Seladelpar (MBX-8025) in Subjects With Primary Biliary Cholangitis (PBC)

Primary Biliary Cirrhosis Clinical Trial

Official title:

An 8-week, Dose Ranging, Open Label, Randomized, Phase 2 Study With a 44-week Extension, to Evaluate the Safety and Efficacy of MBX-8025 in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or Intolerance to Ursodeoxycholic Acid (UDCA)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02955602
• Other study ID #: CB8025-21629
• Status: Completed
• Phase: Phase 2
• Start date: November 28, 2016
• Est. completion date: July 8, 2019

Study information

• Verified date: June 2022
• Source: CymaBay Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

An 8-week, dose ranging, open label, randomized, Phase 2 study with a 44-week extension, to evaluate the safety and efficacy of MBX-8025 in subjects with Primary Biliary Cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

Description:

Primary:

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 8 weeks of treatment

Secondary:

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 12 and 26 weeks of treatment

To evaluate the safety and efficacy of MBX-8025 2 mg, 5 mg, and 10 mg over 52 weeks of treatment

To evaluate the pharmacokinetics (PK) of MBX-8025

Exploratory:

To evaluate the effect of MBX-8025 on bile acids, additional markers of inflammation and renal function

MBX-8025 doses of 1 mg and 15 mg may be evaluated if dose adjustment occurs

Recruitment information / eligibility

• Status: Completed
• Enrollment: 119
• Est. completion date: July 8, 2019
• Est. primary completion date: September 7, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 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

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. 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. AST or ALT > 3 × ULN

3. Total bilirubin > 2.0 mg/dL

4. Total bilirubin > ULN AND albumin < LLN with the exception to subjects with Gilbert's Syndrome. Subjects with Gilbert's syndrome are excluded if Direct Bilirubin > ULN.

5. Auto-immune hepatitis

6. Primary sclerosing cholangitis

7. Known history of alpha-1-Antitrypsin deficiency

8. Known history of chronic viral hepatitis

9. Creatine kinase above ULN

10. Serum creatinine above ULN

11. For females, pregnancy or breast-feeding

12. Use of colchicine, methotrexate, azathioprine, or systemic steroids in the two months preceding screening

13. Current use of fibrates or simvastatin

14. Current use of obeticholic acid

15. Use of an experimental or unapproved treatment for PBC

16. Use of experimental or unapproved immunosuppressant

17. Adverse event leading to MBX-8025 discontinuation from CymaBay's phase 2 PBC study (CB8025-21528)

18. 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

Related Conditions & MeSH terms

• Cholangitis
• Liver Cirrhosis, Biliary
• Primary Biliary Cirrhosis

Intervention

Drug:
• MBX-8025 2 mg Capsule
Initial 8-week treatment: • MBX-8025 2 mg Extension: The 2 mg group will be started after safety and efficacy review of the 5 mg and the 10 mg groups has been completed. Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.
• MBX-8025 5 mg Capsule
Initial 8-week treatment: • MBX-8025 5 mg Extension: Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.
• MBX-8025 10 mg Capsule
Initial 8-week treatment: • MBX-8025 10 mg Extension: Subjects will initially enter the extension on their assigned dose. The dose might be up- or down-titrated after safety and efficacy data review of the first 8 weeks of treatment. During the extension, a subject's dose might be re-adjusted for safety or efficacy reasons.

