A Study of the Pharmacokinetics of Uprifosbuvir (MK-3682) and Ruzasvir (MK-8408) in Participants With Moderate and Severe Hepatic Insufficiency (MK-3682-029)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Completed

CT.gov ID

NCT02666352

Collaborator

(none)

Enrollment

Arms

11.8

Actual Duration (Months)

Study Details

Study Description

Brief Summary

This is a non-randomized, open-label, single-dose study to evaluate the pharmacokinetics (PK) of uprifosbuvir (MK-3682), the M5 and M6 metabolites of uprifosbuvir, and ruzasvir (MK-8408), in participants with moderate hepatic insufficiency (HI), participants with severe HI, and age-matched healthy control participants.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C, Chronic	Drug: Uprifosbuvir Drug: Ruzasvir	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3682 and MK-8408 When Coadministered to Subjects With Moderate and Severe Hepatic Insufficiency

Actual Study Start Date :

Jan 22, 2016

Actual Primary Completion Date :

Jan 16, 2017

Actual Study Completion Date :

Jan 16, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Moderate HI Participants On Day 1, participants with moderate HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Drug: Uprifosbuvir A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth. Other Names: MK-3682 Drug: Ruzasvir A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth. Other Names: MK-8408
Experimental: Severe HI Participants On Day 1, participants with severe HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Drug: Uprifosbuvir A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth. Other Names: MK-3682 Drug: Ruzasvir A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth. Other Names: MK-8408
Experimental: Healthy Participants On Day 1, participants with normal hepatic function will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Drug: Uprifosbuvir A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth. Other Names: MK-3682 Drug: Ruzasvir A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth. Other Names: MK-8408

Arm

Intervention/Treatment

Experimental: Moderate HI Participants

On Day 1, participants with moderate HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.

Drug: Uprifosbuvir

A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.

Other Names:

MK-3682

Drug: Ruzasvir

A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.

Other Names:

MK-8408

Experimental: Severe HI Participants

On Day 1, participants with severe HI will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.

Drug: Uprifosbuvir

A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.

Other Names:

MK-3682

Drug: Ruzasvir

A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.

Other Names:

MK-8408

Experimental: Healthy Participants

On Day 1, participants with normal hepatic function will receive a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.

Drug: Uprifosbuvir

A single dose of uprifosbuvir 450 mg (given as three 150-mg tablets) taken by mouth.

Other Names:

MK-3682

Drug: Ruzasvir

A single dose of ruzasvir 60 mg (given as six 10-mg capsules) taken by mouth.

Other Names:

MK-8408

Outcome Measures

Primary Outcome Measures

Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose]
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir [24 hours post-dose]
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time to Reach Cmax (Tmax) of Uprifosbuvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent Terminal Half-Life (t1/2) of Uprifosbuvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last of Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-inf of Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-24hr of Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose]
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Cmax of Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
C24hr of Uprifosbuvir Metabolite M5 [24 hours post-dose]
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Lag Time (Tlag) for Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Tlag is a measure of the time delay between drug administration and the onset of absorption, where onset of absorption is defined as "the time point prior to the first observed/measured non-zero plasma concentration". The Tlag of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm (in this study Tlag was only calculated for the M5 uprifosbuvir metabolite).
Tmax of Uprifosbuvir Metabolite M5 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent t1/2 of Uprifosbuvir Metabolite M5 [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last of Uprifosbuvir Metabolite M6 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-inf of Uprifosbuvir Metabolite M6 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-24hr of Uprifosbuvir Metabolite M6 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose]
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Cmax of Uprifosbuvir Metabolite M6 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
C24hr of Uprifosbuvir Metabolite M6 [24 hours post-dose]
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Tmax of Uprifosbuvir Metabolite M6 [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Apparent t1/2 of Uprifosbuvir Metabolite M6 [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
AUC0-last of Ruzasvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
AUC0-inf of Ruzasvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
AUC0-24hr of Ruzasvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose]
AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Maximum Plasma Drug Concentration (Cmax) of Ruzasvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
C24hr of Ruzasvir [24 hours post-dose]
C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Tmax of Ruzasvir [Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Apparent t1/2 of Ruzasvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
CL/F of Ruzasvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Vz/F of Ruzasvir [Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose]
Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

HI Participants Only:

Has a diagnosis of chronic (>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI features of cirrhosis;
Part 1 only: Participant's score on the Child-Pugh scale ranges from 7 to 9 (moderate HI) at study start.
Part 2 only: Participant's score on the Child-Pugh scale ranges from 10 to 15 (severe HI) at study start.

All Participants:

Body mass index (BMI) ≥19 and ≤ 40 kg/m^2;
Continuous non-smokers or moderate smokers (of fewer than 20 cigarettes/day or the equivalent). Participants must agree to consume no more than 10 cigarettes or equivalent/day from the time of screening and throughout the period of sample collection;
Health is judged to be stable based on medical history (except for the hepatic impairment condition), physical examination, vital signs, electrocardiogram (ECGs), and laboratory safety tests;
For female participants of childbearing potential: either sexually inactive for 14 days prior to study start and throughout study or be using an acceptable birth control method;
Female participants who are sexually inactive, but become sexually active during the course of the study must agree to use a double physical barrier method (e.g., condom and diaphragm) and a chemical barrier (e.g., spermicide) from the time of the start of sexual activity through completion of the study;
Vasectomized or non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing;
Male participants must agree not to donate sperm from dosing until 90 days after dosing;
Able to swallow multiple tablets and capsules.

Exclusion Criteria:

HI Participants Only:

Presence of moderate or severe renal insufficiency (estimated glomerular filtration rate [eGFR] ≤50 mL/min/1.73 m^2 calculated according to the Modification of Diet in Renal Disease [MDRD] study equation);
Presence of drug abuse within the past 6 months prior to dosing.

Healthy Participants Only:

Presence of moderate or severe renal insufficiency (eGFR ≤60 mL/min/1.73 m^2 calculated according to the MDRD study equation);
History or presence of alcoholism or drug abuse within the past 2 years prior to dosing;

All Participants:

Is mentally or legally incapacitated or has significant emotional problems at the time of study start or expected during the study;
History or presence of clinically significant medical or psychiatric condition or disease;
History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds;
Female participants who are pregnant or lactating;
Positive results at study start for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV);
Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements) for the prohibited time period;
Has taken amiodarone at any time in their life;
Donation of blood >500 mL or had significant blood loss within 56 days prior to the dose of study drugs;
Plasma donation within 7 days prior to the dose of study drugs;
Dosed in another clinical trial within 28 days prior to dosing of study drugs;

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Merck Sharp & Dohme LLC

ClinicalTrials.gov Identifier:

NCT02666352

Other Study ID Numbers:

3682-029

First Posted:

Jan 28, 2016

Last Update Posted:

Sep 17, 2018

Last Verified:

Jan 1, 2018

Additional relevant MeSH terms:

Hepatitis C

Hepatitis C, Chronic

Hepatic Insufficiency

Liver Failure

Uprifosbuvir

Ruzasvir

Study Results

Participant Flow

Recruitment Details	Participants with moderate hepatic insufficiency (HI), severe HI, and healthy controls were recruited at 2 study centers in the United States.
Pre-assignment Detail

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Period Title: Overall Study
STARTED	8	8	8
COMPLETED	8	8	8
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants	Total
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Total of all reporting groups
Overall Participants	8	8	8	24
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	58.3 (8.7)	55.4 (8.2)	57.6 (6.3)	57.1 (7.5)
Sex: Female, Male (Count of Participants)
Female	2 25%	3 37.5%	3 37.5%	8 33.3%
Male	6 75%	5 62.5%	5 62.5%	16 66.7%

Outcome Measures

1. Primary Outcome

Title	Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Time of the Last Quantifiable Sample (AUC0-last) of Uprifosbuvir
Description	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	5.34	8.02	3.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 90% 0.89 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 90% 1.33 to 3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Area Under the Drug Plasma Concentration-Time Curve From Start of Dosing to Infinity (AUC0-inf) of Uprifosbuvir
Description	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	5.39	8.09	3.76

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 90% 0.88 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	2.15
	Confidence Interval	() 90% 1.33 to 3.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Area Under the Plasma Drug Concentration-Time Curve From Start of Dosing to 24 Hours Post-Dose (AUC0-24hr) of Uprifosbuvir
Description	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	5.35	8.02	3.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 90% 0.89 to 2.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 90% 1.33 to 3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Maximum Plasma Drug Concentration (Cmax) of Uprifosbuvir
Description	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	1560	2130	1180

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 90% 0.81 to 2.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.81
	Confidence Interval	(2-Sided) 90% 1.11 to 2.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Plasma Drug Concentration at 24 Hours (C24hr) of Uprifosbuvir
Description	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [nM]	7.01	8.56	2.55

6. Primary Outcome

Title	Time to Reach Cmax (Tmax) of Uprifosbuvir
Description	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [hr]	1.00	0.50	1.25

7. Primary Outcome

Title	Apparent Terminal Half-Life (t1/2) of Uprifosbuvir
Description	t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [hr]	3.66 (21.7)	3.56 (47.5)	3.17 (38.5)

8. Primary Outcome

Title	Apparent Total Clearance From Plasma After Oral Administration (CL/F) of Uprifosbuvir
Description	CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	153 (39.9)	102 (61.1)	219 (77.6)

9. Primary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase After Extravascular Administration (Vz/F) of Uprifosbuvir
Description	Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [L]	809 (43.8)	524 (57.0)	1000 (83.0)

10. Primary Outcome

Title	AUC0-last of Uprifosbuvir Metabolite M5
Description	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	6.46	6.79	8.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 90% 0.58 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 90% 0.61 to 1.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	AUC0-inf of Uprifosbuvir Metabolite M5
Description	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	6.78	7.22	8.44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 90% 0.58 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.86
	Confidence Interval	() 90% 0.62 to 1.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	AUC0-24hr of Uprifosbuvir Metabolite M5
Description	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	2.41	2.28	3.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 90% 0.57 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 90% 0.54 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Primary Outcome

Title	Cmax of Uprifosbuvir Metabolite M5
Description	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	169	151	203

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 90% 0.61 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 90% 0.55 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	C24hr of Uprifosbuvir Metabolite M5
Description	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	124	122	150

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 90% 0.60 to 1.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 90% 0.59 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Lag Time (Tlag) for Uprifosbuvir Metabolite M5
Description	Tlag is a measure of the time delay between drug administration and the onset of absorption, where onset of absorption is defined as "the time point prior to the first observed/measured non-zero plasma concentration". The Tlag of the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm (in this study Tlag was only calculated for the M5 uprifosbuvir metabolite).
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [hr]	3.00	2.53	2.00

16. Primary Outcome

Title	Tmax of Uprifosbuvir Metabolite M5
Description	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [hr]	14.00	16.00	15.00

17. Primary Outcome

Title	Apparent t1/2 of Uprifosbuvir Metabolite M5
Description	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M5 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [hr]	24.09 (17.2)	25.64 (19.2)	23.59 (9.7)

18. Primary Outcome

Title	AUC0-last of Uprifosbuvir Metabolite M6
Description	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	28.6	27.4	41.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 90% 0.52 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 90% 0.50 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Primary Outcome

Title	AUC0-inf of Uprifosbuvir Metabolite M6
Description	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	30.1	28.7	47.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 90% 0.48 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.61
	Confidence Interval	() 90% 0.46 to 0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Primary Outcome

Title	AUC0-24hr of Uprifosbuvir Metabolite M6
Description	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	13.1	13.2	16.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 90% 0.62 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 90% 0.63 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Primary Outcome

Title	Cmax of Uprifosbuvir Metabolite M6
Description	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	851	834	1070

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 90% 0.61 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 90% 0.60 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Primary Outcome

Title	C24hr of Uprifosbuvir Metabolite M6
Description	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	402	410	564

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 90% 0.57 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 90% 0.58 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Primary Outcome

Title	Tmax of Uprifosbuvir Metabolite M6
Description	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [hr]	6.00	4.00	4.00

24. Primary Outcome

Title	Apparent t1/2 of Uprifosbuvir Metabolite M6
Description	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for the M6 metabolite of uprifosbuvir 450 mg (given in combination with ruzasvir 60 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [hr]	26.96 (19.4)	26.45 (31.3)	33.98 (37.7)

25. Primary Outcome

Title	AUC0-last of Ruzasvir
Description	AUC0-last is a measure of the mean plasma drug concentration from time of dosing to the last quantifiable sample. The AUC0-last for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	2.30	2.70	1.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio (GMR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 90% 0.85 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 90% 1.00 to 1.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Primary Outcome

