Ensayos clínicos

Inclusion Criteria:

• Willing and able to provide signed informed consent at the screening visit as well as comply with all study visits and requirements through the end of the study.
• Male or female, age ≥ 18 years at the screening visit.
• Have a diagnosis of PBC in line with the AASLD guidelines as demonstrated by having at least 2 of the following (Lindor et al. 2019):
  • History of sustained increased ALP levels > ULN first recognized at least 6 months prior to the screening visit (sustained ALP elevations at the time of screening is not required, recognizing that the ALP may have decreased on UDCA therapy);
  • Documented positive AMA titer (> 1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific ANA immuno-fluorescence patterns (multiple nuclear dots and/or punctuate nuclear rim);
  • Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. Liver biopsy could have been done at any time in the past.
• Those treated with UDCA will be allowed to enroll if they meet one of the following criteria at Visit 1:
  • A minimum of 8 weeks of stable treatment at a dose of ≤ 20 mg/kg/day; OR
  • A minimum of 8 weeks off treatment and consequently determined by the investigator to be clinically stable
• Systemic therapies intended to address cholestatic pruritus, specifically fibrates, SSRIs, rifampin/rifampicin, gabapentin, cholestyramine, and opioid-receptor antagonists are allowed if one of the following criteria is met at the screening visit:
  • A minimum of 8 weeks of stable treatment (12 weeks of stable treatment for cholestyramine) OR b. A minimum of 4 weeks off treatment.
• Average daily Adult ItchRO score ≥ 4 during screening to be enrolled in the study at Visit 2.
• Overall compliance of ≥ 80% in daily completion of the Adult ItchRO assessments during the screening period.
• To be eligible for randomization, participants must meet the following additional criteria specific to the 4-week, single-blind, placebo run-in period:
• Completion of ≥ 80% of Adult ItchRO assessments during the single-blind, placebo run‑in period.
• Study drug compliance of ≥ 80% during the single-blind, placebo run-in period

Exclusion Criteria:

• Pruritus associated with an etiology other than PBC.
• Evidence or clinical suspicion of decompensated cirrhosis or a history of decompensation events (e.g., variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome).
• Current symptomatic cholelithiasis or inflammatory gallbladder disease. Those with history of cholecystectomy ≥ 3 months before the screening visit may be eligible for enrollment.
• History of small bowel surgery/resection impacting the terminal ileum (e.g., ileostomy, ileo-anal pouch, or other surgeries/conditions) that may disrupt the enterohepatic circulation.
• Evidence, history, or suspicion of other liver diseases, including but not limited to:
  • Active hepatitis A or E infection;
  • Active hepatitis B infection as defined by the presence of hepatitis B surface antigen (HBsAg) or presence of hepatitis B virus DNA;
  • c. Hepatitis C as defined by the presence of hepatitis C virus (HCV) antibody and positive HCV RNA. Infection documented to have been cured for >1 year prior to the screening visit may be eligible;
  • Secondary sclerosing cholangitis, autoimmune hepatitis, PSC, immunoglobulin G4-related cholangitis, Wilson disease, alpha-1-antitrypsin deficiency, or hemochromatosis;
  • Suspected or proven cholangiocarcinoma or hepatocellular carcinoma;
  • History of liver transplantation;
  • Histologically confirmed diagnosis of NASH;
  • Alcohol-related liver disease.
• Unstable and/or serious medical disease that is likely to impair the participant’s ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea):
  • Previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed. The investigator should contact the sponsor medical monitor to discuss these cases and seek approval before the screening period.
• Moderate alcohol consumption as defined for this study by > 1 and > 2 standard drinks on average per day for women and men, respectively, within 24 weeks of screening visit. A standard drink is defined as 1.5 oz (one shot) of liquor, 5 oz of nonfortified wine, or 12 oz of beer (1 oz=29.57 mL; NIAAA).
• Drug abuse within the 24 weeks prior to, or a positive drug screening result, at the screening visit unless it can be explained by a drug prescription:
  • Use of cannabinoids (legal, prescribed, or otherwise) is allowed, provided use is stable for at least 12 weeks prior to screening and throughout the entire study.
• Women who are pregnant or nursing. Specific criteria for defining childbearing potential and acceptable methods of birth control are outlined in the protocol.
• Known intolerance/hypersensitivity to volixibat or its excipients.
• History of nonadherence to medical regimens, unreliability, medical condition, mental instability, or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures.
• Participation in an interventional clinical study within 4 weeks OR, if applicable, 5 times the half-life, whichever is greater, prior to the screening visit. Always adhere to other eligibility criteria that apply to specified concomitant medication.

Eligibility Criteria - Open-Label Extension:

To maintain eligibility for the OLE, participants must:

• Have successfully completed the 24-week double-blind study drug treatment period.
• Have not experienced an AE(s) or SAE(s) related to volixibat during the double-blind study treatment period that led to permanent discontinuation.
• Have no changes in their medical condition or treatment that would preclude their participation in the LTE period at the discretion of the investigator or medical monitor.
• Complete ≥ 80% of Adult ItchRO assessments during the double-blind study treatment period.

Eligibility last updated 12/20/23. Questions regarding updates should be directed to the study team contact.