Dose Ranging of GSK2336805 in Combination Therapy

GlaxoSmithKline286 enrolled

Overview

GSK2336805 is a novel hepatitis C virus (HCV) non-structural 5A (NS5A) inhibitor being developed for the treatment of chronic HCV infection. This Phase II, multicenter, parallel-group, randomized, dose-ranging study will assess the safety and tolerability, antiviral activity, and pharmacokinetics of GSK2336805 at 2 dose levels (40 and 60 mg) in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA) in approximately 100 treatment-naïve subjects with chronic genotype 1 HCV infection. In a separate nonrandomized single-arm cohort, up to 15 treatment-naïve subjects with genotype 4 chronic HCV infection will be enrolled in parallel at the dose level of 60 mg of GSK2336805.

Subjects with chronic genotype 1 hepatitis C virus (HCV) infection will be randomly assigned on a 2:2:1 basis to 1 of 3 treatment arms: T40 (GSK2336805 40 mg and PEG + RIBA) or T60 (GSK2336805 60 mg and PEG + RIBA) or PEG + RIBA and telaprevir (PRT). Randomization will be stratified by interleukin 28B (IL28B) rs12979860 status (C/C versus carriage of the T allele), HCV genotype (1a vs. 1b), and plasma HCV Ribonucleic Acid (RNA) (\<800,000 IU/mL versus ≥800,000 IU/mL). An additional nonrandomized single-arm cohort of subjects with chronic genotype 4 HCV infection will be enrolled in parallel. A maximum of 15 genotype 4 subjects will receive GSK2336805 60 mg and PEG + RIBA. The purpose of this cohort is to further characterize the antiviral activity of GSK2336805 in subjects with chronic genotype 4 HCV infection. The schedule of assessments for the genotype 4 subjects will be the same as for the genotype 1 subjects. Recruitment of the genotype 4 subjects may be terminated when the target sample of genotype 1 subjects have been randomized. Subjects in a GSK2336805 treatment arm who achieve extended rapid virologic response (eRVR) will receive a total of 24 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 12 weeks PEG + RIBA). Subjects who are HCV detectable at Week 4 and then undetectable at Week 12 will receive a total of 48 weeks of therapy (12 weeks GSK2336805 in combination with PEG + RIBA followed by 36 weeks PEG + RIBA). Subjects in the telaprevir treatment control arm will be managed according to the current product label for treatment-naïve subjects. Subjects who complete treatment will undergo follow-up monitoring for 24 weeks after completion of therapy. At the end of the 24-week follow-up visit, subjects will have completed their participation in the study. The total duration of the study will be 48 weeks for subjects who achieve eRVR at Week 12 and up to 72 weeks for subjects who do not achieve eRVR at Week 12.

Study Type

Interventions

GSK2336805 40 mgDRUG

20 mg tablet, round, 10-mm diameter, white to off-white, no markings

GSK2336805 60 mgDRUG

30 mg tablet, round, 10-mm diameter, white to off-white, no markings

Pegylated interferon alpha-2aDRUG

180 microgram per 0.5 mL prefilled syringe for single use

RibavirinDRUG

200-mg tablet, capsule-shaped, light blue, film-coated, and debossed with "200" on 1 side and the logo "3RP" on the other side

