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

INTERVENTION: Intervention 1: 400mg GKT137831 once daily Intervention 2: 400mg GKT137831 twice daily Intervention 3: Placebo CONDITION: K74.3 ‐ Primary biliary cirrhosis Primary Biliary Cholangits PRIMARY OUTCOME: The percent change from baseline to Week 24 (Visit 7) in serum GGT (gamma glutamyl transferase). SECONDARY OUTCOME: ‐ 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), 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 norma 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 collage 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. 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 antiSP100 and/or antibodies against the major M2 components [PDC‐E2, 2oxo‐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 wi