Study to Evaluate the Effects of Two Doses of Seladelpar (MBX-8025) in Subjects With Primary Biliary Cirrhosis (PBC)
- Conditions
- Primary Biliary Cirrhosis (PBC)
- Interventions
- Drug: Placebo Comparator
- Registration Number
- NCT02609048
- Lead Sponsor
- Gilead Sciences
- Brief Summary
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).
- 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)
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 41
-
Must have given written informed consent (signed and dated) and any authorizations required by local law
-
18 to 75 years old (inclusive)
-
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
-
On a stable and recommended dose of UDCA for the past twelve months
-
AP ≥ 1.67 × ULN
-
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
- 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)
- Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3 × ULN
- Total bilirubin > 2 × ULN
- Auto-immune hepatitis
- Primary sclerosing cholangitis
- Known history of alpha-1-Antitrypsin deficiency
- Known history of chronic viral hepatitis
- Creatine kinase above ULN
- Serum creatinine above ULN
- For females, pregnancy or breast-feeding
- Use of colchicine, methotrexate, azathioprine, or systemic steroids in the two months preceding screening
- Current use of fibrates, including fenofibrates, or simvastatin
- Use of an experimental treatment for PBC
- Use of experimental or unapproved immunosuppressant
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Dose Placebo Comparator Participants received 2 placebo-to-match (PTM) seladelpar capsules, orally, once daily for 12 weeks. Seladelpar 50 mg Dose Placebo Comparator Participants received seladelpar 50 mg capsule (1 x 50 mg capsule) and a PTM seladelpar capsule, orally, once daily for 12 weeks.
- Primary Outcome Measures
Name Time Method Baseline Alkaline Phosphatase (AP) Levels Baseline Baseline for AP level was defined as the mean between assessments at Visit 1 (Week -4 to Week 0) and Visit 2 (Week 0).
Percent Change From Baseline in Alkaline Phosphatase (AP) Levels Baseline, Week 12 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).
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Response as Determined by Composite Endpoint of Alkaline Phosphatase and Total Bilirubin Week 12 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 \[0.1-1.1 milligrams/deciliter (mg/dL)\].
Percent Change From Baseline in Aspartate Aminotransferase (AST) Baseline, Week 12 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.
Percent Change From Baseline in Alanine Aminotransferase (ALT) Baseline, Week 12 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.
Percent Change From Baseline in Gamma-glutamyl Transferase (GGT) Baseline, Week 12 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.
Percent Change From Baseline in 5'Nucleotidase (5NT) Baseline, Week 12 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.
Percent Change From Baseline in Total Bilirubin Baseline, Week 12 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.
Percent Change From Baseline in Conjugated Bilirubin Baseline, Week 12 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.
Percent Change From Baseline in Unconjugated Bilirubin Baseline, Week 12 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.
Percent Change From Baseline in Bone-specific AP Levels Baseline, Week 12 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.
Percent Change From Baseline in Triglycerides (TG) Baseline, Week 12 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.
Percent Change From Baseline in Total Cholesterol (TC) Baseline, Week 12 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.
Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) Baseline, Week 12 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.
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) Baseline, Week 12 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.
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Paris I) Week 12 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.
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Paris II) Week 12 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.
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Toronto I) Week 12 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.
Number of Participants Who Were Non-responders as Determined by Published PBC Response Criteria (Toronto II) Week 12 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.
United Kingdom-Primary Biliary Cirrhosis/Cholangitis (UK-PBC) Risk Score Week 12 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
Change From Baseline in 5-Dimension (5-D) Itch Scale Score Baseline, Week 12 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.
Change From Baseline in Pruritus Visual Analog Scale (VAS) Score Baseline, Week 12 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.
Change From Baseline in PBC-40 Quality of Life Questionnaire Baseline, Week 12 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.
