|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Primary biliary cholangitis (PBC, formerly known as primary biliary
cirrhosis) is a serious and potentially life threatening autoimmune
disease of the liver characterized by impaired bile flow (cholestasis) and accumulation of toxic bile acids (BA).
|Medical condition in easily understood language
|Body processes [G] - Immune system processes [G12]
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective of this study is to evaluate the treatment effect of seladelpar on composite biochemical improvement in cholestasis markers based on ALP and total bilirubin and to evaluate the safety of seladelpar over 12 months of treatment compared to placebo.
|Secondary objectives of the trial
|The key secondary objectives of this study are to evaluate the effect of seladelpar on the normalization of ALP values at 12 months of treatment compared to placebo and to evaluate the effect of seladelpar on pruritus at 6 months of treatment compared to placebo in subjects with baseline moderate to severe pruritus.
Other secondary objectives of the study are to evaluate the effect of seladelpar on other measures of cholestasis, metabolic markers, and PBC prognostic criteria; to evaluate the effect of seladelpar on quality of life (QoL); and to evaluate the effect of seladelpar on PBC-associated clinical outcomes.
|Trial contains a sub-study
|Principal inclusion criteria
|Subjects must meet all of the following criteria to be eligible for study participation:
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 based on any two of the following criteria:
a. History of ALP above 1.0× ULN for at least 6 months
b. Positive AMA titer (>1:40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies (ANAs)
c. Documented liver biopsy results consistent with PBC
4. UDCA for the past 12 months (stable dose for >3 months prior to screening) OR intolerant to UDCA (last dose of UDCA >3 months prior to screening)
5. Laboratory parameters measured by the Central Laboratory at screening:
a. ALP ≥1.67× ULN
b. Aspartate aminotransferase (AST) ≤3× ULN
c. ALT ≤3× ULN
d. Total bilirubin ≤2× ULN
e. Estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m2 (calculated by the Modification of Diet in Renal Disease study equation)
f. International normalized ratio (INR) below 1.1× ULN
For subjects on anticoagulation therapy, INR must be maintained in the range required for prophylaxis for their specific disease.
g. Platelet count ≥100×103/μL
NOTE: PT, INR and platelets can be performed locally at the Screening Visit, if deemed necessary by the investigator after consultation with the medical monitor, in cases where centrally read samples are deemed invalid
6. Females of reproductive potential (refer to Section 8.1.1) must use at least 1 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
|Principal 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 (eg, cancer) or confound its results (e.g., Paget’s disease, any active infection)
3. Advanced PBC as defined by the Rotterdam criteria (albumin below the lower limit of normal AND total bilirubin above 1.0× ULN)
4. Presence of clinically important hepatic decompensation, including the following:
a. History of liver transplantation, current placement on liver transplantation list, or current Model for End-Stage Liver Disease (MELD) score ≥12. For subjects on anticoagulation medication, evaluation of the baseline INR, in concert with their current dose adjustments of their anticoagulant medication, will be taken into account when calculating the MELD score. This will be done in consultation with the medical monitor.
b. Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), ascites, and hepatic encephalopathy
c. Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis, hepatocellular carcinoma, or hepatorenal syndrome
5. Other chronic liver diseases:
a. Current features of autoimmune hepatitis as determined by the investigator based on immunoserology, liver biochemistry, or historic confirmed liver histology
b. Primary sclerosing cholangitis determined by the presence of diagnostic cholangiographic findings
c. History or clinical evidence of alcoholic liver disease
d. History or clinical evidence of alpha-1-antitrypsin deficiency
e. History of biopsy confirmed NASH
f. History or evidence of Gilbert’s syndrome with elevated total bilirubin
g. History or evidence of hemochromatosis
h. Hepatitis B, defined as the presence of hepatitis B surface antigen (HBsAg)
i. Hepatitis C, defined as the presence of hepatitis C virus (HCV) ribonucleic acid (RNA)
j. History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms
6. Known history of human immunodeficiency virus (HIV) or positive antibody test at screening
7. Clinically important alcohol consumption, defined as more than 2 drink units per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, or inability to quantify alcohol intake reliably
8. History of malignancy diagnosed or treated, actively or within 2 years, or ongoing evaluation for malignancy; localized treatment of squamous or noninvasive basal cell skin cancers and cervical carcinoma in situ is allowed if appropriately treated prior to screening.
9. Treatment with OCA and fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) 6 weeks prior to screening
10. Treatment with colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (>2 weeks) during 2 months prior to screening. See Section 7 for additional medications that may be excluded.
11. Treatment with anti-pruritic drugs (e.g., cholestyramine, naltrexone, rifampicin, sertraline, or any experimental approach) must be on a stable dose within 1 month prior to screening
12. Treatment with any other investigational therapy or device within 30 days or within 5 half-lives, whichever is longer, prior to screening
13. For females, pregnancy or breastfeeding
14. 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
15. Patients who are eligible for treatment with OCA therapy (e.g., patients not known to have an inadequate response to OCA, a medical contraindication or are intolerant to OCA, or refuse to take OCA).
16. Immunosuppressant therapies (e.g., cyclosporine, tacrolimus, antiTNF or other immunosuppressive biologics).
17. Other medications that effect liver or GI functions, such as absorption of medications or the roux-en-y gastric procedure, may be prohibited and should be discussed with the medical monitor on a case-by-case basis.
18. Active COVID-19 infection during Screening.
|E.5 End points
|Primary end point(s)
|1. Proportion of subjects who are considered responders at 12 months based on the following composite endpoint of ALP and total bilirubin at 12 months requiring
a. ALP <1.67× ULN
b. ≥15% decrease in ALP
c. Total bilirubin ≤1.0× ULN
2. Assessment of TEAEs (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0), biochemistry, and hematology
|Timepoint(s) of evaluation of this end point
|1. 12 months
2. Throughout the study
|Secondary end point(s)
|1. Proportion of subjects with ALP ≤1.0× ULN at 12 months (ie, normalization)
2. Change from baseline in weekly averaged pruritus NRS in subjects with baseline NRS ≥4 at 6 months
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|LVLS is the Post-Treatment Safety Follow-up visit that will occur 1 month (4 weeks±7 days) after the last dose of the study drug.
At the end of the visit, subjects will be invited to participate in the long-term study (Study CB8025-31731-RE).
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days