Locations

Country	Name	City	State
Canada	University of Calgary Liver Unit	Calgary	Alberta
Canada	Toronto Centre for Liver Disease	Toronto	Ontario
Germany	Outpatient Clinic of Internal Medicine	Berlin
Germany	University Hospital Erlangen	Erlangen
Germany	Ifi-Studien und Projekte GmbH, An der Asklepios Klinik St. Georg	Hamburg
Germany	Center of Internal Medicine - Medical School of Hannover	Hannover
Germany	University Medical Centre of the Johannes Guttenberg-University	Mainz
Germany	Universitatsklinikum Giessen und Marburg GmbH	Marburg
Germany	Medizinische Universitatsklinik Tubingen	Tubingen
United Kingdom	University Hospitals Birmingham	Birmingham
United Kingdom	Cambridge University Hospitals NHS Foundation Trust	Cambridge
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust	Hull
United Kingdom	Royal Free London NHS Foundation Trust	London
United Kingdom	Plymouth Hospitals NHS Trust	Plymouth
United Kingdom	Portsmouth Hospitals NHS Trust	Portsmouth
United States	Atlanta Gastroenterology Associates, LLC	Atlanta	Georgia
United States	Digestive Healthcare of Georgia	Atlanta	Georgia
United States	Mercy Medical Center	Baltimore	Maryland
United States	Northest Clinical Research Center, LLC.	Bethlehem	Pennsylvania
United States	Institute for Liver Health	Chandler	Arizona
United States	Northwestern University	Chicago	Illinois
United States	Southern California Research Center	Coronado	California
United States	UT Southwestern Medical Center Investigation Drug Service	Dallas	Texas
United States	Baylor College of Medicine	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Florida Research Institute	Lakewood Ranch	Florida
United States	Gastroenterology Consultants of SA	Live Oak	Texas
United States	Northwell Health - Center for Liver Disease and Transplantation	Manhasset	New York
United States	University of Miami - Center for Liver Diseases	Miami	Florida
United States	NYU Langone Medical Center	New York	New York
United States	The Mount Sinai Medical Center	New York	New York
United States	Bon Secours St. Mary's Immaculate Hospital	Newport News	Virginia
United States	Henry Ford Health System	Novi	Michigan
United States	Standford University Medicine	Palo Alto	California
United States	University of California, Davis Medical Center	Sacramento	California
United States	Saint Louis University, Gastroenterology & Hepatology	Saint Louis	Missouri
United States	University of Washington	Seattle	Washington
United States	Ventura Clinical Trials	Ventura	California

Sponsors (1)