Title	AUC0-inf of Ruzasvir
Description	AUC0-inf is a measure of the mean plasma drug concentration from time of dosing to infinity. The AUC0-inf for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	2.60	3.32	2.10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 90% 0.91 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.58
	Confidence Interval	() 90% 1.17 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Primary Outcome

Title	AUC0-24hr of Ruzasvir
Description	AUC0-24hr is a measure of the mean plasma drug concentration from time of dosing to 24 hours post-dose. The AUC0-24hr for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [µM*hr]	1.04	1.05	1.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 90% 0.60 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 90% 0.60 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Primary Outcome

Title	Maximum Plasma Drug Concentration (Cmax) of Ruzasvir
Description	Cmax is the maximum observed plasma drug concentration after dosing. The Cmax for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	105	92.5	137

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 90% 0.45 to 1.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 90% 0.40 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Primary Outcome

Title	C24hr of Ruzasvir
Description	C24hr is a measure of plasma drug concentration 24 hours after dosing. The C24hr of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	24 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Least Squares Mean (95% Confidence Interval) [nM]	27.6	32.4	23.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 90% 0.90 to 1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Severe HI Participants, Healthy Participants
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric least-squares mean ratio
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 90% 1.06 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Primary Outcome

Title	Tmax of Ruzasvir
Description	Tmax is the time required to reach maximum plasma drug concentration (i.e., Cmax). The Tmax of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Median (Full Range) [hr]	3.00	2.03	3.00

31. Primary Outcome

Title	Apparent t1/2 of Ruzasvir
Description	Apparent t1/2 is a measure of how long it takes to clear 50% of drug after reaching Cmax. The t1/2 for ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [hr]	38.08 (23.1)	47.26 (36.6)	30.43 (14.6)

32. Primary Outcome

Title	CL/F of Ruzasvir
Description	CL/F is a measure of the apparent rate at which drug is removed from the body via renal, hepatic, and other clearance pathways after oral administration. The CL/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [L/hr]	28.4 (36.7)	20.6 (52.8)	32.6 (54.6)

33. Primary Outcome

Title	Vz/F of Ruzasvir
Description	Vz/F is the apparent volume of distribution during the terminal phase after non-intravenous administration. The Vz/F of ruzasvir 60 mg (given in combination with uprifosbuvir 450 mg) was calculated for each arm.
Time Frame	Pre-dose (0) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 14, 16, 18, 20, 24, 48, 72, 96, and 120 hours post-dose

Outcome Measure Data

Analysis Population Description
All participants are included in the analysis.

Arm/Group Title	Moderate HI Participants	Severe HI Participants	Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.	Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
Measure Participants	8	8	8
Geometric Mean (Geometric Coefficient of Variation) [L]	1560 (49.8)	1400 (37.9)	1430 (48.1)

Adverse Events

	Moderate HI Participants		Severe HI Participants		Healthy Participants
Time Frame	Up to 14 days
Adverse Event Reporting Description	An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All participants are included in the safety analysis.

Arm/Group Title	Moderate HI Participants		Severe HI Participants		Healthy Participants
Arm/Group Description	Participants with moderate HI (Child-Pugh score 7 to 9) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.		Participants with severe HI (Child-Pugh score 10 to 15) received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.		Participants with normal hepatic function received a single oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Moderate HI Participants		Severe HI Participants		Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Moderate HI Participants		Severe HI Participants		Healthy Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/8 (12.5%)		3/8 (37.5%)		0/8 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/8 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Flatulence	1/8 (12.5%)	1	0/8 (0%)	0	0/8 (0%)	0
Nervous system disorders
Dizziness	0/8 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Hepatic encephalopathy	0/8 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0
Headache	0/8 (0%)	0	1/8 (12.5%)	1	0/8 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor will provide separate guidance on the criteria for publication of clinical trial data when contacted for permission to publish.

Results Point of Contact

Name/Title	Senior Vice President, Global Clinical Development
Organization	Merck Sharp & Dohme Corp.
Phone	1-800-672-6372
Email	ClinicalTrialsDisclosure@merck.com

Responsible Party:

Merck Sharp & Dohme LLC

ClinicalTrials.gov Identifier:

NCT02666352

Other Study ID Numbers:

3682-029

First Posted:

Jan 28, 2016

Last Update Posted:

Sep 17, 2018

Last Verified:

Jan 1, 2018