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

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

Detailed Description
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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.

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

Conditions
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Hepatitis C Virus-infected Cirrhosis

Intervention / Treatment
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* Drug: PRI-724


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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). Child-Pugh Class A or B at the time of informed consent, with no likelihood of improvement with existing medical treatment. Performance Status: 0 - 2. Between =>20 and <75 years of age at the time of providing written consent. Having provided voluntary written consent for participation in this study. Esophageal and gastric varices are well controlled Exclusion Criteria: Patients with cirrhosis due to causes other than hepatitis C virus; or patients with cirrhosis due to unknown causes. Patients with a history of primary liver cancer or a complication thereof. Patients with a complication of malignant tumor or a history thereof (within 5 years prior to screening). Patients in whom such active viral infections as HBV, HIV or ATCL or syphilis infection cannot be ruled out. Patients with serum creatinine >1.5 times over upper normal or creatinine clearance =<60 mL/min/1.73 m2. Patients with hemoglobin <8 g/dL. Patients with platelet count <50,000 /&micro;L. Patients with T.Bil =>3.0 mg/dL. Patients with a complication of poorly controlled diabetes, hypertension or heart failure. Patients with a complication of mental disorder requiring treatment. Patients with serious allergy to contrast media or a history thereof. Patients with allergy to inactive ingredients of the study drug. Patients who have received interferon, ribavirin or anti-HCV agents within 12 weeks before registration in this study. 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. 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. 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. Patients contraindicated for liver biopsy. 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. Male patients who do not consent to practice birth control during the clinical study.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRI-724<br>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<br>* 10 - 160 mg/m2, 7 days CIV (in the vein) with 7 days rest per one cycle. Number of Cycles: 6.<br>* Other names: OP-724;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C virus, cirrhosis