GSK2336805 is a hepatitis C virus (HCV) NS5A inhibitor being developed for the treatment of chronic hepatitis C (CHC). This study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with chronic hepatitis C (CHC).
HCV infection is a major public health problem globally and a leading cause of chronic liver disease. New medications are needed that are better tolerated and offer a greater chance of achieving sustained viral clearance compared to currently available therapy. GSK2336805 is a HCV NS5A inhibitor being developed for the treatment of subjects with CHC. This Phase II, double blind, randomized, placebo-controlled study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with CHC. Subjects will be randomly allocated on a 2:1 basis to GSK2336805 or matching placebo and will be stratified by IL28B status and HCV viral genotype (genotype 1 or 4). The study consists of 2 parts. In Part 1, GSK2336805 or matching placebo will be given as single-dose monotherapy (Day 1). In Part 2, GSK2336805 or matching placebo will be co-administered with peginterferon alfa-2a and ribavirin through 4 weeks of treatment (Days 2 to 28). After completion of Part 2, GSK2336805/matching placebo will be discontinued and subjects will be offered continued standard-of-care anti-HCV therapy.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
16
GSK Investigational Site
Anaheim, California, United States
GSK Investigational Site
Chula Vista, California, United States
GSK Investigational Site
Coronado, California, United States
Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis
RVR was defined as the proportion of participants below the assay lower limit of detection (LOD) \<18 International units per milliliter (IU/mL) for Hepatitis C virus (HCV) ribonucleic acid (RNA) after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure . Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants.
Time frame: Day 28
Number of Participant Achieving RVR at Day 28, (Primary and Supportive Analyses)
RVR was defined as the proportion of participants LOD \<18 IU/mL for HCV RNA after 4 weeks of treatment (Day 28). Participants achieving RVR at Day 28 were considered treatment responders. Participants with missing HCV RNA values at Day 28 or discontinued before Day 28 were considered as treatment failure. Proportion of participants with HCV genotype 1 achieving RVR was the primary comparison of interest to show superiority of GSK2336805 over placebo in genotype 1 participants. The primary and supportive analysis differs from the nominal analysis as supportive analysis is assessed at Day 28 ± 2 (2 days visit window) whereas, the nominal analysis was assessed at Day 28.
Time frame: Day 28
Probability of Participants With HCV Genotype 1 Achieving RVR At Day 28, Nominal Analysis
The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed by nominal analysis was reported.
Time frame: Day 28
Probability of Participants With HCV Genotype 1 Achieving RVR at Day 28, Primary and Supportive Analyses
The primary comparison of interest was performed using a Bayesian probability model. Probability of achieving undetectable HCV RNA distribution analyzed was reported.
Time frame: Day 28
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Placebo of Investigational Drug
GSK Investigational Site
La Mesa, California, United States
GSK Investigational Site
Oceanside, California, United States
GSK Investigational Site
Miramar, Florida, United States
GSK Investigational Site
Las Vegas, Nevada, United States
GSK Investigational Site
Tulsa, Oklahoma, United States
GSK Investigational Site
Houston, Texas, United States
GSK Investigational Site
San Juan, Puerto Rico
Number of Participants With HCV Genotype 1 With Virologic Response
Serum for determination of HCV genotype was collected at the screening visit. Genotype was determined by the VERSANT HCV genotype 2.0 Assay (LiPA). Number of participants with HCV genotype 1 were reported.
Time frame: Day 7, 14 and 21
Change From Baseline in HCV Viral Load During 24 Hour (h) Following a Single Dose of GSK2336805 on the Log 10 Scale
Blood samples for determination of HCV RNA levels were collected at immediately prior to and 1, 2, 4, 6, and 8 and 24 h after the first dose in Part 1 (Day 1). Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. Change from Baseline was computed as value at post Baseline specified time point minus Baseline value. Virus RNA levels reported as \<43 are undetectable levels. If the result for HCV RNA (IU/ML) was \<43, then change from Baseline was calculated using 42, and the change from Baseline on the log scale was calculated using log (42).
