Study to Evaluate the Effects of Two Doses of Seladelpar (MBX-8025) in Subjects With Primary Biliary Cirrhosis (PBC)

A 12-week, Double-blind, Randomized, Placebo-controlled, Phase 2 Study, to Evaluate the Effects of Two Doses of MBX-8025 in Subjects With Primary Biliary Cirrhosis (PBC) and an Inadequate Response to Ursodeoxycholic Acid (UDCA)

The primary objective of this study is to evaluate the effect of seladelpar (MBX-8025) on alkaline phosphatase (AP) levels in participants with primary biliary cirrhosis (PBC).

Study Overview

• Status: Terminated
• Conditions: Primary Biliary Cirrhosis (PBC)
• Intervention / Treatment: Drug: Placebo Comparator; Drug: Experimental: Seladelpar 50 mg; Drug: Experimental: Seladelpar / MBX-8025 200 mg

Detailed Description

Primary:

To evaluate the effect of MBX-8025 on Alkaline Phosphatase (AP) levels

Secondary:

To evaluate the safety and tolerability of MBX-8025 in subjects with Primary Biliary Cirrhosis (PBC) To evaluate the effects of MBX-8025 on Primary Biliary Cirrhosis (PBC) response criteria To evaluate the effects of MBX-8025 on other markers of liver function, lipids, pruritus and Quality of Life (QoL)

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary Liver Unit (Heritage Medical Research Clinic)
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital
• Germany
  • Berlin, Germany, 10969
    • Leber- und Studienzentrum am Checkpoint
  • Berlin, Germany, 10117
    • Charité Universitätsmedizin Berlin - Campus Mitte
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus an der TU Dresden
  • Erlangen, Germany, 91054
    • University Hospital Erlangen
  • Essen, Germany, 45157
    • Universitatsklinikum Essen, Zentrum fur Innere Medizin
  • Hamburg, Germany, 20099
    • Ifi-Studien und Projekte GmbH, A.d. Asklepios Klinik St. Georg
  • Hamburg, Germany, 20246
    • Universitatsklinikum Hamburg-Eppendorf MARTINISTRASSE 52
  • Hannover, Germany, 30625
    • Med. Hochschule Hannover, Klinik fur Gastroenterologie
  • Heidelberg, Germany, 69120
    • Medizinische Universitätsklinik
  • Herne, Germany, 44623
    • Gastroenterologische Gemeinschaftspraxis Herne
  • Kiel, Germany, 24105
    • UKSH, Campus Kiel, Klinik fur Allgemeine Innere Medizin 1
  • Kiel, Germany, 24105
    • UKSH, Campus Kiel
  • Leipzig, Germany, 04103
    • Universitätsklinikum Leipzig AöR
  • Mainz, Germany, 55131
    • Universitätsmedizin der Johannes Gutenberg - Universität Mainz
• Poland
  • Kujawsko-pomorskie
    • Bydgoszcz, Kujawsko-pomorskie, Poland, 85-030
      • Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza w Bydgoszczy
  • Malopolski
    • Krakow, Malopolski, Poland, 31-531
      • SPZOZ Szpital Uniwersytecki w Krakowie
  • Mazowieckie
    • Warszawa, Mazowieckie, Poland, 02-781
      • Centrum Onkologii-Instytut im. Marii Sklodowskiej-Curie
  • Slaskie
    • Katowice, Slaskie, Poland, 40-752
      • SP CSK im. Prof. K. Gibinskiego SUM w Katowicach
    • Myslowice, Slaskie, Poland, 41-400
      • ID Clinic Arkadiusz Pisula
• United Kingdom
  • Birmingham, United Kingdom, B15 2GW
    • University Hospital Birmingham NHS Foundation Trust
  • Cambridge, United Kingdom, CB2 0QQ
    • Addenbrooke Hospital
  • Hull, United Kingdom, HU3 2JZ
    • Hull and East Yorkshire NHS Trust
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • The Newcastle Upon Tyne Hospitals NHS Foundation Trust
  • Nottingham, United Kingdom, NG7 2UH
    • Nottingham University Hospitals NHS Trust
  • England
    • Plymouth, England, United Kingdom, PL6 8DH
      • Derriford Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic of Arizona
  • California
    • Sacramento, California, United States, 95817
      • University of California, Davis Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Center for Liver Diseases
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Norman Gitlin, MD
    • Atlanta, Georgia, United States, 30309
      • Digestive Helathcare of Georgia
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Hospital - Clinical Research Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Wyoming, Michigan, United States, 49519
      • Gastroenterology Associates of Western Michigan, PLC, d.b.a. West Michigan Clinical Research
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Kansas City Gastroenterology and Hepatology
    • Saint Louis, Missouri, United States, 63110
      • St. Louis University School of Medicine
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center / The Nebraska Medical Center
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore-Long Island Jewish Health System / Division of Gastroenterology
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai - The Mount Sinai Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45249
      • Consultants for Clinical Research
  • Texas
    • Houston, Texas, United States, 77030
      • CHI St. Luke's Health Baylor College of Medicine Medical Center - Advanced Liver Therapies
    • Live Oak, Texas, United States, 78233
      • Pinnacle Clinical Research
    • San Antonio, Texas, United States, 78215
      • American Research Corporation at Texas Liver Institute
  • Virginia
    • Newport News, Virginia, United States, 23602
      • Bon Secours St. Mary's Hospital of Richmond
    • Norfolk, Virginia, United States, 23502
      • Digestive and Liver Disease Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 upper limit of normal (ULN) for at least six months
   • Positive Anti-Mitochondrial Antibodies (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
5. AP ≥ 1.67 × ULN
6. For females of reproductive potential, use of at least one barrier contraceptive and a second effective birth control method during the study and for at least two weeks after the last dose. For male subjects, use of appropriate contraception (e.g., condoms), so their female partners of reproductive potential do not become pregnant during the study and for at least two weeks after the last dose

