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Trial record 11 of 34 for:    Biliary Cirrhosis, Primary, 4

Safety, Tolerability of OP-724 in Patients With Primary Biliary Cholangitis (Phase I)

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ClinicalTrials.gov Identifier: NCT04047160
Recruitment Status : Recruiting
First Posted : August 6, 2019
Last Update Posted : September 18, 2019
Sponsor:
Collaborators:
OHARA Pharmaceutical Co., Ltd.
Japan Agency for Medical Research and Development
Information provided by (Responsible Party):
Kiminori Kimura, MD, Komagome Hospital

Brief Summary:
To evaluate the safety and pharmacokinetics of OP-724 and to determine the recommended dose of OP-724 against Primary Biliary Cholangitis patients.

Condition or disease Intervention/treatment Phase
Primary Biliary Cholangitis (PBC) Liver Cirrhosis, Biliary Drug: OP-724 Phase 1

Detailed Description:

This trial is a phase I trial aimed at examining the safety and tolerability of OP-724 in patients with primary biliary cholangitis and determining the recommended dose.

The subjects are patients diagnosed with primary biliary cholangitis and diagnosed as progress of fibrosis (Scheuer stage III or higher) as a result of liver tissue examination. As a dosing schedule, OP-724 is intravenously administered twice a week (4 hours) for 12 weeks. However, once 7 days prior to the first cycle of administration, a dose scheduled for the first cycle will be administered once by continuous intravenous administration for 4 hours, and safety and pharmacokinetics will be evaluated on the day of administration to the next day after administration. The dose level shall be 3 doses (140 mg/m2/4hrs, 280 mg/m2/4hrs [starting dose], 380 mg/m2/4hrs), of which 2 doses shall be registered for up to 6 patients each. The safety and pharmacokinetic data after OP-724 administration will be decided comprehensively to determine the recommended dose in the next phase.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single-Center, Open-Label, Dose-Escalation Study of Cyclic Adenosine Monophosphate (AMP)-Response Element-binding (CREB)-Binding Protein (CBP) / β-Catenin Inhibitor OP-724 in Patients With Primary Biliary Cholangitis (Phase I)
Actual Study Start Date : August 29, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : September 30, 2021


Arm Intervention/treatment
Experimental: OP-724

Dose: 140, 280, 380 mg/m2/4 hrs

Administration method:

[Level 1] 140 mg/m2/4 hours [Level 2] 280 mg/m2/4 hours (starting dose) [Level 3] 380 mg/m2/4 hours Continuous intravenous administration will be done for 4 hours twice a week. This procedure will be as one cycle and 12 cycles (12 weeks in total) will be conducted. On 7 days prior to the first cycle administration, a dose scheduled in the first cycle will be administered with continuous intravenous for 4 hours and the safety and pharmacokinetics on the day of administration to the next day after administration will be evaluated.

Drug: OP-724
Twice a week for 4 hours continuous intravenous administration of OP-724
Other Names:
  • CBP-beta-catenin inhibitor
  • PRI-724 (former name)




Primary Outcome Measures :
  1. Occurrence Rate of Serious Adverse Events (Side Effects) [ Time Frame: 28 days after the last administration of OP-724 ]
    Occurrence Rate of Serious Adverse Events (Side Effects) whose causal relationship with the investigational drug can not be denied. The data will be aggregated by each adverse event and cohort.


Secondary Outcome Measures :
  1. Expression Ratio of Adverse Events [ Time Frame: 28 days after the last administration of OP-724 ]
    The data will be aggregated by each adverse event and cohort.

  2. Percentage of Occurrence of Side Effects [ Time Frame: 28 days after the last administration of OP-724 ]
    The data will be aggregated by each side effect and cohort.

  3. Drug Concentration (OP-724 and C-82) in Plasma [ Time Frame: A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) ]
    The data will be aggregated by each cohort.

  4. Parameters on Pharmacokinetics (OP-724 and C-82) : Maximum Plasma Concentration (Cmax) [ Time Frame: A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) ]
    The data will be aggregated by each cohort.

