Study of E6011 in Japanese Subjects With Primary Biliary Cholangitis Inadequately Responding to Ursodeoxycholic Acid

Study Overview
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Brief Summary
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This study is a placebo-controlled, randomized, double-blind, multicenter, parallel-group comparison study in primary biliary cholangitis participants inadequately responding to ursodeoxycholic acid.

Official Title
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A Clinical Phase 2 Study of E6011 in Japanese Subjects With Primary Biliary Cholangitis Inadequately Responding to Ursodeoxycholic Acid

Conditions
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Primary Biliary Cholangitis

Intervention / Treatment
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* Drug: E6011
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosed with primary biliary cholangitis corresponding to one of the following criteria: Histologically confirmed chronic non-suppurative destructive cholangitis (CNSDC) with laboratory findings compatible with primary biliary cholangitis (PBC) Positivity for antimitochondrial antibodies (AMAs) with histological findings compatible with PBC but in the absence of characteristic histological findings of CNSDC No histological findings available, but positivity for AMAs as well as clinical findings and a course indicative of typical cholestatic PBC Aged ≥20 and <75 years old at the time of informed consent Taking stable dose of ursodeoxycholic acid for at least 6 months (≥600 milligrams [mg]/day) prior to Screening Screening and Week 0 alkaline phosphatase (ALP) values between 1.67 and 10 times the upper limit of normal Outpatient Has voluntarily consented, in writing, to participate in this study, and is able to comply with all aspects of the protocol Exclusion Criteria: Received the following drugs within 12 weeks before starting the study treatment: Drugs that suppose the efficacy to PBC: o azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, penicillamine, fibrates, and other systemic corticosteroids Potentially hepatotoxic drugs o methyl-dopa, sodium valproic acid, and isoniazide History or current condition of hepatic decompensation with variceal bleeds, encephalopathy ≥ grade 2 and poorly controlled ascites, and history of liver transplantation History or current condition of other concomitant liver diseases including hepatitis due to hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, primary sclerosing cholangitis, alcoholic liver disease (including liver cirrhosis), autoimmune liver disease requiring the treatment of systemic corticosteroids or biopsy proven non-alcoholic steatohepatitis (NASH) History or current clinical condition of malignant tumor, lymphoma, leukemia, or lymphoproliferative disease, except for skin carcinoma (epithelial carcinoma or basal cell carcinoma) and cervix carcinoma which has completely excised and without metastasis or recurrence for more than 5 years before informed consent Immunodeficiency or history of human immunodeficiency virus (HIV) infection Infection requiring hospitalization or intravenous administration of antibiotics or disease requiring administration of antivirus drugs (eg, herpes zoster) within 4 weeks before starting the study treatment History of tuberculosis or current complication of active tuberculosis Positive tuberculosis test (QuantiFERON®TB Gold Test or T-SPOT®.TB Test) at Screening History of clinically important vasculitis History of severe allergy (shock or anaphylactoid symptoms) Complication of uncontrolled disorders such as acute cardiac infarction, unstable angina, brain infarct, or symptomatic intracerebral hemorrhage Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, or renal disease) that could affect the participant's safety or interfere with the study assessments in the opinion of the investigator or subinvestigator Tested positive for any of the following at Screening: HIV, hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B core (HBc) antibody, HBV deoxyribonucleic acid (DNA), HCV antibody, human T-lymphotropic virus type 1 (HTLV-1) antibody, or syphilis Demonstrated prolonged QT interval corrected using Fridericia's formula (QTcF) interval (>450 milliseconds [ms]) in repeated electrocardiogram examinations Received immunoglobulin preparations or blood products within 24 weeks before starting the study treatment Received a live vaccine within 12 weeks before starting the study treatment, or is planning to receive Females who are, or may be pregnant, who are breastfeeding, who wish to become pregnant during the study period, and females or their partners who do not wish to use reliable contraceptive measures. Scheduled for surgery before Week 64 Has been treated with investigational drugs in other E6011 study Currently enrolled in another clinical study, including the follow-up Used any investigational drug within 28 days (or 5× the half-life, whichever is longer) before informed consent Judged to be ineligible to participate in this study by the investigator or sub-investigator

