 1.2 unless subject is on anticoagulant therapy.
    4. ALT > 3 x ULN.
    5. Total bilirubin > 1 x ULN.
    6. Planned or current plasmapheresis or other extra-corporeal treatments (e.g., molecular adsorbent recirculation system (MARS)) for treatment-refractory pruritus.
    7. History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15.
    8. Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma.
    9. Hepatorenal syndrome (type I or II) or Screening serum creatinine > ULN.
    10. Competing etiology for liver disease (e.g., hepatitis C, active hepatitis B, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), autoimmune hepatitis, primary sclerosing cholangitis, Gilbert’s Syndrome).
    11. Subjects receiving prohibited medications within 3 months of Screening (Visit 1) according to the list (a, b and c) provided in Section 6.6.2.
    12. Treatment with any investigational agent within 4 weeks of Visit 1 or 5 half-lives of the investigational medicinal product (whichever is longer).

    13. A history of long QT syndrome.
    14. Evidence of any of the following cardiac conduction abnormalities during the screening period:
    - A QTc Fredericia interval >450 milliseconds for males and >470 milliseconds for females.
    - A second or third degree atrioventricular block not successfully treated with a pacemaker.
    15. A history of severe cardiovascular disease defined as any of the following within the 12 weeks preceding initiation of study treatment:
    - Acute myocardial infarction or unstable angina pectoris.
    - A coronary revascularization procedure.
    - Congestive heart failure New York Health Association (NYHA) Class III or IV.
    - Stroke, including a transient ischemic attack.
    16. History of cancer in the preceding 5 years, except adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, in situ prostate cancer, in situ breast ductal carcinoma, or superficial bladder cancer stage 0).
    17. The occurrence of any acute infection requiring systemic antibiotic therapy within the 2 weeks prior the Screening Visit (Visit 1), or human immunodeficiency virus (HIV) infection.
    18. A history of bone marrow disorder including aplastic anemia, or marked anemia defined as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).
    19. A known hypersensitivity to GKT137831 or to any of the excipients.
    20. Any condition which, in the opinion of the Investigator, constitutes a risk or contraindication for the participation of the subject in the study, or which could interfere with the study objectives, conduct, or evaluation.


    E.5 End points
    E.5.1Primary end point(s)
    Primary:
    •The percent change from baseline to Week 24 (Visit 7) in serum GGT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The percent change from baseline to Week 24 (Visit 7) in serum GGT.
    Serum GGT will be assessed during every treatment visit. (visit's 2-7)
    E.5.2Secondary end point(s)
    - Absolute and percent change in serum GGT from baseline to each assessment.

    - Absolute change in Enhanced Liver Fibrosis (ELF) score from baseline to Weeks 12 and 24.

    - Absolute and percent change in serum ALP from baseline to each assessment.

    - Absolute and percent change in serum levels of highsensitivity C-reactive protein (hsCRP) and fibrinogen from baseline to each assessment.

    - Absolute and percent change in serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and conjugated and total bilirubin, from baseline to each assessment.

    - Absolute and percent change in the Fibrosis-4 (FIB-4) and AST to Platelet Ratio Index (APRI) scores, from baseline to each assessment (FIB-4: age (years) x AST (IU/L)/(platelet count (109/L) x (ALT (IU/L)1⁄2, APRI: AST (IU/L)/ upper normal limit AST)x100/platelet count (109/L).

    - Absolute and percent change in liver stiffness as assessed by transient elastography (FibroScan® or similar technology), from baseline to Week 24, in patients with values at baseline and Week 24.

    - Absolute and percent change in serum levels of collagen fragments indicative of collagen formation and degradation from baseline to Weeks 12 and 24.

    -Absolute and percent change in Quality of Life (QoL), Fatigue and Pruritus scores based on the PBC-40 and Pruritus Visual Analogue Score (VAS), from baseline to Weeks 12 and 24.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints of the secondary endponts are included within the secondary objective endpoints section E.5.2 (above)

    Most secondary assessments will be assessed from baseline to each visit however the ELF score and collagen fragments will be assessed from baseline to week 12 and week 24.
    The change in liver stiffness (FibroScan® or similar technology) will be assessed from baseline to week 24.
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 trial3
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    Belgium
    Canada
    Germany
    Greece
    Israel
    Italy
    Spain
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months3
    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: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 7
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 50
    F.4.2.2In the whole clinical trial 102
    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)
    None
    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 Decision2017-05-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-08-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-04-02
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