A Study to Assess Safety and Pharmacokinetics of Telaprevir in Patients With Hepatic Impairment

A Phase I Study to Assess the Safety and Pharmacokinetics of Telaprevir (VX-950) in Subjects With Moderate and Severe Hepatic Impairment

The purpose of this study is to determine whether the pharmacokinetic (what the body does to the drug) parameters of telaprevir are altered in patients with moderate hepatic impairment, compared to the pharmacokinetic parameters in patients with normal liver function, and measure the relative unbound plasma concentrations of telaprevir.

Study Overview

• Status: Completed
• Conditions: Hepatic Impairment
• Intervention / Treatment: Drug: telaprevir

Detailed Description

This is a Phase I, open-label (all people know the identity of the intervention) study to investigate the single dose and steady state pharmacokinetics of telaprevir in patients with moderate hepatic impairment, and measure the relative unbound plasma concentrations of telaprevir. In addition, a small group of patients with severe hepatic impairment will be included to further characterize the pharmacokinetics of telaprevir as a function of liver disease. In this study 24 patients will be enrolled. Based upon physical examination and laboratory assessments, patients will be scored and classified into hepatic function groups on the basis of the Child-Pugh classification (Classification is based on Child-Pugh score which is used to assess prognosis of chronic hepatic disease). A Child-Pugh score of 7 to 9 is considered Child-Pugh category B (CPB) and indicative of moderate liver function impairment; a Child-Pugh score of 10 or greater is considered Child Pugh category C (CPC), indicative of severe liver impairment. Hepatic function groups will consists of Group 1: 10 patients with moderate hepatic impairment (CPB 7 to 9]); Group 2: 10 healthy control patients with normal hepatic function. Each healthy control patient is matched to a patient in Group 1 with respect to sex, age (+5 years or -5 years) and body mass index (BMI) (+15% or -15%); Group 3: 4 patients with severe hepatic impairment (CPC [limited to Child Pugh score 10 to 12]). Safety and tolerability evaluations including adverse events, clinical laboratory tests, 12-lead electrocardiogram, vital signs and physical examination will be recorded throughout the study period.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Czech Republic
  • Praha 7, Czech Republic
• Germany
  • Kiel, Germany

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

For Group 1:

• Moderate liver function impairment (Child Pugh score of 7 to 9)
• History of hepatic disease, such as hepatitis B, previous hepatitis C, alcoholic liver disease, autoimmune hepatitis, non-alcoholic fatty liver disease, hereditary/metabolic, cryptogenic, other
• Consistent with the disease process of hepatic impairment and associated symptoms

For Group 2:

- Matched to a patient with moderate hepatic impairment with regards to sex, age (± 5 years), and BMI (± 15%) and healthy on the basis of a medical evaluation that reveals the absence of any clinically relevant abnormality

For Group 3:

• Severe liver function impairment (limited to Child Pugh score of 10 to 12)
• Hepatic impairment due to different etiologies such as hepatitis B, previous hepatitis C, alcoholic liver disease, autoimmune hepatitis, non-alcoholic fatty liver disease, hereditary/metabolic, cryptogenic, other
• Consistent with the disease process of hepatic impairment and associated symptoms

Exclusion Criteria:

For Group 1 and 3:

• Has acute infectious hepatitis
• Has grade 3 or 4 encephalopathy
• Has grade 3 or 4 creatinine elevation
• Is an active candidate for liver transplantation
• Has had variceal bleeding or spontaneous bacterial peritonitis

For Group 1 only:

- Has a porta-caval shunt or transjugular intrahepatic porto-systemic shunts

For Group 2:

Has acute hepatitis A or hepatitis B or hepatitis C infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1; 10 patients with moderate hepatic impairment (CPB [Child-Pugh score 7 to 9])	Drug: telaprevir; Type=exact number, unit=mg, number=375, form=tablet, route=oral. Multiple doses of 2 oral tablets of telaprevir will be administered every 8 hours on Days 1 to 5 and a single dose of 2 oral tablets of telaprevir will be administered in the morning on Day 6.; Other Names: VX-950
Experimental: Group 2; 10 healthy control patients with normal hepatic function. Each healthy control patient is matched to a patient in Group 1 with respect to sex, age (± 5 years) and body mass index (BMI) (± 15%)	Drug: telaprevir; Type=exact number, unit=mg, number=375, form=tablet, route=oral. Multiple doses of 2 oral tablets of telaprevir will be administered every 8 hours on Days 1 to 5 and a single dose of 2 oral tablets of telaprevir will be administered in the morning on Day 6.; Other Names: VX-950
Experimental: Group 3; up to 4 patients with severe hepatic impairment (CPC [limited to Child Pugh score 10 to 12])	Drug: telaprevir; Type=exact number, unit=mg, number=375, form=tablet, route=oral. Multiple doses of 2 oral tablets of telaprevir will be administered every 8 hours on Days 1 to 5 and a single dose of 2 oral tablets of telaprevir will be administered in the morning on Day 6.; Other Names: VX-950

