Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 With Peginterferon and Ribavirin in Chronic Hepatitis C Subjects

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Double-Blind, Randomized, Placebo-Controlled Study to Assess Safety, Efficacy, and Pharmacokinetics (PK) of GSK2336805 in Combination With Peginterferon and Ribavirin in Treatment-naive Chronic Hepatitis C Subjects With Hepatitis C Virus Genotypes 1 or 4

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: GSK2336805
* Drug: Pegylated interferon alfa-2a
* Drug: Ribavirin
* Drug: GSK2336805 Matching Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented chronic genotype 1 or genotype 4 HCV infection Naïve to all HCV antiviral treatment(s) Agree to IL28B genotyping A body mass index >18 kg/m2 but not exceeding 36 kg/m2 Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic. If no recent (<36 months) liver biopsy is available, a study qualifying biopsy must be performed prior to Baseline (Day 1) All fertile males and females must use two forms of effective contraception between them during treatment and during the 24 weeks after treatment ends Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening Key Exclusion Criteria: Positive test at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody History of any other clinically significant chronic liver disease History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease Positive results on urine screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription) History of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation program) Screening ECG corrected QT interval value greater than 450 ms and/or clinically significant ECG findings A personal or family history of Torsade de Pointes findings Pregnant or nursing women Males with a female partner who is pregnant Abnormal hematological and biochemical parameters as specified in the protocol History of major organ transplantation with an existing functional graft Thyroid dysfunction not adequately controlled Subjects with a history of suicide attempt or hospitalization for depression in the past 5 years and/or any current (within 6 months) severe or poorly controlled psychiatric disorder History or current evidence of immunologic disorder; pulmonary, cardiac, or pulmonary disease; seizure disorder; cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2336805<br>Study Part 1 | Drug: GSK2336805<br>* Active Investigational Drug<br>|
| Placebo Comparator: Placebo<br>Study Part 1 | Drug: GSK2336805 Matching Placebo<br>* Placebo of Investigational Drug<br>* Other names: Placebo;|
| Experimental: GSK2336805 + pegylated interferon alfa-2a + ribavrin<br>Study Part 2 | Drug: GSK2336805<br>* Active Investigational Drug<br>Drug: Pegylated interferon alfa-2a<br>* Standard of Care drug<br>* Other names: Pegasys;Drug: Ribavirin<br>* Standard of Care drug<br>|
| Active Comparator: Placebo + pegylated interferon alfa-2a + ribavirin<br>Study Part 2 | Drug: Pegylated interferon alfa-2a<br>* Standard of Care drug<br>* Other names: Pegasys;Drug: Ribavirin<br>* Standard of Care drug<br>Drug: GSK2336805 Matching Placebo<br>* Placebo of Investigational Drug<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | Day 28 | 
| 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. | 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). | 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. | 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. | Baseline (Day 1, Pre-dose ), Day 2 and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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. | 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 | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic hepatitis C, NS5A inhibitor, ribavirin, pegylated interferon, GSK2336805