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: low-dose, high-frequency E6011; high-dose, low-frequency E6011<br>Participants will receive low-dose E6011 at a relatively higher frequency up to approximately Week 12. Participants will then receive high-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: low-dose, high-frequency E6011; low-dose, low-frequency E6011<br>Participants will receive low-dose E6011 at a relatively higher frequency up to approximately Week 12. Participants will then receive low-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: high-dose, low-frequency E6011; high-dose, low-frequency E6011<br>Participants will receive high-dose E6011 at a relatively lower frequency up to approximately Week 12. Participants will then receive high-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: high-dose, low-frequency E6011; low-dose, low-frequency E6011<br>Participants will receive high-dose E6011 at a relatively lower frequency up to approximately Week 12. Participants will then receive low-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: low-dose, low-frequency E6011; high-dose, low-frequency E6011<br>Participants will receive low-dose E6011 at a relatively lower frequency up to approximately Week 12. Participants will then receive high-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: low-dose, low-frequency E6011; low-dose, low-frequency E6011<br>Participants will receive low-dose E6011 at a relatively lower frequency up to approximately Week 12. Participants will then receive low-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>|
| Experimental: Placebo; high-dose, low-frequency E6011<br>Participants will receive placebo up to approximately Week 12. Participants will then receive high-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>Drug: Placebo<br>* Intravenous administration<br>|
| Experimental: Placebo; low-dose, low-frequency E6011<br>Participants will receive placebo up to approximately Week 12. Participants will then receive low-dose E6011 at a relatively lower frequency from Week 12 to Week 64. | Drug: E6011<br>* Intravenous administration<br>Drug: Placebo<br>* Intravenous administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of change from Baseline in serum alkaline phosphatase (ALP) values at Week 12 | This assessment will be conducted as a measure of efficacy. | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with a decrease in ALP response rates of 15%, 20%, and 40% from Baseline | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Number of participants with an ALP value less than 1.67 times the upper limit normal and a total bilirubin value within normal limits and a greater than or equal to 15% decrease in ALP from Baseline | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean values of serum ALP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean values of gamma-guanosine-5'-triphosphate (γGTP) at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean values of serum total bilirubin and direct bilirubin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean values of serum total bile acids at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean values of serum albumin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in serum ALP, AST, and ALT at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in serum γGTP at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in serum total bilirubin and direct bilirubin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in serum total bile acids at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in serum albumin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in serum ALP, AST, and ALT at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in serum γGTP at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in serum total bilirubin and direct bilirubin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in serum total bile acids at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in serum albumin at each visit | This assessment will be conducted as a measure of efficacy. | Baseline; up to Week 64 | 
| Mean change from Baseline in individual domain and total primary biliary cholangitis (PBC) version Child-Pugh scores | The Child-Pugh classification is used to assess the prognosis of chronic liver disease. The score employs five clinical measures of liver disease. Each measure is scored from 1 to 3, with 3 indicating most severe derangement. The total score ranges from 5 to 15 and is a sum of the individual domain scores. A higher score indicates a worse prognosis. | Screening; up to Week 64 | 
| Mean change from Baseline in domain (Symptoms, Itch, Fatigue, Cognitive, Emotional, Social) and total scores on the PBC-40 | The PBC-40 is measures quality of life. Participants are asked to respond to 40 questions, each of which is scored on a scale of 0 to 5 (where 0=not applicable; 1=least impact; 5=greatest impact), grouped into six domains (symptoms, itch, fatigue, cognition, social, and emotional). For each domain, scoring involves summing individual question response scores. A higher score indicates a poorer quality of life. | Baseline; up to Week 64 | 
| Mean change from Baseline in each score (fibrosis, bile duct loss, deposition of orcein-positive granules) and total scores, in the stage based on the total scores, in each score of cholangitis activity and hepatitis activity on Nakanuma classification | Scores for fibrosis, bile duct loss, and chronic cholestasis are combined for staging: stage 1, total score of 0; stage 2, score 1 to 3; stage 3, score 4 to 6; and stage 4, score 7 to 9. Cholangitis activity and hepatitis activity are graded as CA0-3 and HA0-3, respectively. A higher score indicates more severe disease. | Screening; Weeks 52 to 60 | 
| Mean values of fibrosis marker at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 
| Mean change from Baseline in fibrosis marker at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in fibrosis marker at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 
| Mean values of fibrosis 4 (Fib-4) index at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 
| Mean change from Baseline in Fib-4 index at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 
| Mean rate of change from Baseline in Fib-4 index at each visit | The presence of serum fibrosis markers may be correlated with PBC. | Baseline; up to Week 64 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E6011, Ursodeoxycholic acid, Japan