ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)
Condition: Primary Biliary Cholangitis
MeSH terms: Cholangitis; Liver Cirrhosis, Biliary
Intervention: seladelpar 5-10 mg; seladelpar 10 mg; Placebo
Intervention description: Seladelpar 5 mg for 6 months and then titrating up to 10 mg based on tolerability and response for remainder of double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects will continue the seladelpar dose (5 or 10 mg) received during the double-blinded study; Seladelpar 10 mg for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label safety study. Subjects will continue the seladelpar dose (10 mg) received during the double-blinded study; One capsule daily for double-blind period. After completion of the 1-year double-blind period subjects will be offered the opportunity to enter an open label long term safety study. Subjects on placebo will be re-randomized to initiate seladelpar at 5 or 10 mg once daily
Intervention MeSH terms: Seladelpar
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 265.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: PBC; Primary Biliary Cholangitis (PBC)

Summary:

      A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy
      of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response
      to or intolerance to ursodeoxycholic acid (UDCA)

      The participants might enter the ongoing open-label safety study (NCT03301506) following this
      double-blind study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Must have given written informed consent (signed and dated) and any authorizations
             required by local law

          2. 18 to 75 years old (inclusive)

          3. Male or female with a diagnosis of PBC, by at least two of the following criteria:

               -  History of AP above ULN for at least six months

               -  Positive anti-mitochondrial antibody (AMA) titers (>1/40 on immunofluorescence or
                  M2 positive by enzyme linked immunosorbent assay [ELISA]) or positive
                  PBC-specific antinuclear antibodies

               -  Documented liver biopsy result consistent with PBC

          4. On a stable and recommended dose of UDCA for the past twelve months OR intolerant to
             UDCA (last dose of UDCA > 3 months prior to Screening)

          5. AP ≥ 1.67 × ULN

          6. Females of reproductive potential must use at least one barrier contraceptive and a
             second effective birth control method during the study and for at least 90 days after
             the last dose. Male subjects who are sexually active with female partners of
             reproductive potential must use barrier contraception and their female partners must
             use a second effective birth control method during the study and for at least 90 days
             after the last dose

        Exclusion Criteria:

          1. Previous exposure to seladelpar (MBX-8025)

          2. A medical condition, other than PBC, that in the investigator's opinion would preclude
             full participation in the study or confound its results (e.g., cancer)

          3. AST above 3 × ULN

          4. ALT above 3 × ULN

          5. Total bilirubin above 2.0 × ULN

          6. Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total
             bilirubin above 1 × ULN)

          7. Creatine kinase (CK) above 1.0 × ULN

          8. eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula)

          9. International normalized ratio (INR) above 1.0 × ULN

         10. Platelet count below 100 × 103/µL

         11. Presence of clinically significant hepatic decompensation, including:

               -  History of liver transplantation, current placement on liver transplantation
                  list, or current MELD score ≥ 15

               -  Complications of portal hypertension, including known esophageal varices, history
                  of variceal bleeds or related interventions (e.g., transjugular intrahepatic
                  portosystemic shunt placement), relevant ascites, hepatic encephalopathy

               -  Cirrhosis with complications, including history or presence of spontaneous
                  bacterial peritonitis

         12. Other chronic liver diseases:

               -  Current features of auto-immune hepatitis as determined by the investigator based
                  on immunoserology, liver biochemistry and histology

               -  Primary sclerosing cholangitis determined by presence of diagnostic
                  cholangiographic findings

               -  History or clinical evidence of alcoholic liver disease

               -  History or clinical evidence of alpha-1-antitrypsin deficiency

               -  Biopsy confirmed nonalcoholic steatohepatitis

               -  History or evidence of Gilbert' Syndrome with elevated total bilirubin

               -  History or evidence of hemochromatosis

               -  Hepatitis B defined as presence of hepatitis B surface antigen (HBsAg)

               -  Hepatitis C defined as presence of HCV RNA

         13. Known history of HIV

         14. Evidence of significant alcohol consumption

         15. Evidence of drug abuse

         16. Subjects with inadequate response to obeticholic acid (OCA) or intolerance to OCA: OCA
             must be discontinued 30 days prior to Screening

         17. Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids
             (> 2 weeks) within two months prior to Screening

         18. Use of fibrates within 30 days prior to Screening

         19. Use of simvastatin within 7 days prior to Screening

         20. Use of an experimental or unapproved treatment for PBC within 30 days prior to
             Screening

         21. Use of experimental or unapproved immunosuppressant within 30 days prior to Screening

         22. Treatment with any other investigational therapy or device within 30 days or within
             five half-lives, whatever is longer, prior to Screening

         23. For females, pregnancy or breast-feeding

         24. Any other condition(s) that would compromise the safety of the subject or compromise
             the quality of the clinical study, as judged by the investigator