Exclusion Criteria:

1. 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 on active treatment)
2. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3 × ULN
3. Total bilirubin > 2 × ULN
4. Auto-immune hepatitis
5. Primary sclerosing cholangitis
6. Known history of alpha-1-Antitrypsin deficiency
7. Known history of chronic viral hepatitis
8. Creatine kinase above ULN
9. Serum creatinine above ULN
10. For females, pregnancy or breast-feeding
11. Use of colchicine, methotrexate, azathioprine, or systemic steroids in the two months preceding screening
12. Current use of fibrates, including fenofibrates, or simvastatin
13. Use of an experimental treatment for PBC
14. Use of experimental or unapproved immunosuppressant
15. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Dose; Participants received 2 placebo-to-match (PTM) seladelpar capsules, orally, once daily for 12 weeks.	Drug: Placebo Comparator; Placebo Capsule; Other Names: Placebo
Experimental: Seladelpar 50 mg Dose; Participants received seladelpar 50 mg capsule (1 x 50 mg capsule) and a PTM seladelpar capsule, orally, once daily for 12 weeks.	Drug: Placebo Comparator; Placebo Capsule; Other Names: Placebo; Drug: Experimental: Seladelpar 50 mg; Seladelpar 50 mg capsule; Other Names: MBX-8025; Livdelzi®
Experimental: Seladelpar 200 mg Dose; Participants received seladelpar 200 mg capsules (2 x 100 mg capsules), orally, once daily for 12 weeks.	Drug: Experimental: Seladelpar / MBX-8025 200 mg; Seladelpar 100 mg capsules; Other Names: MBX-8025; Livdelzi®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Alkaline Phosphatase (AP) Levels	Baseline for AP level was defined as the mean between assessments at Visit 1 (Week -4 to Week 0) and Visit 2 (Week 0).	Baseline
Percent Change From Baseline in Alkaline Phosphatase (AP) Levels	Percent change in AP serum levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by last observation carried forward (LOCF). Baseline for AP level was defined as the mean between assessments at Visit 1 (Week -4 to Week 0) and Visit 2 (Week 0).	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Response as Determined by Composite Endpoint of Alkaline Phosphatase and Total Bilirubin	Participants were defined as responders for the composite endpoint of AP and total bilirubin if their AP level was <1.67 × upper limit of normal (ULN) and had decreased at least 15% from their Baseline level and their total bilirubin value was within the normal range [0.1-1.1 milligrams/deciliter (mg/dL)].	Week 12
Percent Change From Baseline in Aspartate Aminotransferase (AST)	Percentage change in AST levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for AST level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Alanine Aminotransferase (ALT)	Percentage change in ALT levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for ALT level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Gamma-glutamyl Transferase (GGT)	Percentage change in GGT levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for GGT level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in 5'Nucleotidase (5NT)	Percentage change in 5'Nucleotidase levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for 5NT level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Total Bilirubin	Percentage change in total bilirubin levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for total bilirubin level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Conjugated Bilirubin	Percentage change in conjugated bilirubin levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for conjugated bilirubin level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Unconjugated Bilirubin	Percentage change in unconjugated bilirubin levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for unconjugated bilirubin level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Bone-specific AP Levels	Percentage change in bone-specific AP levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for bone-specific level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Triglycerides (TG)	Percentage change in TG levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for TG level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Total Cholesterol (TC)	Percentage change in TC levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for TC level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C)	Percentage change in HDL-C levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for HDL-C level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C)	Percentage change in LDL-C levels from Baseline to the end of treatment was analyzed. For missing postbaseline data, the last non-missing postbaseline value on treatment was carried forward, with missing assessments imputed by LOCF. Baseline for LDL-C level was defined as the last non-missing assessments prior to or on the date of the first study dose.	Baseline, Week 12
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Paris I)	Published criteria for response to treatment in PBC included Paris I criteria. For Paris I, the criteria used to measure the PBC participants' response to study treatment was: AP ≤ 3x ULN and AST ≤ 2x ULN and Total Bilirubin ≤ 1 mg/dL. Participants who satisfied the criteria were defined as responders and those who did not were considered nonresponders if all the elements had non-missing assessments at that visit. The number of nonresponders were reported, the missing assessments were imputed by LOCF.	Week 12
