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

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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:
Information provided by (Responsible Party):
CymaBay Therapeutics, Inc.

Study Description
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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.


Condition or disease Intervention/treatment Phase
Primary Biliary Cholangitis Drug: seladelpar 5-10 mg Drug: seladelpar 10 mg Drug: Placebo Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 265 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 1, 2018
Actual Primary Completion Date : February 16, 2020
Actual Study Completion Date : February 16, 2020

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Seladelpar 5-10 mg 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
Experimental: Seladelpar 10 mg 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
Placebo Comparator: Placebo 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


Outcome Measures
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Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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.

  2. 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03602560


Locations
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Sponsors and Collaborators
CymaBay Therapeutics, Inc.
  Study Documents (Full-Text)

Documents provided by CymaBay Therapeutics, Inc.:
Study Protocol  [PDF] July 3, 2018
Statistical Analysis Plan  [PDF] April 30, 2020

More Information
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Responsible Party: CymaBay Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT03602560    
Other Study ID Numbers: CB8025-31735
First Posted: July 27, 2018    Key Record Dates
Results First Posted: May 31, 2022
Last Update Posted: August 2, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by CymaBay Therapeutics, Inc.:
PBC
Primary Biliary Cholangitis (PBC)
Additional relevant MeSH terms:
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Cholangitis
Liver Cirrhosis, Biliary
Bile Duct Diseases
Biliary Tract Diseases
Digestive System Diseases
Cholestasis, Intrahepatic
Cholestasis
Liver Diseases
 Liver Cirrhosis
Fibrosis
Pathologic Processes
Seladelpar
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents