A Safety And Pharmacokinetic Study of Setrobuvir Alone and In Combination With Ritonavir-Boosted Danoprevir in Subjects With Mild Hepatic Impairment Compared to Healthy Controls

A Multi Center, Sequential, Open-Label, Multiple-Dose Study of Setrobuvir (STV) Alone and With Co-Administration of Ritonavir-boosted Danoprevir to Evaluate the Safety, Tolerability and Pharmacokinetics of STV, DNV, and Ritonavir (RTV) in Subjects With Mild Hepatic Impairment Compared to Healthy Controls

This multi-center, fixed-sequence, open-label, multiple-dose, 2-period study will evaluate the safety, tolerability and pharmacokinetics of setrobuvir alone or in combination with ritonavir-boosted danoprevir in subjects with mild hepatic impairment compared to healthy controls. All subjects will receive multiple doses of setrobuvir orally for 10 days in Period 1 and multiple doses of setrobuvir plus ritonavir-boosted danoprevir orally for 10 days in Period 2, with a washout phase of at least 9 days between treatments.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteer
• Intervention / Treatment: Drug: setrobuvir; Drug: danoprevir; Drug: ritonavir

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Balatonfuered, Hungary, 8230
  • Budapest, Hungary, 1076
• Poland
  • Warszawa, Poland, 01-201

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:

• Male and female adults, 18-65 years of age, inclusive
• Weight >/= 45.0 kg
• Body mass index (BMI) 18.0 - 35.0 kg/m2, inclusive
• Females of childbearing potential and males and their female partners of childbearing potential must agree to use two forms of non-hormonal contraception as defined by protocol
• Subjects with a history of substance abuse may be enrolled provided they have not abused drugs or alcohol for at least 6 months
• Healthy subjects only:

Medical history without major recent or ongoing pathology Laboratory values at screening and Day -1 within the normal range or showing no clinically relevant deviations

• Subjects with hepatic impairment only:

Stable mild liver disease (Child-Pugh A) of cryptogenic, post-hepatic, hepatitis B/C, or alcoholic origin Stable hepatic impairment defined as no clinically significant change in disease status within the last 30 days Must be on stable dose of medication and/or treatment regimen at least 2 weeks before dosing of study medication

Exclusion Criteria:

• Pregnant or lactating women or males with female partners who are pregnant or lactating
• Active infection or febrile illness </= 10 days prior to the first dose of study medication
• Uncontrolled/untreated hypertension
• Inadequate renal function
• Positive urine drug screen or positive breath alcohol test at screening and on Day -1 of each period
• An average alcohol intake of more than 2 units per day or 14 units per week until 48 hours prior to enrollment
• History of any significant drug-related allergy or hepatotoxicity
• Participation in other clinical studies with an investigational drug or new chemical entity within 3 months (6 months for biologic therapies) prior to the first dose of study medication
• Positive for HIV infection
• Any clinically significant cardiovascular or cerebrovascular disease
• Healthy subjects only:

Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, absorption of medication, or that would, in the opinion of the investigator, pose an unacceptable risk to the subject in this study Positive screening test for HBsAg or HCV antibody

• Subjects with hepatic impairment only:

Severe ascites at screening or Day -1 History of or current severe hepatic encephalopathy (Grade 3 or higher) Biliary liver cirrhosis or other causes of hepatic impairment not related to parenchymal disorder and/or disease of the liver Positive screening test for HCV antigen

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: setrobuvir	Drug: setrobuvir; 200 mg orally every 12 hours
Experimental: B: setrobuvir + DNV/r	Drug: setrobuvir; 200 mg orally every 12 hours; Drug: danoprevir; 100 mg orally every 12 hours; Drug: ritonavir; 100 mg orally every 12 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety: Incidence of adverse events	approximately 40 days
Pharmacokinetics: Maximum plasma concentration at steady-state (Css,max)	up to 16 days
Pharmacokinetics: Total area under the concentration-time curve form time 0 to 12 hours post-dose at steady-state (AUCss,0-12h)	up to 16 days
Pharmacokinetics: Plasma concentration at steady-state 12 hours post-dose (Css, 12h)	up to 16 days

Secondary Outcome Measures

Outcome Measure	Time Frame
Pharmacokinetics: Time to maximum plasma concentration (tmax)	up to 16 days
Pharmacokinetics: Elimination half-life (t1/2)	up to 16 days
Pharmacokinetics: Apparent oral clearance at steady-state (CLss/F)	up to 16 days
Pharmacokinetics: Cumulative amount excreted at steady-state (Aess)	up to 16 days
Pharmacokinetics: Fraction of orally administered drug excreted into urine (fe/f)	up to 16 days
Pharmacokinetics of danoprevir in combination with setrobuvir: Area under the concentration-time curve (AUC)	up to 12 days
Pharmacokinetics of ritonavir in combination with setrobuvir: Area under the concentration-time curve (AUC)	up to 12 days

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: October 23, 2012
• First Submitted That Met QC Criteria: October 23, 2012
• First Posted (Estimate): October 25, 2012

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir
• Other Study ID Numbers: NP28326; 2012-002283-28 (EudraCT Number)