An Open Label, Single Arm, Dose Escalation Phase 1 Trial of PRI-724 in Patients With HCV-induced Cirrhosis

The purpose of this study is to investigate the safety and tolerability of PRI-724 in patients with HCV-induced cirrhosis.

Study Overview

• Status: Completed
• Conditions: Hepatitis C Virus-infected Cirrhosis
• Intervention / Treatment: Drug: PRI-724

Detailed Description

This is a single-center, open-label, continuous i.v. administration, dose escalation Phase I study in patients with hepatitis C cirrhosis.

One cycle consisted of one-week continuous i.v. administration of PRI-724 followed by a one-week observation period. One cohort was a total of six cycles, a 12-week treatment period.

PRI-724 was administered at a dose of 10 mg/m2/day in Cohort 1, 40 mg/m2/day in Cohort 2, and 160 mg/m2/day in Cohort 3 in a dose escalation manner. Each cohort was to include 6 subjects.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan
    • Tokyo Metropolitan Komagome Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Presence of cirrhosis due to hepatitis C virus. 1) Serum HCV-RNA test positive 2) Definitive diagnosis of cirrhosis established by liver biopsy (HAI score: Grade IV-D).
2. Child-Pugh Class A or B at the time of informed consent, with no likelihood of improvement with existing medical treatment.
3. Performance Status: 0 - 2.
4. Between =>20 and <75 years of age at the time of providing written consent.
5. Having provided voluntary written consent for participation in this study.
6. Esophageal and gastric varices are well controlled

Exclusion Criteria:

1. Patients with cirrhosis due to causes other than hepatitis C virus; or patients with cirrhosis due to unknown causes.
2. Patients with a history of primary liver cancer or a complication thereof.
3. Patients with a complication of malignant tumor or a history thereof (within 5 years prior to screening).
4. Patients in whom such active viral infections as HBV, HIV or ATCL or syphilis infection cannot be ruled out.
5. Patients with serum creatinine >1.5 times over upper normal or creatinine clearance =<60 mL/min/1.73 m2.
6. Patients with hemoglobin <8 g/dL.
7. Patients with platelet count <50,000 /µL.
8. Patients with T.Bil =>3.0 mg/dL.
9. Patients with a complication of poorly controlled diabetes, hypertension or heart failure.
10. Patients with a complication of mental disorder requiring treatment.
11. Patients with serious allergy to contrast media or a history thereof.
12. Patients with allergy to inactive ingredients of the study drug.
13. Patients who have received interferon, ribavirin or anti-HCV agents within 12 weeks before registration in this study.
14. When the medical treatment to a primary disease is carried out, Patient who was changed the dosage and administration within the 12 weeks before registration.
15. Patients with a history of drug or alcohol addiction within five years at the time of providing written consent or a history of drug or alcohol abuse within the past one year.
16. The patient who received a liver transplant or other organ transplants (a bone marrow transplantation is included), and the patient for whom intravenous administration and venous access are difficult.
17. Patients contraindicated for liver biopsy.
18. Female patients who are pregnant or suspected to be pregnant; or those who desire to get pregnant during the study period or those of childbearing potential.
19. Male patients who do not consent to practice birth control during the clinical study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: PRI-724; 3 cohorts (PRI-724: 10, 40, 160 mg/m2/day), 6 cycles (1 cycle: 1-week continuous i.v. administration+1-week observation period) *Cycle 2 will not be started until plasma drug concentrations of PRI-724 and C-82 on Days 1 and 2 in Cycle 1 are confirmed. Cohort 1: 10 mg/m2/day (6 subjects) Cohort 2: 40 mg/m2/day (6 subjects) Cohort 3: 160 mg/m2/day (6 subjects) One cycle consists of 1-week continuous i.v. administration of PRI-724 followed by a 1-week observation period. The tolerability and safety after 6 cycles will be confirmed.

Drug: PRI-724; 10 - 160 mg/m2, 7 days CIV (in the vein) with 7 days rest per one cycle. Number of Cycles: 6.; Other Names: CBP-beta-catennin inhibitor; OP-724

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events and adverse drug reactions (including subjective symptoms and abnormal laboratory values)	Items and ratio%	12 weeks after the initiation of PRI-724 administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Child-Pugh Score	Changes of score	12 weeks after the initiation of PRI-724 administration
Liver biopsy: Histology Activity Index (HAI)	Changes of index	12 weeks after the initiation of PRI-724 administration
Serum albumin level	Changes of level	12 weeks after the initiation of PRI-724 administration
Serum fibrosis marker level(s)	Changes of level	12 weeks after the initiation of PRI-724 administration
Ascitic fluid level	Changes of level	12 weeks after the initiation of PRI-724 administration
Improvement rate of lower leg edema	Changes of rate	12 weeks after the initiation of PRI-724 administration
Assessment of Area under the plasma concentration versus time curve (AUCinf) of PRI-724 through analysis of blood samples	Comparison of AUC	Days 1-2 for preinfusion, 0.5, 1.0, 2.0, 4.0, and 24h; Day 7-8 for prestopping, 0.5, 1.0, 2.0, 4.0, and 24h
Assessment of Steady State Plasma Concentration (Css) of PRI-724 through analysis of blood samples	Comparison of Css	Days 1-2 for preinfusion, 0.5, 1.0, 2.0, 4.0, and 24h; Day 7-8 for prestopping, 0.5, 1.0, 2.0, 4.0, and 24h

Collaborators and Investigators

• Sponsor: Komagome Hospital
• Collaborators: Japan Agency for Medical Research and Development; Prism Pharma Co., Ltd.

Publications and helpful links

General Publications

• Kimura K, Ikoma A, Shibakawa M, Shimoda S, Harada K, Saio M, Imamura J, Osawa Y, Kimura M, Nishikawa K, Okusaka T, Morita S, Inoue K, Kanto T, Todaka K, Nakanishi Y, Kohara M, Mizokami M. Safety, Tolerability, and Preliminary Efficacy of the Anti-Fibrotic Small Molecule PRI-724, a CBP/beta-Catenin Inhibitor, in Patients with Hepatitis C Virus-related Cirrhosis: A Single-Center, Open-Label, Dose Escalation Phase 1 Trial. EBioMedicine. 2017 Sep;23:79-87. doi: 10.1016/j.ebiom.2017.08.016. Epub 2017 Aug 19.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): March 31, 2017

Study Registration Dates

• First Submitted: July 8, 2014
• First Submitted That Met QC Criteria: July 17, 2014
• First Posted (Estimate): July 21, 2014

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 4, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Hepatitis C virus, cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Fibrosis; Hepatitis; Hepatitis C; Liver Cirrhosis
• Other Study ID Numbers: PRI-724-1101; UMIN000014395 (Other Identifier: UMIN (University Hospital Medical Information) CTR)