Safety And Efficacy Of Oral PF-4136309 In Patients With Chronic Hepatitis C Infection And Abnormal Liver Enzymes

Study Overview
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Brief Summary
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This study will evaluate the effect of PF-04136309 in patients with chronic hepatitic C virus infection and abnormal liver enzymes.

Detailed Description
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Study recruitment was stopped on Dec 15, 2011 due to difficulty in enrolling the targeted number of patients. Subjects currently enrolled into the study will complete the study as per protocol. There were no safety concerns involved in the decision to stop enrollment. The new anticipated Last Subject Last Visit (LSLV) is February 2012.

Official Title
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A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF ORAL PF-04136309 500 MG BID IN SUBJECTS WITH CHRONIC HCV INFECTION AND RAISED AMINOTRANSFERASES

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-04136309


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic HCV infection ALT >1.5 but <10 times upper limit of normal Exclusion Criteria: Decompensated or severe liver disease defined by one or more of the following criteria: Prior liver biopsy showing cirrhosis. International Normalized Ratio (INR) greater than or equal to 1.5. Total bilirubin greater than or equal to 1.5X ULN, or >2X ULN for unconjugated bilirubin. Serum albumin below normal. ALT or aspartate aminotransferase (AST) >10 x ULN. Evidence of portal hypertension including splenomegaly, ascites, encephalopathy, and/or esophageal varices. Presence of human immunodeficiency virus (HIV). Co-infection with hepatitis B virus (HBV). Co-infection with Epstein Barr Virus (EBV) and/or Cytomegalovirus (CMV).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Take 4 capsules twice daily 12 hours apart with water. Swallow whole.<br>|
| Active Comparator: PF-04136309<br> | Drug: PF-04136309<br>* Take 4 capsules twice daily 12 hours apart with water. Swallow whole.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response in Serum Alanine Aminotransferase (ALT) Level at Week 4 | Responder was defined as a participant who experienced reduction in ALT of greater than or equal to (>=) 30 percent (%) of the baseline value. Baseline ALT value was defined as mean of measurements collected at screening visits 1 and 2 and pre-dose Day 1. ALT levels were determined at central lab. | Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Response in Serum Aspartate Aminotransferase (AST) Level From Baseline at Week 4 | AST responder status was defined as a reduction in AST >= 30% of the baseline value and or normalization. Baseline AST level was defined as the mean of measurements collected on screening visit 1 and pre-dose Day 1. AST levels were determined at central lab. | Week 4 | 
| Change From Baseline in Serum ALT at Weeks 1, 2, 3 and 4 | Baseline ALT value was defined as mean of measurements collected at screening visits 1 and 2 and pre-dose Day 1. | Baseline, Weeks 1, 2, 3 and 4 | 
| Serum ALT at Baseline | Baseline ALT level was defined as the mean of measurements collected on Screening visits 1 and 2 and pre-dose Day 1. | Baseline | 
| Change From Baseline in Serum AST at Weeks 1, 2, 3 and 4 | Baseline AST level was defined as the mean of measurements collected on screening visit 1 and pre-dose Day 1. | Baseline, Weeks 1, 2, 3 and 4 | 
| Serum AST at Baseline | Baseline AST level was defined as the mean of measurements collected on screening visit 1 and pre-dose Day 1. | Baseline | 
| Change From Baseline in Methacetin Breath Test (BreathID) at Weeks 1 and 4 | After drinking 13ˆC-methacetin, participants breath was collected using a BreathID® collection system for approximately 60 minutes and the ratio of 13ˆCO2:12ˆCO2 were determined to monitor the function of the liver. Results to be reported in ratio. | Baseline, Weeks 1 and 4 | 
| Change From Baseline in Enhanced Liver Fibrosis Test (ELF) at Week 4 | Markers of fibrosis assessed in the ELF test comprise hyaluronic acid (HA), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), and amino terminal peptide of pro-collagen III (PIIINP). The HA ranges from 0 to 1000 in ng/mL; the TIMP-1 ranges from 0 to 3000 ng/mL; and the PIIINP tissue ranges from 0 to 151 in nanograms/milliliter (ng/mL). ELF algorithm calculates a discriminant score (DS) specified by DS = -7.412 plus (+) 0.681 times (*)ln(HA)+ 0.494 * ln(TIMP1)+ 0.775 * ln(PIIINP). Results to be reported in discriminant score. | Baseline, Week 4 | 
| Maximum Observed Plasma Concentration (Cmax) of PF-04136309 | Cmax was defined as maximum observed plasma concentration of PF-04136309. | Pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose on Day 28 | 
| Plasma Decay Half-Life (t1/2) of PF-04136309 | Plasma decay half-life was the time measured for the plasma concentration to decrease by one half. | Pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose on Day 28 | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of PF-04136309 | AUCtau was defined as area under the concentration curve from time zero to end of dosing interval of PF-04136309. | Pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose on Day 28 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) of PF-04136309 | Tmax was defined as time to reach maximum observed plasma concentration of PF-04136309. | Pre-dose, 0.5, 1, 2, 4, 6, 8 and 12 hours post-dose on Day 28 | 
| Change From Baseline in Phosphorylated Extracellular Signal- Regulated Kinase (p-ERK) Levels at Week 2 and 4 | p-ERK is a biomarker used to assess bioavailability of PF-04136309. Baseline p-ERK level defined as the last pre-dose measurement. | Baseline, Week 2 and 4 | 
| Baseline p-ERK | p-ERK is a biomarker used to assess bioavailability of PF-04136309. Baseline p-ERK level defined as the last pre-dose measurement. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic HCV infection, raised ALT, transaminitis, HCV infection