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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03092765
Recruitment Status : Terminated (Sponsor's decision (non-safety related))
First Posted : March 28, 2017
Last Update Posted : January 4, 2019
Sponsor:
Information provided by (Responsible Party):
Eisai Inc. ( EA Pharma Co., Ltd. )

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

Condition or disease Intervention/treatment Phase
Primary Biliary Cholangitis Drug: E6011 Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 29 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Clinical Phase 2 Study of E6011 in Japanese Subjects With Primary Biliary Cholangitis Inadequately Responding to Ursodeoxycholic Acid
Actual Study Start Date : May 29, 2017
Actual Primary Completion Date : August 27, 2018
Actual Study Completion Date : October 22, 2018


Arm Intervention/treatment
Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Drug: Placebo
Intravenous administration

Experimental: 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.
Drug: E6011
Intravenous administration

Drug: Placebo
Intravenous administration




Primary Outcome Measures :
  1. Rate of change from Baseline in serum alkaline phosphatase (ALP) values at Week 12 [ Time Frame: Baseline; Week 12 ]
    This assessment will be conducted as a measure of efficacy.


Secondary Outcome Measures :
  1. Number of participants with a decrease in ALP response rates of 15%, 20%, and 40% from Baseline [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  2. 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 [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  3. Mean values of serum ALP, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  4. Mean values of gamma-guanosine-5'-triphosphate (γGTP) at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  5. Mean values of serum total bilirubin and direct bilirubin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  6. Mean values of serum total bile acids at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  7. Mean values of serum albumin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  8. Mean change from Baseline in serum ALP, AST, and ALT at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  9. Mean change from Baseline in serum γGTP at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  10. Mean change from Baseline in serum total bilirubin and direct bilirubin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  11. Mean change from Baseline in serum total bile acids at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  12. Mean change from Baseline in serum albumin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  13. Mean rate of change from Baseline in serum ALP, AST, and ALT at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  14. Mean rate of change from Baseline in serum γGTP at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  15. Mean rate of change from Baseline in serum total bilirubin and direct bilirubin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  16. Mean rate of change from Baseline in serum total bile acids at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  17. Mean rate of change from Baseline in serum albumin at each visit [ Time Frame: Baseline; up to Week 64 ]
    This assessment will be conducted as a measure of efficacy.

  18. Mean change from Baseline in individual domain and total primary biliary cholangitis (PBC) version Child-Pugh scores [ Time Frame: Screening; up to Week 64 ]
    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.

  19. Mean change from Baseline in domain (Symptoms, Itch, Fatigue, Cognitive, Emotional, Social) and total scores on the PBC-40 [ Time Frame: Baseline; up to Week 64 ]
    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.

  20. 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 [ Time Frame: Screening; Weeks 52 to 60 ]
    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.

  21. Mean values of fibrosis marker at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.

  22. Mean change from Baseline in fibrosis marker at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.

  23. Mean rate of change from Baseline in fibrosis marker at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.

  24. Mean values of fibrosis 4 (Fib-4) index at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.

  25. Mean change from Baseline in Fib-4 index at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.

  26. Mean rate of change from Baseline in Fib-4 index at each visit [ Time Frame: Baseline; up to Week 64 ]
    The presence of serum fibrosis markers may be correlated with PBC.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 74 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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): NCT03092765


Locations
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Japan
EA Pharma trial site
Nagoya, Aichi, Japan
EA Pharma trial site
Matsudo, Chiba, Japan
EA Pharma trial site
Touon, Ehime, Japan
EA Pharma trial site
Yoshida, Fukui, Japan
EA Pharma trial site
Kurume, Fukuoka, Japan
EA Pharma trial site
Maebashi, Gunma, Japan
EA Pharma trial site #1
Sapporo, Hokkaido, Japan
EA Pharma trial site #2
Sapporo, Hokkaido, Japan
EA Pharma trial site
Kobe, Hyogo, Japan
EA Pharma trial site
Nishinomiya, Hyogo, Japan
EA Pharma trial site
Inashiki, Ibaraki, Japan
EA Pharma trial site
Morioka, Iwate, Japan
EA Pharma trial site
Kita, Kagawa, Japan
EA Pharma trial site
Takamatsu, Kagawa, Japan
EA Pharma trial site #1
Yokohama, Kanagawa, Japan
EA Pharma trial site #2
Yokohama, Kanagawa, Japan
EA Pharma trial site
Sendai, Miyagi, Japan
EA Pharma trial site
Matsumoto, Nagano, Japan
EA Pharma trial site
Oomura, Nagasaki, Japan
EA Pharma trial site
Kashihara, Nara, Japan
EA Pharma trial site
Nakagami, Okinawa, Japan
EA Pharma trial site
Hirakata, Osaka, Japan
EA Pharma trial site #1
Suita, Osaka, Japan
EA Pharma trial site #2
Suita, Osaka, Japan
EA Pharma trial site
Ageo, Saitama, Japan
EA Pharma trial site
Iruma, Saitama, Japan
EA Pharma trial site
Shimotsuga, Tochigi, Japan
EA Pharma trial site
Bunkyo, Tokyo, Japan
EA Pharma trial site
Itabashi, Tokyo, Japan
EA Pharma trial site #1
Minato, Tokyo, Japan
EA Pharma trial site #2
Minato, Tokyo, Japan
EA Pharma trial site
Musashino, Tokyo, Japan
EA Pharma trial site
Shinjuku, Tokyo, Japan
EA Pharma trial site #1
Fukuoka, Japan
EA Pharma trial site #2
Fukuoka, Japan
EA Pharma trial site
Fukushima, Japan
EA Pharma trial site #1
Hiroshima, Japan
EA Pharma trial site #2
Hiroshima, Japan
EA Pharma trial site
Kagoshima, Japan
EA Pharma trial site
Kumamoto, Japan
EA Pharma trial site
Kyoto, Japan
EA Pharma trial site
Niigata, Japan
EA Pharma trial site
Okayama, Japan
EA Pharma trial site
Osaka, Japan
EA Pharma trial site
Saga, Japan
EA Pharma trial site
Yamagata, Japan
Sponsors and Collaborators
EA Pharma Co., Ltd.

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Responsible Party: EA Pharma Co., Ltd.
ClinicalTrials.gov Identifier: NCT03092765     History of Changes
Other Study ID Numbers: E6011/ET1
First Posted: March 28, 2017    Key Record Dates
Last Update Posted: January 4, 2019
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc. ( EA Pharma Co., Ltd. ):
E6011
Ursodeoxycholic acid
Japan
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
E6011
Ursodeoxycholic Acid
Antibodies, Monoclonal
Cholagogues and Choleretics
Gastrointestinal Agents
Antirheumatic Agents
Immunologic Factors
Physiological Effects of Drugs