  5. Parameters on Pharmacokinetics (OP-724 and C-82) : Area Under the Curve (AUC 0-24h) [ Time Frame: A) Single administration part: pre-dose and post-dose at 0.5, 1, 2, 4, 5, 9 and 24 hours. / B) Continuous administration part: pre-dose and post-dose at 4 hours on Day 1 and 4 in Cycle 1, 5, 9 and 12 (each cycle is 7 days) ]
    The data will be aggregated by each cohort.

  6. Liver Tissue Fibrotic Area Ratio by Liver Biopsy [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline in liver tissue fibrotic area ratio by liver biopsy at 12 weeks after administration. The data will be aggregated by each cohort.

  7. Liver Stiffness by Fibro Scan [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline of liver stiffness by Fibro Scan at 12 weeks after administration. The data will be aggregated by each cohort.

  8. Child-Pugh Score [ Time Frame: 12 weeks after administration of OP-724 ]

    Amount of change from baseline of Child-Pugh Score at 12 weeks after administration. Child Pugh score (scale range 5-15 points, the severity increases sequentially from 5 to 15 points) is obtained by adding the score for each parameter (hepatic encephalopathy, ascites, bilirubin, albumin, PT). Based on the total points score (Child-Pugh Score) of each diagnostic parameter shown above, the severity of the disease is classified into Grades A to C shown below. The data will be aggregated by each cohort and score.

    • Grade A: 5-6 points -> Compensated cirrhosis
    • Grade B: 7-9 points -> Decompensated cirrhosis
    • Grade C: 10-15 points -> Decompensated cirrhosis

  9. MELD Score [ Time Frame: 12 weeks after administration of OP-724 ]

    Amount of change from baseline in MELD score at 12 weeks after administration. The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease and uses the subject's values for total bilirubin, serum creatinine, and the international normalized ratio (INR) for prothrombin time to predict survival. MELD is calculated according to the following formula:

    * MELD score = 3.78×ln[serum bilirubin (mg/dL)] + 11.2×ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43 The data will be aggregated by each cohort and score.


  10. Modified Histological Activity Index (HAI) [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline of modified Histological Activity Index (HAI) and classification of Nakanuma et al. by liver biopsy at 12 weeks after administration. The data will be aggregated by each cohort and index

  11. Serum Alkaline Phosphatase (ALP) Level [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline in serum ALP level at 12 weeks after administration. The data will be aggregated by each cohort and Child-Pugh score.

  12. Serum Total Bilirubin Value [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline in serum total bilirubin value at 12 weeks after administration. The data will be aggregated by each cohort and Child-Pugh score.

  13. Enhanced Liver Fibrosis Panel (ELF) Score [ Time Frame: 12 weeks after administration of OP-724 ]

    Amount of change from baseline of ELF score at 12 weeks after administration. Observation items: hyaluronic acid, procollagen III peptide, TIMP-1

    * ELF score = 2.278 + 0.851 ln (hyaluronic acid) + 0.75 ln (P3 NP) + ln (TIMP). The data will be aggregated by each cohort and score.



Other Outcome Measures:
  1. Effectiveness: Serum Fibrosis Marker Level [ Time Frame: 12 weeks after administration of OP-724 ]
    Amount of change from baseline in serum fibrosis marker level at 12 weeks after administration. The data will be aggregated by each cohort.



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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:

  • (1) Of the confirmed patients * of primary biliary cholangitis, patients with progressive fibrosis (Scheuer classification stage III or higher) by liver biopsy.

    * The diagnosis of primary biliary cholangitis (PBC) is based on the diagnostic criteria (2015) of "Study and research on refractory liver and biliary diseases". That is, one that corresponds to any one of the following is diagnosed as PBC.

    1. Histologically, chronic non-suppurative destructive cholangitis (CNSDC) is found and the laboratory findings are consistent as PBC.
    2. A positive antimitochondrial antibody (AMA) with no histologic findings of CNSDC but showing a histology consistent with PBC.
    3. There is no experience of histologic search, but AMA is positive and it is considered as PBC from clinical image and course.
  • (2) Patients with Performance Status 0 to 2.
  • (3) Patients aged 20 years or over and under 75 when acquiring informed consent.
  • (4) Regarding participation in this trial (including liver biopsy), patients who obtained informed consent by their own voluntary intention.

