Open-Label Hepatic Impairment Study

Study Overview
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Brief Summary
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This study will be conducted in Hepatitis C positive patients to determine whether the pharmacodynamic effects of PSI-7977 or PSI-352938 are similar to HCV-infected patients with normal hepatic function, which may allow inclusion of patients with cirrhosis and varying degrees of hepatic dysfunction in future clinical studies.

Detailed Description
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This study is designed per the Food and Drug Administration (FDA) guidance for patients with impaired hepatic function to assess the influence of hepatic impairment on the PK and pharmacodynamics (PD) of PSI-7977 and PSI-352938 This study will be conducted in Hepatitis C positive patients to ascertain whether the PD effects of PSI-7977 or PSI-352938 are similar to HCV-infected patients with normal hepatic function, which may allow inclusion of patients with cirrhosis and varying degrees of hepatic dysfunction in future clinical studies. Data from subjects who participated in the P2938-0212 study (PSI-352938 MAD) will be used as the control group. These subjects were documented non-cirrhotic subjects with normal hepatic function. Hepatitis C Virus (HCV) Genotypes 1-6 will be enrolled in this study.

Official Title
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An Open-Label Study to Characterize the Pharmacokinetics and Pharmacodynamics of Multiple Oral Doses of PSI-7977 or PSI-352938 in HCV-infected Subjects With Varying Degrees of Hepatic Impairment

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: PSI-352938
* Drug: PSI-7977


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatic impaired Males or females of non-childbearing potential aged > 18 years with Chronic HCV-infection Naïve to all direct acting anti-viral (DAA) treatments for chronic HCV infection. Documented Cirrhosis Exclusion Criteria: Prior PEG/RBV null responders. Unstable cardiac disease, recent Myocardial infarction, or family history of QTc prolongation or unexplained cardiac arrest. Positive test at Screening for anti-HAV IgM Ab, HBsAg, anti-HBc IgM Ab, or anti-human immunodeficiency virus (HIV) Ab. History of clinically significant medical condition associated with other chronic liver disease Any current signs or symptoms of severe hepatic encephalopathy History of gastric or esophageal variceal bleeding in which varices have not been adequately treated with medication and surgical procedures Prior placement of a portosystemic shunt History of hepatorenal, or hepatopulmonary syndrome. Active spontaneous bacterial peritonitis. Use of medications associated with QT prolongation within 28 days prior to dosing. Current Hypotension History of Torsades de Pointes, evidence of an active or suspected cancer, or a history of malignancy, Abnormal hematological and biochemical parameters

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PSI-352938 Group A<br>Mild (Child-Pugh Class A; 5-6) hepatic impairment | Drug: PSI-352938<br>* PSI-352938 300mg once daily (QD) for seven days<br>|
| Experimental: PSI-352938 Group B<br>Moderate (Child-Pugh Class B; 7-9) hepatic impairment | Drug: PSI-352938<br>* PSI-352938 300mg once daily (QD) for seven days<br>|
| Experimental: PSI-352938 Group C<br>Severe (Child-Pugh Class C; 10-15) hepatic impairment | Drug: PSI-352938<br>* PSI-352938 300mg once daily (QD) for seven days<br>|
| Experimental: PSI-7977 Group A<br>Mild (Child-Pugh Class A; 5-6) hepatic impairment | Drug: PSI-7977<br>* PSI-7977 400mg QD for seven days<br>|
| Experimental: PSI-7977 Group B<br>Moderate (Child-Pugh Class B; 7-9) hepatic impairment | Drug: PSI-7977<br>* PSI-7977 400mg QD for seven days<br>|
| Experimental: PSI-7977 Group C<br>Severe (Child-Pugh Class C; 10-15) hepatic impairment | Drug: PSI-7977<br>* PSI-7977 400mg QD for seven days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic data derived from plasma samples collected over 7 days | To characterize the pharmacokinetics (PK) of PSI-352938 over 7 days of dosing with PSI-352938 in HCV-infected patients with varying degrees of hepatic impairment compared to historical PK data. | 28 time points over Seven Days | 
| Pharmacokinetic comparison with historical data over 7 days of dosing with PSI-7977 | To characterize the PK of PSI-7977 and metabolites over 7 days of dosing with PSI-7977 in HCV-infected patients with varying degrees of hepatic impairment compared to historical PK data. | Seven Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of adverse events | To assess the safety and tolerability of 7 days of dosing of PSI-352938 or PSI-7977 in HCV infected patients with varying degrees of hepatic impairment. | Seven Days | 
| Viral dynamics/ changes in HCV (ribonucleic acid) RNA | To evaluate the viral dynamics as measured by changes in the HCV RNA in HCV-infected patients with varying degrees of hepatic impairment after 7 days of dosing with PSI-352938 or PSI-7977. | Baseline through follow-up (post-Day 14) | 
| Changes in genotypic or phenotypic measurements | To assess the presence of baseline polymorphisms in viral isolates and development of viral genotypic and phenotypic changes from baseline. | Seven Days | 
| Dosage adjustment in hepatically impaired patients | To provide dosage adjustment guidance for PSI-352938 or PSI-7977 based on the degree of hepatic impairment, if applicable. | Seven days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HEPATITIS C, CHRONIC, HCV, hepatic impairment