Obeticholic Acid Versus Placebo, in Combination with Ursodeoxycholic Acid in Patients with Primary Biliary Cirrhosis

Prior treatment

• Participants with severe pruritus or those requiring systemic treatment for pruritus (for example, with bile acid sequestrants \[BAS\] or rifampicin) within 2 months prior to the first dose
• Patients who took obeticholic acid within 3 months prior to the first dose
• Administration of the following drugs within 2 months prior to the first dose: antibodies or immunotherapy against interleukins or other cytokines or chemokines.
• Anticipated changes to current concomitant medications during the trial;

Other illness

• Known history of human immunodeficiency virus (HIV) infection
• Presence of any other disease or condition that is interfering with the absorption, distribution, metabolism, or excretion of drugs including bile salt metabolism in the intestine. Participants with inflammatory bowel disease or who have undergone gastric bypass procedures will be excluded (gastric lap band is acceptable)
• Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the trial;

Lab values

• History or presence of other concomitant liver diseases including:
  • Hepatitis C virus (HCV) infection; participants with active hepatitis B (HBV) infection will be excluded, however, participants who have seroconverted (hepatitis B surface antigen \[Hbs Ag\] and hepatitis B e antigen \[Hbe Ag\] negative) may be included after consultation with the medical monitor.
  • Primary sclerosing cholangitis (PSC) Alcoholic liver disease Definite autoimmune liver disease or overlap hepatitis Nonalcoholic steatohepatitis (NASH) Gilbert's Syndrome (due to interpretability of bilirubin levels)Child-pugh grade B or C
• Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
  • History of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥ 15 Portal hypertension with complications, including: known gastric or large esophageal varices, poorly controlled or diuretic resistant ascites, history of variceal bleeds or related therapeutic or prophylactic interventions (for example, beta blockers, insertion of variceal bands or transjugular intrahepatic portosystemic shunt \[TIPS\]), or hepatic encephalopathy Cirrhosis with complications, including history or presence of: spontaneous bacterial peritonitis, hepatocellular carcinoma, bilirubin \> 2x ULN Hepatorenal syndrome (type I or II) or Screening serum creatinine \> 2 mg/deciliter dL) (178 micromoles \[µmol\])/liter \[L\])
• Administration of the following drugs within 1 month prior to the first dose: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline, bicyclol and with S.chinensis ingredients; fenofibrate or other fibrates; budesonide and other systemic corticosteroids; hepatotoxic drugs (including α-methyldopa, sodium valproate, isoniazid, nitrofurantoin, etc.);
• ALT≥ 10 × ULN with/or ALT≥ 10 × ULN;
• Direct bilirubin\>3×ULN;
• Serum creatinine (Cr) ≥ 1.5 × ULN and serum creatinine clearance \< 60 mL/min;
• History or presence of clinically concerning cardiac arrhythmias likely to affect survival during the trial, or prolongation of Screening (pretreatment) QT or QTc interval;

Age

• Medical conditions that may cause nonhepatic increases in ALP (for example, Paget's disease) or which may diminish life expectancy to \< 2 years, including known cancers (except carcinomas in situ or other stable, relatively benign conditions such as chronic lymphatic leukemia)

Other

• Women who are pregnant or lactating;
• Mental instability or incompetence;
• Other circumstances that are deemed not appropriate for the study by the investigator.

• Definite PBC diagnosis, as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors: ① Indicators reflecting cholestasis such as elevated ALP；② Positive antimitochondrial antibody (AMA) or AMA-M2, or positive PBC-specific antibody (anti-GP210 and/or anti-SP100) if AMA negative；③ Liver biopsy consistent with PBC;
• At least 1 of the following qualifying biochemistry values: ① ALP ≥ 1.67x ULN；② Total bilirubin \> ULN but \< 2x ULN；
• Taking UDCA for at least 6 months (stable dose for ≥ 2 months) prior to the first dose；
• Patients of childbearing potential must agree to take contraception during the study and for 1 month after the last day of treatment;
• Patients capable of giving written informed consent.