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Paris II)	Published criteria for response to treatment in PBC included Paris II criteria. For Paris II, the criteria used to measure the PBC participants' response to study treatment was: AP ≤ 1.5x ULN and AST ≤ 1.5x ULN and Total Bilirubin ≤ 1 mg/dL. Participants who satisfied the criteria were defined as responders and those who did not were considered nonresponders if all the elements had non-missing assessments at that visit. The number of nonresponders were reported, the missing assessments were imputed by LOCF.	Week 12
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Toronto I)	Published criteria for response to treatment in PBC included Toronto I criteria. For Toronto I, the criteria used to measure the PBC participants' response to study treatment was: AP ≤ 1.67x ULN. Participants who satisfied the criteria were defined as responders and those who did not were considered nonresponders if all the elements had non-missing assessments at that visit. The number of nonresponders were reported, the missing assessments were imputed by LOCF.	Week 12
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Toronto II)	Published criteria for response to treatment in PBC included Toronto II criteria. For Toronto II, the criteria used to measure the PBC participants' response to study treatment was: AP ≤ 1.76x ULN. Participants who satisfied the criteria were defined as responders and those who did not were considered nonresponders if all the elements had non-missing assessments at that visit. The number of nonresponders were reported, the missing assessments were imputed by LOCF.	Week 12
United Kingdom-Primary Biliary Cirrhosis/Cholangitis (UK-PBC) Risk Score	The UK-PBC Risk Score was used to estimate the risk that a PBC participant would develop liver failure that would require liver transplantation within 5, 10 or 15 years from diagnosis. The UK-PBC Risk Score calculation was adapted based on the AP assessment, transaminases (refers to the ALT, where available, otherwise the AST assessment) and total bilirubin assessment respectively at end of treatment divided by its upper limits of the corresponding normal ranges; "albumin" and "platelet" refer to the baseline values of these parameters divided by their corresponding lower limits of normal ranges. Missing assessments at end of treatment was imputed by last observation carried forward (LOCF). The UK-PBC risk scores for 5, 10 and 15 years was calculated for each treatment group	Week 12
Change From Baseline in 5-Dimension (5-D) Itch Scale Score	The 5-D itch scale was used to for the multidimensional quantification of pruritus over time. It assessed five aspects of itching: degree, duration, direction, disability, and distribution.The 5-D itch Scale is a measure of itching that has been validated in patients with chronic pruritus to detect changes over time. A 5-D itch scale score typically ranges from 5 to 25 with a higher score indicating greater itch severity, where 5 represents no pruritus (itching) and 25 represents the most severe pruritus; Each dimension is scored separately, and the scores are added together to get a total 5-D itch score. Higher scores indicate worsening of itching. The total 5-D itch Scale score change from Baseline was calculated. Baseline for 5-D itch scale was defined as the last non-missing assessments prior to or on the date of the first study dose. Missing assessments at end of treatment was imputed by LOCF.	Baseline, Week 12
Change From Baseline in Pruritus Visual Analog Scale (VAS) Score	VAS was used to measure pruritis in participants with PBC. Participants placed a mark representing their level of itching since the previous measurement on a 100-mm VAS with 0 indicating no itching and 100 mm indicating the worst possible itching. Higher scores indicated worsening of itching The change from Baseline was presented by treatment group. Baseline for VAS score was defined as the last non-missing assessments prior to or on the date of the first study dose. Missing assessments at end of treatment was imputed by LOCF.	Baseline, Week 12
Change From Baseline in PBC-40 Quality of Life Questionnaire	The PBC-40 questionnaire was used to evaluate health-related quality of life measures, specifically fatigue. The PBC-40 questionnaire is a disease-specific tool developed to specifically measure the psychometric profile of PBC patients. It consists of 40 items divided into the six domains relevant to PBC including Cognitive, Social, EmotionalFunction, Fatigue, Itch, and Other Symptoms/General Questions. Items are scored from 1 to 5 and individual items scores are summed to give a total domain score. PBC 40 QoL domain score ranges are:Cognitive (6-30), Emotional Function (3-15),Fatigue (11-55), Itch (3-15),Social (10-50),Symptoms (7-35).Higher scores represent high impact and lower scores low impact of PBC on quality of life.The change and percentage change from Baseline for individual domain score at end of treatment were reported. Baseline for PBC-40 questionnaire was the last non-missing assessments prior to or on the date of the first study dose.Missing assessments imputed by LOCF.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Chair: Pol F Boudes, M.D., Gilead Sciences

