A Clinical Phase 2 Study of E6011 in Japanese Subjects With Primary Biliary Cholangitis Inadequately Responding to Ursodeoxycholic Acid
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 29
- 试验地点
- 3
- 主要终点
- Rate of change from Baseline in serum alkaline phosphatase (ALP) values at Week 12
研究概览
简要总结
This study is a placebo-controlled, randomized, double-blind, multicenter, parallel-group comparison study in primary biliary cholangitis participants inadequately responding to ursodeoxycholic acid.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 74 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo; low-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
low-dose, high-frequency E6011; high-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
low-dose, high-frequency E6011; low-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
high-dose, low-frequency E6011; high-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
high-dose, low-frequency E6011; low-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
low-dose, low-frequency E6011; high-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
low-dose, low-frequency E6011; low-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
Placebo; high-dose, low-frequency E6011
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.
干预措施: E6011 (Drug)
Placebo; high-dose, low-frequency E6011
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.
干预措施: Placebo (Drug)
Placebo; low-dose, low-frequency E6011
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Rate of change from Baseline in serum alkaline phosphatase (ALP) values at Week 12
时间窗: Baseline; Week 12
This assessment will be conducted as a measure of efficacy.
次要结局
- 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(Baseline; up to Week 64)
- Mean values of serum ALP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at each visit(Baseline; up to Week 64)
- Mean values of gamma-guanosine-5'-triphosphate (γGTP) at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in fibrosis marker at each visit(Baseline; up to Week 64)
- Number of participants with a decrease in ALP response rates of 15%, 20%, and 40% from Baseline(Baseline; up to Week 64)
- Mean rate of change from Baseline in serum ALP, AST, and ALT at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in serum γGTP at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in serum total bilirubin and direct bilirubin at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in serum total bile acids at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in serum albumin at each visit(Baseline; up to Week 64)
- Mean change from Baseline in individual domain and total primary biliary cholangitis (PBC) version Child-Pugh scores(Screening; up to Week 64)
- Mean change from Baseline in domain (Symptoms, Itch, Fatigue, Cognitive, Emotional, Social) and total scores on the PBC-40(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(Screening; Weeks 52 to 60)
- Mean values of fibrosis marker at each visit(Baseline; up to Week 64)
- Mean change from Baseline in fibrosis marker at each visit(Baseline; up to Week 64)
- Mean values of fibrosis 4 (Fib-4) index at each visit(Baseline; up to Week 64)
- Mean change from Baseline in Fib-4 index at each visit(Baseline; up to Week 64)
- Mean rate of change from Baseline in Fib-4 index at each visit(Baseline; up to Week 64)
- Mean values of serum total bilirubin and direct bilirubin at each visit(Baseline; up to Week 64)
- Mean values of serum total bile acids at each visit(Baseline; up to Week 64)
- Mean values of serum albumin at each visit(Baseline; up to Week 64)
- Mean change from Baseline in serum ALP, AST, and ALT at each visit(Baseline; up to Week 64)
- Mean change from Baseline in serum γGTP at each visit(Baseline; up to Week 64)
- Mean change from Baseline in serum total bilirubin and direct bilirubin at each visit(Baseline; up to Week 64)
- Mean change from Baseline in serum total bile acids at each visit(Baseline; up to Week 64)
- Mean change from Baseline in serum albumin at each visit(Baseline; up to Week 64)