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

Phase 3

Completed

Conditions: Primary Biliary Cholangitis

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

Registration Number: NCT03602560

Lead Sponsor: CymaBay Therapeutics, Inc.

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 265

Inclusion Criteria

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 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
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)
AP ≥ 1.67 × ULN
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

Previous exposure to seladelpar (MBX-8025)
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)
AST above 3 × ULN
ALT above 3 × ULN
Total bilirubin above 2.0 × ULN
Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total bilirubin above 1 × ULN)
Creatine kinase (CK) above 1.0 × ULN
eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula)
International normalized ratio (INR) above 1.0 × ULN
Platelet count below 100 × 103/µL
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
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
Known history of HIV
Evidence of significant alcohol consumption
Evidence of drug abuse
Subjects with inadequate response to obeticholic acid (OCA) or intolerance to OCA: OCA must be discontinued 30 days prior to Screening
Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (> 2 weeks) within two months prior to Screening
Use of fibrates within 30 days prior to Screening
Use of simvastatin within 7 days prior to Screening
Use of an experimental or unapproved treatment for PBC within 30 days prior to Screening
Use of experimental or unapproved immunosuppressant within 30 days prior to Screening
Treatment with any other investigational therapy or device within 30 days or within five half-lives, whatever is longer, prior to Screening
For females, pregnancy or breast-feeding
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
Seladelpar 5-10 mg	seladelpar 5-10 mg	-
Seladelpar 10 mg	seladelpar 10 mg	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
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	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

Name	Time	Method
Change From Baseline in Pruritus NRS for Subjects With Baseline NRS ≥4 at Month 3	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.
Percentage of Participants With Response Defined by Normalized Alkaline Phosphatase Levels at Month 3	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.

Trial Locations

Locations (156): Institute for Liver Health
🇺🇸
Chandler, Arizona, United States
Mayo Clinic Arizona - PPDS
🇺🇸
Phoenix, Arizona, United States
The Institute for Liver Health-Tucson
🇺🇸
Tucson, Arizona, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
Stanford University School of Medicine
🇺🇸
Redwood City, California, United States
University of California Davis Medical Center
🇺🇸
Sacramento, California, United States
California Pacific Medical Center
🇺🇸
San Francisco, California, United States
Univeristy of Colorado Denver and Hospital
🇺🇸
Aurora, Colorado, United States
Yale School of Medicine Digestive Diseases, Internal Medicine
🇺🇸
New Haven, Connecticut, United States
Excel Medical Clinical Trials, LLC
🇺🇸
Boca Raton, Florida, United States
Scroll for more (146 remaining)
Institute for Liver Health
🇺🇸Chandler, Arizona, United States