Ensayos clínicos

Inclusion Criteria:

1. Must have provided written informed consent
2. Definite or probable PBC diagnosis as demonstrated by the presence of at least 2 of the following 3 diagnostic factors:
   • History of elevated ALP levels for at least 6 months prior to Day 0 (randomization visit)
   • Positive Anti-Mitochondrial Antibodies (AMA) titers (> 1/40 on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay (ELISA)
   • Liver biopsy consistent with PBC
3. ALP ≥ 1.67x upper limit of normal (ULN) (‘inadequate response to UDCA’)
4. Taking UDCA for at least 12 months (stable dose for ≥ 6 months) prior to screening visit
5. Contraception: Females participating in this study must be of non-childbearing potential or must be using highly efficient contraception for the full duration of the study and for 1 month after the end of treatment.

Exclusion Criteria:

1. History or presence of other concomitant liver diseases:
   • Positive hepatitis B surface antigen (HBsAg) at Screening
   • Positive HCV RNA (tested for in case of known cured HCV infection, or positive
   • HCV Ab at Screening)
   • Alcoholic liver disease
   • Primary sclerosing cholangitis (PSC)

   • Definite autoimmune hepatitis (AIH), or ‘AIH-PBC overlap syndrome’; (the existence of) AIH is defined as continuing use of budesonide or other systemic corticosteroid therapy, and/or azathioprine, and/or other immunosuppressive therapy following an historical AIH diagnosis (EASL 2015). ‘AIH-PBC overlap syndrome’ is based upon fulfilment of the Paris criteria (Chazouilléres 1998)for both AIH (ALT ≥5x ULN; IgG ≥2x ULN or smooth muscle antibody; interface hepatitis), and PBC (ALP ≥2x ULN; AMA, and non-suppurative bile duct injury/destruction),, and requiring corticosteroid therapy for disease management, either currently or in the past.

2. Biopsy confirmed Nonalcoholic Steatohepatitis NASH)
3. Known history of alpha-1 antitrypsin deficiency, or other metabolic forms of chronic liver disease.
4. Gilbert's Syndrome (due to interpretability of bilirubin levels)
5. Screening CPK > ULN
6. Screening ALT or AST > 5 ULN
7. Screening total bilirubin > 2 ULN
8. Screening serum creatinine > 1.5 mg/dl and eGFR < 60 mL/min/1.73 m2,
9. Significant renal disease, including nephritic syndrome, chronic kidney disease (defined as patients with markers of kidney damage or estimated glomerular filtration rate [eGFR] of less than 60 mL/min/1.73 m2).
10. Patients with moderate or severe hepatic impairment (defined as Child-Pugh B/C)
11. Platelet count <150 X 10 3/microliter
12. Albumin <3.5 g/dL
13. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:
    • Current Model for End-Stage Liver Disease score ≥15; current placement on a liver transplant waiting list, or history of undergoing liver transplantation.
    • Any record of complications of cirrhosis and/or portal hypertension such as:
    • Gastroesophageal variceal bleeding and endoscopic therapy and/or transjugular intrahepatic portosystemic shunt [TIPS] insertion
    • Ascites formation requiring intervention, e.g. diuretic therapy
    • Spontaneous bacterial peritonitis
    • Hepatic encephalopathy
    • Confirmed or suspected hepatocellular carcinoma
14. If female: known pregnancy, or has a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
15. Known history of human immunodeficiency virus (HIV) infection
16. Medical conditions that may cause non-hepatic increases in ALP (e.g., Paget's disease)
17. Hepatorenal syndrome (type I or II) Administration of the following medications is prohibited as specified below:
    • From pre-randomization to EOT or V5 visit : indomethacin
    • 2 months preceding screening throughout the trial (up to last study visit) : fibrates or obeticholic acid, thiazoledinediones (glitazones)
    • 3 months prior to screening and throughout the trial (up to last study visit) : azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other chronic systemic corticosteroids; and potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
    • 12 months prior to inclusion visit and throughout the trial (up to last study visit): antibodies or immunotherapy directed against interleukins or other cytokines or chemokines NOTE : Anti-pruritus treatment, including rifamycin, is allowed if prescribed for at least 6 months prior to screening, and on stable dose at least 3 months prior to screening. and continues at the same dose throughout the study