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

Phase 2TerminatedNCT02609048

Gilead Sciences41 enrolled

Overview

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).

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Primary Biliary Cirrhosis (PBC)

Interventions

Placebo ComparatorDRUG

Placebo Capsule

Experimental: Seladelpar 50 mgDRUG

Seladelpar 50 mg capsule

Experimental: Seladelpar / MBX-8025 200 mgDRUG

Seladelpar 100 mg capsules

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

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

Locations (49)

Outcomes

Primary Outcomes

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).

Time frame: 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).

Time frame: Baseline, Week 12

Secondary Outcomes

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 \[0.1-1.1 milligrams/deciliter (mg/dL)\].

Time frame: 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.

Time frame: 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.

Data from ClinicalTrials.gov

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Mayo Clinic of Arizona

Phoenix, Arizona, United States

University of California, Davis Medical Center

Sacramento, California, United States

University of Florida

Gainesville, Florida, United States

University of Miami, Center for Liver Diseases

Miami, Florida, United States

Norman Gitlin, MD

Atlanta, Georgia, United States

Digestive Helathcare of Georgia

Atlanta, Georgia, United States

Indiana University Hospital - Clinical Research Center

Indianapolis, Indiana, United States

Henry Ford Health System

Detroit, Michigan, United States

Gastroenterology Associates of Western Michigan, PLC, d.b.a. West Michigan Clinical Research

Wyoming, Michigan, United States

Kansas City Gastroenterology and Hepatology

Kansas City, Missouri, United States

...and 39 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 12