Study to Assess Safety & Efficacy of GKT137831 in Patients With Primary Biliary Cholangitis Receiving Ursodiol.
Condition: Primary Biliary Cirrhosis
MeSH terms: Cholangitis; Liver Cirrhosis, Biliary
Intervention: GKT137831; Placebo oral capsule
Intervention description: GKT137831 100mg capsules. To be taken as part of two dose arms which are 400mg twice daily or 400mg once daily.; Matching capsules.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This will be a double-blind, randomized, placebo-controlled, multicenter, parallel group phase 2 trial. A total of 102 subjects will be randomized and allocated to placebo or one of the 2 active treatment arms, according to a 1:1:1 randomization ratio, stratified at study entry by disease severity defined as baseline serum gamma glutamyl transferase (GGT) < 2.5 x ULN or ≥ 2.5 x ULN). Accordingly, approximately 34 subjects will be allocated to each of the 3 treatment arms.
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: This is a double-blind study: the Sponsor, subjects, investigator staff, persons performing the assessments and data reviewers and statisticians will remain blinded to the identity of the study treatments.
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to assess the safety and efficacy of GKT13783 in patients with
      Primary Biliary Cholangitis (PBC) who are taking a stable dose of ursodeoxycholic acid (UDCA)
      treatment, and have persistently high levels of a liver enzyme called Alkaline Phosphatase
      (ALP).
    

Eligibility 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:

               -  History of elevated ALP levels (> ULN) for at least 6 months

               -  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])

               -  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 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.

        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. 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).

         16. 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.

         17. A history of bone marrow disorder including aplastic anemia, or marked anemia defined
             as hemoglobin < 10.0 g/dL (or 6.2 mmol/L).

         18. 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.