Lead Sponsor	Collaborator
CymaBay Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  Canada,  Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Relative Change From Baseline in Serum Alkaline Phosphatase (ALP) at Week 8	Relative change from baseline in serum ALP levels at Week 8 (endpoint). The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment. n, denotes number of subjects evaluable for the respective timepoints	8 weeks
Secondary	Absolute Change From Baseline in Serum Alkaline Phosphatase (ALP) at Week 12 and Week 52	Absolute change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change in Aspartate Aminotransferase (AST) From Baseline to 12 Weeks and 52 Weeks	Change from baseline in AST levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change in Alanine Aminotransferase (ALT) From Baseline to 12 Weeks and 52 Weeks	Change from baseline in ALT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change in Gamma-glutamyl Transferase (GGT) From Baseline to 12 Weeks and 52 Weeks	Change from baseline in GGT levels at endpoint was reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change in Bilirubin - Total Bilirubin (TB) From Baseline to 12 Weeks and 52 Weeks	Change from baseline in TB levels at endpoint is being reported. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Percentage of Participants Meet Composite Endpoint Criteria of ALP and Total Bilirubin	Participant meets composite endpoint is defined by participant meets all of the following criteria: ALP < 1.67 × upper limit of normal (ULN); Total Bilirubin within normal limit; > 15% decrease in ALP; Endpoint of Alkaline Phosphatase and Total Bilirubin by Visit (mITT Population)	12 Weeks and 52 Weeks
Secondary	Percentage of Participants Meet Published PBC Response Criteria - Paris I	Percentage of participants with response based on Paris I risk score was defined as ALP less than or equal to (=) 3x ULN and aspartate aminotransferase (AST) less than or equal to (=) 2 x ULN and Total Bilirubin = 1 mg/dL.; The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Percentage of Participants Meet Published PBC Response Criteria - Paris II	Percentage of participants with response based on Paris II risk score was defined as ALP=1.5xULN and AST=1.5xULN and Total Bilirubin = 1 mg/dL.; The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Percentage of Participants Meet Published PBC Response Criteria - Toronto I	Percentage of participants with response based on Toronto I risk score defined as ALP = 1.67 x ULN. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	UK-PBC Risk Score Value	The UK-PBC Risk Score at endpoint is defined by the mean percentage risk that a PBC patient treated with ursodeoxycholic acid (UDCA) would develop liver failure requiring liver transplantation in 5, 10 and 15 years from diagnosis. The higher the score might indicate higher risk to death or live transplantation. Formula used for UK-PBC risk score = 1- 0.982 ^EXP(0.0287854*(ALP12 x ULN-1.722136304) - 0.0422873*(((TA12 xULN/10)^-1) - 8.675729006) + 1.4199 * (LN(BIL12 x ULN/10)+2.709607778)-1.960303*(Albumin x LLN-1.17673001)-0.4161954*(Platelet x LLN-1.873564875)). Where, Baseline survivor function = 0.982, 0.941, and 0.893 for 5 years, 10 years and 15 years respectively. ALP12, TA12 and BIL12 refers to the ALP, transaminases (ALT, AST), and total bilirubin assessments, respectively. The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change From Baseline in Pruritus Visual Analog Score (VAS) at Week 12 and Week 52	VAS is the commonly used graphic tool for self-reporting of pruritus intensity in patients. VAS is a simple to use, validated, reliable and widely applicable tool that does not determine the impact of pruritus to quality of life. It comprises of a 100-mm horizontal line labelled as "no symptom" on left end and "worst imaginable symptom" on right end. Based on the intensity of the itch patient is instructed to draw a vertical line on the horizontal scale having a range [VAS values (unit: mm) ranging from 0 to 100, where 0 represents "no itching" and 100 "worst possible itching"].; The modified Intent-to-Treat (mITT) analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Change From Baseline in PBC-40 Quality of Life (QoL) at Week 12 and Week 52	The PBC-40 QoL questionnaire is a disease-specific health-related tool developed for measuring the psychometric profile in PBC patients. It has 10 domains and 43 questions relevant to PBC, including Cognitive, Social, Emotional Function, Fatigue, Itch, and Other Symptoms. Questions in domains: 1) digestion and diet (questions 1-3); 2) experiences (questions 4-7); 3) itching (questions 8-10); 4) fatigue (questions 11-18); 5) effort and planning (questions 19-21); 6) memory and concentration (questions 22-27); 7) affects to you as person (questions 28-33); 8) affects to your social life (questions 34-37); 9) overall impact on your life (questions 38-40); 10) general health and well-being (questions A-C). Within a domain, items are scored from 1 to 5 and the individual item scores are summed to give a total domain score. High scores represent high impact and low scores low impact of PBC on QoL (mITT Population).	12 weeks and 52 weeks
Secondary	Percentage of Participants Meet Published PBC Response Criteria - Barcelona	Percentage of participants with response based on Barcelona risk scores was defined as Normalization of ALP or a Decrease of ALP = 40%. The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Absolute Change in MELD Score From Baseline to 12 Weeks and 52 Weeks	Change from baseline to 12 weeks and 52 weeks in Model for End-stage Liver Disease (MELD) Score (mITT Population) The MELD score ranges from 6 to 40 and is a measure of how severe a patient's liver disease is. The higher the score, the more likely the patients will need a liver transplant. A calculated prognostic risk factor used to assess the potential need for a liver transplant.; MELD(i) score = 10*[0.957*ln(creatinine mg/dL) + 0. 378*ln(total bilirubin mg/dL) + 1.120*ln (INR) + 0.643].; If MELD(i) is less than or equal to 11 then MELD = MELD(i). If MELD(i) is greater than 11 then MELD = MELD(i) + (1.32 *(137 - (Na)) - (0.033*MELD(i)*(137 - Na))	12 weeks and 52 weeks
Secondary	Change in GLOBE PBC Score From Baseline to 12 Weeks and 52 Weeks	Change from Baseline to 12 weeks and 52 weeks in Global PBC Study Group (GLOBE) score (mITT Population); The GLOBE score is a validated risk assessment tool providing an estimate of transplant-free survival for patients with PBC. It was developed by the Global PBC Study Group using Cox regression model on over 4,000 patients with PBC. Lower GLOBE score predicts lower risk. It is calculated from the following equation: GLOBE score = (0.044378 * age + 0.93982 * LN(total bilirubin/ULN) +(0.335648 * LN(alkaline phosphatase/ULN)) - 2.266708 * albumin /LLN -0.002581 * platelet count per 109/L) + 1.216865	12 weeks and 52 weeks
Secondary	Participants Meet Rotterdam Criteria	participants with Response Based on Rotterdam Criteria at Weeks 12 and 52 Rotterdam Published PBC Response Criteria by Visit (mITT Population) Rotterdam criteria: Early (normal total bilirubin and normal albumin), Moderately advanced (either abnormal albumin or abnormal total bilirubin), and Advanced (both abnormal albumin and abnormal total bilirubin). From Early stage to Moderate Stage and to Advanced Stage, it becomes worse and worse in abnormality.	12 weeks and 52 weeks
Secondary	Percentage of Participants Meet Composite Endpoint of AP and Total Bilirubin Criteria at Week 12 and Week 52	Percentage of participants with Response Defined by Composite Endpoint (ALP< 1.67 * Upper Limit of Normal [ULN] at Endpoint, Total Bilirubin [BIL] within Normal Limits at Endpoint, and Greater Than Equal To [=] 15% ALP Reduction) from Baseline to Week 12 and Week 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks
Secondary	Percent Change in Serum Alkaline Phosphatase (ALP)	Percent change in ALP from baseline to Weeks 12 and 52 The mITT analysis set included all randomized subjects with confirmed PBC who received at least one study drug dose and had at least one post baseline ALP evaluation on treatment.	12 weeks and 52 weeks