Clinical Trials

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:
  • 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 immunofluorescence 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 24 weeks of stable treatment at a dose of ≤ 20 mg/kg/day; OR
  • A minimum of 12 weeks off treatment and consequently determined by the investigator to be clinically stable.
• Systemic therapies intended to address cholestatic pruritus, specifically fibrates, selective serotonin reuptake inhibitors, rifampin/rifampicin, and opioid-receptor antagonists are allowed if one of the following criteria is met at the screening visit:
  • A minimum of 12 weeks of stable treatment; OR
  • 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 score in the eDiary during:
  • Screening in order to be enrolled in the study at Visit 2;
  • Single-blind, placebo run-in in order to be randomized at Visit 4.
• Willing to maintain an ≥ 80% average in daily completion of the Adult ItchRO between Visits 2 and 10.

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;
  • 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 nonalcoholic steatohepatitis;
  • 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 malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea).
• 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).
• 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 duration.
• Positive for HIV antibody.
• Specific clinically significant ECG abnormalities, including but not limited to:
  • Evidence of acute ischemia;
  • Q-wave infarction identified within 6 months of screening visit;
  • QT interval corrected using Fridericia’s correction formula (QTcF) > 470 msec (unless individual has a pacemaker);
  • Congenital long QT syndrome;
  • Active conduction abnormalities including:
    • Mobits Type II second-degree heart block without a permanent pacemaker;
    • Third-degree heart block without a permanent pacemaker;
    • Untreated supraventricular tachycardia (heart rate ≥ 120 beats per minute);
    • Ventricular arrhythmias (i.e., ventricular tachycardia, ventricular fibrillation, torsade de pointes);
    • Uncontrolled atrial fibrillation.
• Results provided by the central laboratory for any of the following laboratory parameters collected during the screening visit:
  • Platelet count ≤ 100,000/mm^3;
  • Estimated glomerular filtration rate ≤ 45 mL/min, as calculated by the Chronic Kidney Disease-Epidemiology Collaboration equation;
  • Serum creatinine > 2 mg/dL (178 μmol/L);
  • ALT or AST > 5 × ULN.
  • Note: If ALT at Visit 2 or at an unscheduled visit during the single-blind, placebo run-in is > 5 × ULN, the participant may still be enrolled if the average of the 2 ALT values from the screening visit and the eligible repeat assessment remain ≤ 5 × ULN;
  • Total bilirubin > 2 × ULN, unless the individual has a diagnosis of Gilbert syndrome or hemolytic anemia as confirmed by investigator and direct bilirubin is within normal range (i.e., 0.1–0.3 mg/dL [1.7–5.1μmol/L]).
    • Note: If total bilirubin at Visit 2 or at an unscheduled visit during the single-blind, placebo run-in is > 2 × ULN, he or she may still be enrolled if the average of the 2 total bilirubin values from the screening visit and the eligible repeat assessment remain ≤ 2 × ULN;
    • International normalized ratio (INR) ≥ 1.7 unless due to therapeutic anticoagulation.
• Statin dosing that is not stable for a minimum of 12 weeks prior to the screening visit.
• Use of obeticholic acid treatment within 12 weeks prior to the screening visit.
• Use of an ASBT inhibitor within 24 weeks prior to the screening visit.
• Bile acid sequestrants, including cholestyramine and colestipol, within 4 weeks prior to the screening visit.
• Use of any other prohibited medication including for PBC and cholestatic pruritus as listed in the protocol within 4 weeks or 5 times the half-life, whichever is greater, prior to the screening visit.
• 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 OLE.

Eligibility last updated 5/13/22. Questions regarding updates should be directed to the study team contact.