Publications and helpful links

General Publications

• Jones D, Boudes PF, Swain MG, Bowlus CL, Galambos MR, Bacon BR, Doerffel Y, Gitlin N, Gordon SC, Odin JA, Sheridan D, Worns MA, Clark V, Corless L, Hartmann H, Jonas ME, Kremer AE, Mells GF, Buggisch P, Freilich BL, Levy C, Vierling JM, Bernstein DE, Hartleb M, Janczewska E, Rochling F, Shah H, Shiffman ML, Smith JH, Choi YJ, Steinberg A, Varga M, Chera H, Martin R, McWherter CA, Hirschfield GM. Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol. 2017 Oct;2(10):716-726. doi: 10.1016/S2468-1253(17)30246-7. Epub 2017 Aug 14.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2015
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: November 13, 2015
• First Submitted That Met QC Criteria: November 18, 2015
• First Posted (Estimated): November 20, 2015

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 31, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: PBC
• Additional Relevant MeSH Terms: Pathologic Processes; Digestive System Diseases; Biliary Tract Diseases; Liver Diseases; Bile Duct Diseases; Cholestasis, Intrahepatic; Cholestasis; Fibrosis; Liver Cirrhosis; Liver Cirrhosis, Biliary; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Seladelpar
• Other Study ID Numbers: CB8025-21528; 2015-002698-39 (EudraCT Number)