Exclusion Criteria:

  • (1) Patients who have liver fibrosis other than primary biliary cholangitis or patients whose cause of liver fibrosis is unknown.
  • (2) Patients with esophageal gastric varices determined to be treated by endoscopic examination at screening.
  • (3) Patients with complication or previous history of primary liver cancer (excluding those who have had more than one year of hepatocarcinoma resection / radiofrequency ablation).
  • (4) Merger of malignant tumor or past patients (within 3 years before screening). However, the following diseases are excluded: treated basal cell carcinoma, treated lung intraepithelial carcinoma, treated cervical carcinoma, or control superficial (not invasive) bladder carcinoma.
  • (5) Patients who can not be denied hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-cell leukemia virus 1 (HTLV-1) or syphilis.
  • (6) Serum creatinine value: Patients with more than 1.5 times the upper limit of the facility reference value.
  • (7) Patients with poor control of diabetes, hypertension or heart failure.
  • (8) Patients with psychiatric diseases judged to have the potential to influence the implementation of clinical trials.
  • (9) Patients who have severe allergy to or contrast media.
  • (10) Patients whose dosage regimen was changed within 12 weeks prior to enrollment.
  • (11) Patients who have history of drug or alcohol intoxication within 5 years before acquiring informed consent or who have history of drug or alcohol abuse within the past year.
  • (12) Patients who participated in other clinical trials and clinical trials within 30 days prior to acquisition of consent, patients who used investigational drugs or investigational equipment.
  • (13) Patients who received liver transplantation or other organ transplantation (including bone marrow transplantation) and patients who are difficult to intravenously administer.
  • (14) Patients whose liver biopsy is expected to be difficult to perform.
  • (15) Patients who are pregnant or nursing, or who are likely to become pregnant.
  • (16) Male patients who do not obtain consent to contraception from the time of acquiring informed consent until the end of 12 weeks after the administration of investigational drug.
  • (17) In addition, patients investigated by investigators or clinical trial doctors as judged unsuitable for this trial.

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): NCT04047160


Contacts
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Contact: Kiminori Kimura, MD +81-3-3823-2101 kkimura@cick.jp
Contact: Maiko Nishihara +81-3-4463-7577 mnishihara@cick.jp

Locations
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Japan
Tokyo Metropolitan Komagome Hospital Recruiting
Bunkyō-Ku, Tokyo, Japan, 113-8677
Contact: Kiminori Kimura, MD    +81-3-3823-2101    kkimura@cick.jp   
Contact: Maiko Nishihara    +81-3-4463-7577    mnishihara@cick.jp   
Sponsors and Collaborators
Komagome Hospital
OHARA Pharmaceutical Co., Ltd.
Japan Agency for Medical Research and Development
Investigators
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Principal Investigator: Kiminori Kimura, MD Tokyo Metropolitan Komagome Hospital

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Responsible Party: Kiminori Kimura, MD, Head, Department of Hepatology, Komagome Hospital
ClinicalTrials.gov Identifier: NCT04047160     History of Changes
Other Study ID Numbers: OP-724-P101
jRCT2031190073 ( Other Identifier: Japan Registry of Clinical Trials (jRCT) )
First Posted: August 6, 2019    Key Record Dates
Last Update Posted: September 18, 2019
Last Verified: September 2019

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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 Kiminori Kimura, MD, Komagome Hospital:
Primary Biliary Cholangitis (PBC)
Liver Cirrhosis, Biliary
Cholangitis, Chronic Nonsuppurative Destructive
Liver Cirrhosis, Obstructive
Secondary Biliary Cholangitis
Primary Biliary Cirrhosis
Secondary Biliary Cirrhosis
Additional relevant MeSH terms:
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Liver Cirrhosis
Liver Cirrhosis, Biliary
Biliary Tract Diseases
Cholangitis
Fibrosis
Pathologic Processes
Liver Diseases
Digestive System Diseases
Bile Duct Diseases
Cholestasis, Intrahepatic
Cholestasis