Time frame: Day 1 (Baseline [Pre-dose], 1, 2, 4, 6, and 8 and 24 h)
Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE) During Treatment Period
AE was defined as any untoward medical occurrence in a participant temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE include AEs those result in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Time frame: Up to Day 28
Change From Baseline in QTcF Interval at Day 2 and 28
Single 12-lead electrocardiogram (ECG) was obtained. The standard ECG criteria of potential clinical importance were 1) absolute QTc Interval, \> 450 milliseconds (msec), 2) absolute PR Interval, \<110 msec, 3) absolute QRS Interval, \< 75 msec and 4) increase from baseline in QTc \> 60 msec. QTc Interval was calculated using Frederica correction formula: QTcF = QT / (RR)\^1/3. Change from Baseline was calculated by subtracting the Baseline assessment value from post Baseline visit value. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. The change from Baseline in QTc Interval at Day 2 and 28 were reported.
Time frame: Baseline (Day 1, Pre-dose ), Day 2 and Day 28
Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade Hematology Parameters for Day 1 to Day 28
Laboratory abnormalities were graded according to the modified division of AIDS ( DAIDS）version 1.0. Shift from Baseline to worst post baseline toxicity grade (where applicable) were presented for Day 1 to Day 28. The toxicity Grades were, Grade 1: mild (no or minimal interference with usual social \& functional activities); Grade 2: moderate (greater than minimal interference with usual social and functional activities); Grade 3: severe (inability to perform usual social and functional activities); Grade 4: potentially life threatening (inability to perform basic self-care functions or Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death). Hematology parameters were red blood cell, hemoglobin, hematocrit, platelet white blood cell count with differential leukocyte count, mean corpuscular volume, prothrombin time and international normalized ratio.
Time frame: Baseline (Day 1) to Day 28
Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade for Serum Chemistry Parameters for Day 1 to Day 28
Abnormalities were graded according to the modified DAIDS version 1.0. Shift from Baseline to worst post Baseline toxicity grade were presented for Day 1 to Day 28. The toxicity Grades were, Grade 1: mild (no or minimal interference with usual social \& functional activities); Grade 2: moderate (greater than minimal interference with usual social and functional activities); Grade 3: severe (inability to perform usual social and functional activities); Grade 4: potentially life threatening (inability to perform basic self-care functions or Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death). Clinical chemistry parameters were alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatine phosphokinase, total CO2, chloride, creatinine, glucose, sodium, phosphate, potassium, total albumin, total bilirubin, and direct bilirubin. Only participants with change in toxicity grades are reported.
Time frame: Baseline (Day 1) and 28
Number of Participants With Shifts in Urinalysis Parameters From Normal at Baseline to Abnormal
The urinalysis parameters analyzed were Leukocyte esterase, bilirubin, occult blood, glucose, ketones, nitrite, pH, specific gravity and dipstick assessments. Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important urinalysis findings at specified visit were reported. Visits where no abnormal values were observed not reported.
Time frame: Day 14, 28, Follow-up (Day 42)
Number of Participants With Vital Signs of Potential Clinical Concern
The potential clinical importance ranges (low and high) of the vital sign parameters were for systolic blood pressure (\<85 and \>160 millimeter of mercury \[mmHg\]), diastolic blood pressure (\<45 and \>100 mmHg) and heart rate (\<40 and \>110 beats per minute). Only those parameters for which at least one value of potential clinical importance was reported are summarized. The number of participants with potential clinical important vital parameter findings at any visit were reported.
Time frame: Up to 42 days
Mean Serum HCV RNA Levels at Baseline (Day 1), Day 2 and Day 28
Blood samples for determination of HCV RNA levels were collected from screening, immediately prior to and 1, 2, 4, 6, and 8 h after the first dose in Part 1 (Day 1), during Part 2 on Days 2 (24 h after the Day 1 dose), 7, 14, 21, and 28, and at the post-treatment follow-up visit on Day 42. All viral load samples, with the exception of the one taken during the screening visit, were taken in duplicate. The actual time and date of each sample collection will be recorded. Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test.
