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

Primary Purpose

Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary

Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
OP-724
Sponsored by
Kiminori Kimura, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Biliary Cholangitis (PBC) focused on measuring Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary, Cholangitis, Chronic Nonsuppurative Destructive, Liver Cirrhosis, Obstructive, Secondary Biliary Cholangitis, Primary Biliary Cirrhosis, Secondary Biliary Cirrhosis

Eligibility Criteria

20 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Tokyo Metropolitan Komagome Hospital
  • Kyushu University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

OP-724

Arm Description

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.

Outcomes

Primary Outcome Measures

Occurrence Rate of Serious Adverse Events (Side Effects)
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

Expression Ratio of Adverse Events
The data will be aggregated by each adverse event and cohort.
Percentage of Occurrence of Side Effects
The data will be aggregated by each side effect and cohort.
Drug Concentration (OP-724 and C-82) in Plasma
The data will be aggregated by each cohort.
Parameters on Pharmacokinetics (OP-724 and C-82) : Maximum Plasma Concentration (Cmax)
The data will be aggregated by each cohort.
Parameters on Pharmacokinetics (OP-724 and C-82) : Area Under the Curve (AUC 0-24h)
The data will be aggregated by each cohort.
Liver Tissue Fibrotic Area Ratio by Liver Biopsy
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.
Liver Stiffness by Fibro Scan
Amount of change from baseline of liver stiffness by Fibro Scan at 12 weeks after administration. The data will be aggregated by each cohort.
Child-Pugh Score
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
MELD Score
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.
Modified Histological Activity Index (HAI)
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
Serum Alkaline Phosphatase (ALP) Level
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.
Serum Total Bilirubin Value
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.
Enhanced Liver Fibrosis Panel (ELF) Score
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.

Full Information

First Posted
July 30, 2019
Last Updated
July 4, 2022
Sponsor
Kiminori Kimura, MD
Collaborators
Ohara Pharmaceutical Co., Ltd., Japan Agency for Medical Research and Development
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1. Study Identification

Unique Protocol Identification Number
NCT04047160
Brief Title
Safety, Tolerability of OP-724 in Patients With Primary Biliary Cholangitis (Phase I)
Official Title
An Open-Label, Dose-Finding Study for the CBP / β-catenin Inhibitor OP-724 in Patients With Primary Biliary Cholangitis (Phase I)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Completed
Study Start Date
August 29, 2019 (Actual)
Primary Completion Date
September 21, 2021 (Actual)
Study Completion Date
March 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Kiminori Kimura, MD
Collaborators
Ohara Pharmaceutical Co., Ltd., Japan Agency for Medical Research and Development

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary
Keywords
Primary Biliary Cholangitis (PBC), Liver Cirrhosis, Biliary, Cholangitis, Chronic Nonsuppurative Destructive, Liver Cirrhosis, Obstructive, Secondary Biliary Cholangitis, Primary Biliary Cirrhosis, Secondary Biliary Cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
OP-724
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
OP-724
Other Intervention Name(s)
CBP-beta-catenin inhibitor, PRI-724 (former name)
Intervention Description
Twice a week for 4 hours continuous intravenous administration of OP-724
Primary Outcome Measure Information:
Title
Occurrence Rate of Serious Adverse Events (Side Effects)
Description
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.
Time Frame
28 days after the last administration of OP-724
Secondary Outcome Measure Information:
Title
Expression Ratio of Adverse Events
Description
The data will be aggregated by each adverse event and cohort.
Time Frame
28 days after the last administration of OP-724
Title
Percentage of Occurrence of Side Effects
Description
The data will be aggregated by each side effect and cohort.
Time Frame
28 days after the last administration of OP-724
Title
Drug Concentration (OP-724 and C-82) in Plasma
Description
The data will be aggregated by each cohort.
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)
Title
Parameters on Pharmacokinetics (OP-724 and C-82) : Maximum Plasma Concentration (Cmax)
Description
The data will be aggregated by each cohort.
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)
Title
Parameters on Pharmacokinetics (OP-724 and C-82) : Area Under the Curve (AUC 0-24h)
Description
The data will be aggregated by each cohort.
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)
Title
Liver Tissue Fibrotic Area Ratio by Liver Biopsy
Description
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.
Time Frame
12 weeks after administration of OP-724
Title
Liver Stiffness by Fibro Scan
Description
Amount of change from baseline of liver stiffness by Fibro Scan at 12 weeks after administration. The data will be aggregated by each cohort.
Time Frame
12 weeks after administration of OP-724
Title
Child-Pugh Score
Description
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
Time Frame
12 weeks after administration of OP-724
Title
MELD Score
Description
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.
Time Frame
12 weeks after administration of OP-724
Title
Modified Histological Activity Index (HAI)
Description
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
Time Frame
12 weeks after administration of OP-724
Title
Serum Alkaline Phosphatase (ALP) Level
Description
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.
Time Frame
12 weeks after administration of OP-724
Title
Serum Total Bilirubin Value
Description
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.
Time Frame
12 weeks after administration of OP-724
Title
Enhanced Liver Fibrosis Panel (ELF) Score
Description
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.
Time Frame
12 weeks after administration of OP-724
Other Pre-specified Outcome Measures:
Title
Effectiveness: Serum Fibrosis Marker Level
Description
Amount of change from baseline in serum fibrosis marker level at 12 weeks after administration. The data will be aggregated by each cohort.
Time Frame
12 weeks after administration of OP-724

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
74 Years
Accepts Healthy Volunteers
No
Eligibility 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. Histologically, chronic non-suppurative destructive cholangitis (CNSDC) is found and the laboratory findings are consistent as PBC. A positive antimitochondrial antibody (AMA) with no histologic findings of CNSDC but showing a histology consistent with PBC. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kiminori Kimura, MD
Organizational Affiliation
Tokyo Metropolitan Komagome Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tokyo Metropolitan Komagome Hospital
City
Bunkyō-Ku
State/Province
Tokyo
ZIP/Postal Code
113-8677
Country
Japan
Facility Name
Kyushu University Hospital
City
Fukuoka
ZIP/Postal Code
812-8582
Country
Japan

12. IPD Sharing Statement

Learn more about this trial

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

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