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparing the maximum plasma analyte concentration (Cmax) of telaprevir in patients of Group 2 and Group 1	The pharmacokinetic parameter Cmax of telaprevir following administration of single and multiple oral doses of telaprevir in patients with moderate hepatic impairment (CPB [Child-Pugh score 7 to 9]) ie, Group 1, as compared to matched healthy patients ie, Group 2	Day 1 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), Day 2 to Day 5 (predose), Day 6 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), and Day 7 (24 hour)
Comparing the area under the plasma concentration-time curve (AUC8h) of telaprevir in patients of Group 2 and Group 1	The pharmacokinetic parameter AUC8h will be measured from time of administration up to 8 hours post dose of telaprevir following administration of single and multiple oral doses of telaprevir in patients with moderate hepatic impairment (CPB) ie, Group 1, as compared to matched healthy patients ie, Group 2	Day 1 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), Day 2 to Day 5 (predose), Day 6 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), and Day 7 (24 hour)
Comparing the actual sampling time to reach the maximum plasma analyte concentration (tmax) of telaprevir in patients of Group 2 and Group 1	The pharmacokinetic parameter tmax will be measured following administration of single and multiple oral doses of telaprevir in patients with moderate hepatic impairment (CPB) ie, Group 1, as compared to matched healthy patients ie, Group 2	Day 1 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), Day 2 to Day 5 (predose), Day 6 (-1 hour, predose, 0, 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 9, 12, 15, 18 hours postdose), and Day 7 (24 hour)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of adverse events in Group 1 patients as a measure of safety	Number of adverse events in Group 1 patients as a measure of safety will be assessed following administration of single and multiple oral doses of telaprevir in patients with moderate hepatic impairment (CPB) ie, Group 1	up to Day 6
Comparing unbound fractions of telaprevir in patients of Group 1 and Group 2	The unbound fractions of telaprevir after single and multiple doses of telaprevir in patients with moderate hepatic impairment ie, Group 1, as compared to matched healthy patients ie, Group 2	up to Day 6
Comparing any relationship between the measures of hepatic function and selected pharmacokinetic parameters of telaprevir in patients of Group 1 and Group 2	To assess any relationship between the measures of hepatic function (ie, Child-Pugh score, albumin, bilirubin, alpha-1 acid glycoprotein, and prothrombin time) and selected pharmacokinetic parameters of telaprevir in patients with moderate hepatic impairment (CPB) ie, Group 1 and healthy patients ie, Group 2	up to Day 6

Collaborators and Investigators

• Sponsor: Janssen Infectious Diseases BVBA

Publications and helpful links

General Publications

• Ouwerkerk-Mahadevan S, Halabi A, Cieslarova B, Aerts I, Witek J, Van Solingen-Ristea R, Luo D. Pharmacokinetics of bound and unbound telaprevir in cirrhotic patients with moderate and severe hepatic impairment. J Clin Pharmacol. 2015 Oct;55(10):1147-56. doi: 10.1002/jcph.545. Epub 2015 Jul 7.

Helpful Links

• A Phase I study to assess the safety and pharmacokinetics of telaprevir (VX-950) in subjects with moderate and severe hepatic impairment

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): November 1, 2012

Study Registration Dates

• First Submitted: May 15, 2012
• First Submitted That Met QC Criteria: May 16, 2012
• First Posted (Estimate): May 17, 2012

Study Record Updates

• Last Update Posted (Estimate): November 11, 2013
• Last Update Submitted That Met QC Criteria: November 8, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Safety; Pharmacokinetics; Hepatitis C; Hepatic impairment; VX-950; Telaprevir; Unbound plasma concentrations; Child-Pugh score
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases
• Other Study ID Numbers: CR100872; VX-950HPC1001 (Other Identifier: Janssen Infectious Diseases BVBA); 2012-001627-13 (EudraCT Number)