Time frame: Baseline (Day 1, pre-dose), Day 2 (24 h, Post-dose) and Day 28
Mean Change From Baseline in Serum HCV RNA Levels at Day 2 and Day 28
Blood samples for determination of HCV RNA levels were collected from screening, immediately prior to and 1, 2, 4, 6, and 8 h after the first dose in Part 1 (Day 1), during Part 2 on Days 2 (24 h after the Day 1 dose), 7, 14, 21, and 28, and at the post-treatment follow-up visit on Day 42. All viral load samples, with the exception of the one taken during the screening visit, were taken in duplicate. The actual time and date of each sample collection will be recorded. Measurement of HCV viral load was analyzed by the central laboratory using the COBAS AmpliPrep/COBAS TaqMan HCV test.
Time frame: Baseline (Day 1, Pre -dose ) and Day 2 (24 h, post-dose), Day 28
Change From Baseline in Serum Alanine Aminotransferase Levels
Blood samples were collected at Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42 for determination of serum alanine aminotransferase levels. Baseline was defined as the last non-missing assessment on or before the first dose of study drug. Change from Baseline was computed as value at post Baseline specified time point minus Baseline value.
Time frame: Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42
Median Serum Alanine Aminotransferase at Baseline, Day 7, 14, 21, 28 and 42
Blood samples were collected at Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42 for determination of serum alanine aminotransferase levels.
Time frame: Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42
Mean Area Under the Concentration-time Curve (AUC[0-24]), AUC From Time 0 Extrapolated to Infinity (AUC[0-inf]) of GSK2336805, at Day 1
AUC values were determined using the linear-up, log-down trapezoidal rule. The individual plasma concentration and actual time data was used to derive the PK parameters of GSK2336805 on Day 1 by noncompartmental PK analyses. For the calculation of PK parameters all plasma concentrations that were below quantification limit (BLQ) before the first measurable concentration were set to zero. The BLQ values that occur at the end of the profile after the last quantifiable concentration were set to missing. Actual sampling times, rather than scheduled sampling times, were used in all computations of PK parameters.
Time frame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2)
Median Time of Maximal Plasma Concentration (Tmax) of GSK2336805 and Lag Time Before First Observation of Quantifiable Concentration (Tlag) at Day 1
The individual plasma concentration and actual time data was used to derive the PK parameters of GSK2336805 on Day 1 by noncompartmental PK analyses. For the calculation of PK parameters all plasma concentrations that were BLQ before the first measurable concentration were set to zero. The BLQ values that occur at the end of the profile after the last quantifiable concentration were set to missing. Actual sampling times, rather than scheduled sampling times, were used in all computations of PK parameters
Time frame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2)
Mean Maximum Plasma Concentration of GSK2336805 (Cmax) and Concentration at 24 h (C24) at Day 1
The individual plasma concentration and actual time data was used to derive the PK parameters of GSK2336805 on Day 1 by non-compartmental PK analyses. For the calculation of PK parameters all plasma concentrations that were BLQ before the first measurable concentration were set to zero. The BLQ values that occur at the end of the profile after the last quantifiable concentration were set to missing. Actual sampling times, rather than scheduled sampling times, were used in all computations of PK parameters.
Time frame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1)
Mean Apparent Clearance (CL/F) of GSK2336805
The individual plasma concentration and actual time data was used to derive the PK parameters of GSK2336805 on Day 1 by noncompartmental PK analyses. For the calculation of PK parameters all plasma concentrations that were BLQ before the first measurable concentration were set to zero. The BLQ values that occur at the end of the profile after the last quantifiable concentration were set to missing. Actual sampling times, rather than scheduled sampling times, were used in all computations of PK parameters
Time frame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1)
Mean Pre-dose Concentration and Concentration at 2 to 4 h Post-dose of GSK2336805 at Days 7, 14, 21, and 28
The individual plasma concentration and actual time data was used to derive the PK parameters of GSK2336805 on Day 1 by noncompartmental PK analyses. For the calculation of PK parameters all plasma concentrations that were BLQ before the first measurable concentration were set to zero. The BLQ values that occur at the end of the profile after the last quantifiable concentration were set to missing. Actual sampling times, rather than scheduled sampling times, were used in all computations of PK parameters.
Time frame: 0 (pre-dose), 0 to 2 h, > 2 h up to 4 h, > 4 h up to 6 h, or > 6 h up to 10 h on Days 7, 14, 21 and 28