Trial Locations
- Locations (49)
Gastroenterology Associates of Western Michigan, PLC, d.b.a. West Michigan Clinical Research
🇺🇸Wyoming, Michigan, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Wojewodzki Szpital Obserwacyjno-Zakazny im. Tadeusza w Bydgoszczy
🇵🇱Bydgoszcz, Kujawsko-pomorskie, Poland
Centrum Onkologii-Instytut Im. Marii Sklodowskiej-Curie
🇵🇱Warszawa, Mazowieckie, Poland
Derriford Hospital
🇬🇧Plymouth, England, United Kingdom
Digestive Helathcare of Georgia
🇺🇸Atlanta, Georgia, United States
Icahn School of Medicine at Mount Sinai - The Mount Sinai Medical Center
🇺🇸New York, New York, United States
SP CSK im. Prof. K. Gibinskiego SUM w Katowicach
🇵🇱Katowice, Slaskie, Poland
Norman Gitlin, MD
🇺🇸Atlanta, Georgia, United States
Universitatsmedizin der Johannes Gutenberg - Universitat Mainz
🇩🇪Mainz, Germany
Consultants for Clinical Research
🇺🇸Cincinnati, Ohio, United States
Gastroenterologische Gemeinschaftspraxis Herne
🇩🇪Herne, Germany
Universitatsklinikum Leipzig AOR
🇩🇪Leipzig, Germany
Charite Universitatsmedizin Berlin - Campus Mitte
🇩🇪Berlin, Germany
University Hospital Birmingham NHS Foundation Trust
🇬🇧Birmingham, United Kingdom
Toronto General Hospital
🇨🇦Toronto, Ontario, Canada
Universitatsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪Dresden, Germany
Medizinische Universitatsklinik
🇩🇪Heidelberg, Germany
SPZOZ Szpital Uniwersytecki w Krakowie
🇵🇱Krakow, Malopolski, Poland
NYU Langone Medical Center
🇺🇸New York, New York, United States
Universitatsklinikum Bonn
🇩🇪Bonn, Germany
UKSH, Campus Kiel
🇩🇪Kiel, Germany
Digestive and Liver Disease Specialists
🇺🇸Norfolk, Virginia, United States
University of Calgary Liver Unit (Heritage Medical Research Clinic)
🇨🇦Calgary, Alberta, Canada
Ifi-Studien und Projekte GmbH, A.d. Asklepios Klinik St. Georg
🇩🇪Hamburg, Germany
Universitatsklinikum Hamburg-Eppendorf MARTINISTRASSE 52
🇩🇪Hamburg, Germany
Universitatsklinikum Essen, Zentrum fur Innere Medizin
🇩🇪Essen, Germany
Addenbrooke Hospital
🇬🇧Cambridge, United Kingdom
Leber- und Studienzentrum am Checkpoint
🇩🇪Berlin, Germany
University Hospital Erlangen
🇩🇪Erlangen, Germany
UKSH, Campus Kiel, Klinik fur Allgemeine Innere Medizin 1
🇩🇪Kiel, Germany
ID Clinic Arkadiusz Pisula
🇵🇱Myslowice, Slaskie, Poland
Mayo Clinic of Arizona
🇺🇸Phoenix, Arizona, United States
University of Miami, Center for Liver Diseases
🇺🇸Miami, Florida, United States
University of California, Davis Medical Center
🇺🇸Sacramento, California, United States
Indiana University Hospital - Clinical Research Center
🇺🇸Indianapolis, Indiana, United States
University of Nebraska Medical Center / The Nebraska Medical Center
🇺🇸Omaha, Nebraska, United States
St. Louis University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Pinnacle Clinical Research
🇺🇸Live Oak, Texas, United States
North Shore-Long Island Jewish Health System / Division of Gastroenterology
🇺🇸Manhasset, New York, United States
CHI St. Luke's Health Baylor College of Medicine Medical Center - Advanced Liver Therapies
🇺🇸Houston, Texas, United States
Med. Hochschule Hannover, Klinik fur Gastroenterologie
🇩🇪Hannover, Germany
Hull and East Yorkshire NHS Trust
🇬🇧Hull, United Kingdom
The Newcastle upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle upon Tyne, United Kingdom
Nottingham University Hospitals NHS Trust
🇬🇧Nottingham, United Kingdom
University of Florida
🇺🇸Gainesville, Florida, United States
Kansas City Gastroenterology and Hepatology
🇺🇸Kansas City, Missouri, United States
American Research Corporation at Texas Liver Institute
🇺🇸San Antonio, Texas, United States
Bon Secours St. Mary's Hospital of Richmond
🇺🇸Newport News, Virginia, United States