ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)

• ClinicalTrials.gov Identifier: NCT03602560
• Recruitment Status: Completed
• First Posted: July 27, 2018
• Results First Posted: May 31, 2022
• Last Update Posted: August 2, 2022
• Sponsor: CymaBay Therapeutics, Inc.
• Information provided by (Responsible Party): CymaBay Therapeutics, Inc.

Tracking Information

• First Submitted Date: July 18, 2018
• First Posted Date: July 27, 2018
• Results First Submitted Date: March 23, 2022
• Results First Posted Date: May 31, 2022
• Last Update Posted Date: August 2, 2022
• Actual Study Start Date: October 1, 2018
• Actual Primary Completion Date: February 16, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 7, 2022)

Percentage of Participants With Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% Reduction in ALP, and Total Bilirubin ≤ ULN) at Month 3 [ Time Frame: Month 3 ]

Percentage of Participants with Response to Composite Endpoint of ALP <1.67 × Upper Limit of Normal [ULN], ≥15% reduction in ALP, and total bilirubin ≤ ULN) at Month 3. The mITT analysis set included all randomized subjects who received at least one study drug dose. The primary endpoint was analyzed using Cochran-Mantel-Haenszel (CMH) test adjusted for both randomization stratification variables (ALP level: <350 U/L and 2:350 U/L; pruritus NRS: <4 and 2:4). The CMH tests were performed for the comparison of 10 mg versus placebo and 5 mg/10 mg versus placebo separately.

Original Primary Outcome Measures (submitted: July 18, 2018)

Composite endpoint of AP and total bilirubin [ Time Frame: 12 months ]

• AP < 1.67 × ULN,
• ≥ 15% decrease in AP, and
• Total bilirubin ≤ ULN

Current Secondary Outcome Measures (submitted: July 7, 2022)

• Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3 [ Time Frame: Month 3 ]
  The response was defined by normalized ALP levels (ALP ≤1.0 × ULN) at endpoint. The mITT analysis set included all randomized subjects who received at least one study drug dose.
• Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3 [ Time Frame: Month 3 ]
  Pruritus Numerical Rating Scale (NRS) used to rate the intensity of the worst itching you experienced in the past 24 hours from no itching to worst possible itching by selecting a number from 0 to 10 on Itch Scale. Zero means no itching and 10 means worst imaginable itching. The analysis will be limited to those subjects in the mITT analysis set with a baseline NRS ≥ 4.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ENHANCE: Seladelpar in Subjects With Primary Biliary Cholangitis (PBC) and an Inadequate Response to or an Intolerance to Ursodeoxycholic Acid (UDCA)
• Official Title: 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 an Intolerance to Ursodeoxycholic Acid (UDCA)

Brief 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.

Detailed Description

Primary:

• To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo

Key Secondary:

• To evaluate the effect of seladelpar on normalization of alkaline phosphatase (AP) levels
• To evaluate the effect of seladelpar on pruritus

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Primary Biliary Cholangitis

Intervention

• Drug: seladelpar 5-10 mg
  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
• Drug: seladelpar 10 mg
  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
• Drug: Placebo
  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

Study Arms

• Experimental: Seladelpar 5-10 mg
  Intervention: Drug: seladelpar 5-10 mg
• Experimental: Seladelpar 10 mg
  Intervention: Drug: seladelpar 10 mg
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 26, 2021): 265
• Original Estimated Enrollment (submitted: July 18, 2018): 240
• Actual Study Completion Date: February 16, 2020
• Actual Primary Completion Date: February 16, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Canada, Chile, France, Germany, Greece, Hungary, Israel, Italy, Korea, Republic of, Mexico, Netherlands, New Zealand, Poland, Romania, Russian Federation, Serbia, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03602560
• Other Study ID Numbers: CB8025-31735
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: CymaBay Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: CymaBay Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: CymaBay Therapeutics, Inc.
• Verification Date: July 2022