Clinical trial NCT01439373: Safety, Antiviral Activity, and Pharmacokinetics of GSK2336805 With Peginterferon and Ribavirin in Chronic Hepatitis C Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Keywords: chronic hepatitis C
NS5A inhibitor
ribavirin
pegylated interferon
GSK2336805
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2011-09-23
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participant Achieving Rapid Virological Response (RVR) at Day 28, Nominal Analysis
timeFrame: Day 28
measure: Number of Participant Achieving RVR at Day 28, (Primary and Supportive Analyses)
timeFrame: Day 28
measure: Probability of Participants With HCV Genotype 1 Achieving RVR At Day 28, Nominal Analysis
timeFrame: Day 28
measure: Probability of Participants With HCV Genotype 1 Achieving RVR at Day 28, Primary and Supportive Analyses
timeFrame: Day 28
measure: Number of Participants With HCV Genotype 1 With Virologic Response
timeFrame: Day 7, 14 and 21
measure: Change From Baseline in HCV Viral Load During 24 Hour (h) Following a Single Dose of GSK2336805 on the Log 10 Scale
timeFrame: Day 1 (Baseline [Pre-dose], 1, 2, 4, 6, and 8 and 24 h)
measure: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Event (SAE) During Treatment Period
timeFrame: Up to Day 28
measure: Change From Baseline in QTcF Interval at Day 2 and 28
timeFrame: Baseline (Day 1, Pre-dose ), Day 2 and Day 28
Secondary outcomes:
measure: Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade Hematology Parameters for Day 1 to Day 28
timeFrame: Baseline (Day 1) to Day 28
measure: Number of Participants With Shift From Baseline to Worst Post Baseline Toxicity Grade for Serum Chemistry Parameters for Day 1 to Day 28
timeFrame: Baseline (Day 1) and 28
measure: Number of Participants With Shifts in Urinalysis Parameters From Normal at Baseline to Abnormal
timeFrame: Day 14, 28, Follow-up (Day 42)
measure: Number of Participants With Vital Signs of Potential Clinical Concern
timeFrame: Up to 42 days
measure: Mean Serum HCV RNA Levels at Baseline (Day 1), Day 2 and Day 28
timeFrame: Baseline (Day 1, pre-dose), Day 2 (24 h, Post-dose) and Day 28
measure: Mean Change From Baseline in Serum HCV RNA Levels at Day 2 and Day 28
timeFrame: Baseline (Day 1, Pre -dose ) and Day 2 (24 h, post-dose), Day 28
measure: Change From Baseline in Serum Alanine Aminotransferase Levels
timeFrame: Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42
measure: Median Serum Alanine Aminotransferase at Baseline, Day 7, 14, 21, 28 and 42
timeFrame: Baseline (Day 1, Pre-dose), Day 7, 14, 21, 28 and 42
measure: 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
timeFrame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2)
measure: Median Time of Maximal Plasma Concentration (Tmax) of GSK2336805 and Lag Time Before First Observation of Quantifiable Concentration (Tlag) at Day 1
timeFrame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 2)
measure: Mean Maximum Plasma Concentration of GSK2336805 (Cmax) and Concentration at 24 h (C24) at Day 1
timeFrame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1)
measure: Mean Apparent Clearance (CL/F) of GSK2336805
timeFrame: 0.0 (pre-dose) and 1, 2, 4, 6, 8, and 24 h post-dose (morning of Day 1)
measure: Mean Pre-dose Concentration and Concentration at 2 to 4 h Post-dose of GSK2336805 at Days 7, 14, 21, and 28
timeFrame: 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
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: GSK Investigational Site
state: California
city: Chula Vista
country: United States
facility: GSK Investigational Site
state: California
city: Coronado
country: United States
facility: GSK Investigational Site
state: California
city: La Mesa
country: United States
facility: GSK Investigational Site
state: California
city: Oceanside
country: United States
facility: GSK Investigational Site
state: California
city: Miramar
country: United States
facility: GSK Investigational Site
state: Florida
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Tulsa
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Gardner S, Cutrell A, Elko-Simms C, Adkison K, Hamatake R, Walker J, Rodriguez-Torres M, Hong Z. A double-blind, randomized, placebo-controlled study to assess the safety, antiviral activity and pharmacokinetics of GSK2336805 when given as monotherapy and in combination with peginterferon alfa-2a and ribavirin in hepatitis C virus genotype 1-infected treatment-naive subjects. Liver Int. 2014 Jul;34(6):e89-95. doi: 10.1111/liv.12334. Epub 2013 Oct 16.