TelaprevirDRUG

375 mg film-coated tablet

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Male or female aged 18 to 70 years of age, inclusive, at Screening. * Genotype 1 or genotype 4 hepatitis C virus (HCV) infection as assessed by Versant HCV Genotype assay 2.0 (LiPA). * Chronic HCV infection documented by at least 1 measurement of serum HCV RNA greater than or equal to 100,000 IU/mL measured during Screening by the COBAS High Pure/COBAS TaqMan HCV Test v2.0 and at least one of the following: * A positive anti-HCV antibody, HCV RNA, or HCV genotype test at least 6 months prior to Baseline (Day 1) together with positive HCV RNA and anti-HCV antibody tests at the time of Screening; or * A positive HCV RNA test and anti-HCV antibody test at the time of Screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic hepatitis C disease, such as the presence of fibrosis). * Naïve to all HCV antiviral treatment(s), including, but not limited to, immunomodulatory and nucleoside/nucleotide treatments for chronic HCV infection. * Agree to interleukin 28B (IL28B) genotyping. * A subject, who, in the opinion of the investigator, is an appropriate candidate for pegylated interferon alpha-2a (PEG)/ribavirin (RIBA)/protease inhibitor combination therapy for genotype 1 subjects and PEG/RIBA combination therapy for genotype 4 subjects. * Body mass index \>18 kg/m2 but not exceeding 36 kg/m2. * A liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of noncirrhotic as judged by a local pathologist (defined as Knodell less than or equal to 3, Metavir less than or equal to 2, Ishak less than or equal to 4, or Batts and Ludwig less than or equal to 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis. 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 2 forms of effective contraception between them during treatment and during the 24 weeks after treatment ends. * Females, is eligible to enter and participate in the study if of non-childbearing potential (i.e., physiologically incapable of becoming pregnant) and includes any female who has had a hysterectomy or has had a bilateral oophorectomy (ovariectomy) or has had a bilateral tubal ligation or is postmenopausal (demonstrate total cessation of menses for greater than 1 year). * Females, is eligible to enter and participate in the study if of childbearing potential and has a negative urine or serum pregnancy test at Screening and within the 24-hour period prior to the first dose of study medication and completely abstains from intercourse for 2 weeks before exposure to the study medication, throughout the clinical study, and for 24 weeks after completion or premature discontinuation from this study or uses 2 of the following acceptable methods of contraception throughout the clinical study and for 24 weeks after completion or premature discontinuation from this study: * Any intrauterine device with a documented failure rate of \<1% per year * Double-barrier contraception (condom, diaphragm, or cervical cap used with spermicidal jelly) * Male partner who is sterile prior to the female subject's study entry and is the sole sexual partner for that female * Any other contraceptive method with a documented failure rate of \<1% per year * Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening. Exclusion Criteria: * Positive test at Screening visit for hepatitis B surface antigen (HBsAg) or antihuman immunodeficiency virus antibody * History of any other clinically significant chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, Wilson's disease, 1-antitrypsin deficiency, alcoholic liver disease, \>Grade 1 nonalcoholic steatohepatitis, and toxin exposures). Subjects with Gilbert's syndrome who otherwise meet all inclusion/exclusion criteria are eligible. * 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 visit electrocardiogram corrected QT (QTc) interval value \>450 ms and/or clinically significant electrocardiogram findings * Personal or family history of Torsade de Pointes findings * Pregnant or nursing * Male with a female partner who is pregnant * Abnormal hematological and biochemical parameters, including: * Neutrophil count \<1500 cells/mm3 (or \<1250 cells/mm3 for African American/Black subjects) * Hemoglobin \<11 g/dL in females or \<12 g/dL in males * Creatinine greater than or equal to 1.5 × the upper limit of normal (ULN) * Estimated creatinine clearance less than or equal to 50 mL/min (as calculated using the Cockcroft-Gault formula) * Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase greater than or equal to 5 × ULN * Total bilirubin greater than or equal to 2.0 × ULN (except subjects with Gilbert's syndrome) * Albumin less than or equal to 3.0 g/dL * Platelet count less than or equal to 90,000/mm3 * History of major organ transplantation with an existing functional graft * Thyroid dysfunction not adequately controlled * History of suicide attempt or hospitalization for depression in the past 5 years * History of any current (within 6 months) severe or poorly controlled psychiatric disorder * Subjects who have had a severe or poorly controlled psychiatric disorder more than 6 months ago but less than 5 years ago are eligible for study participation but must be assessed and followed (if recommended) by a mental health professional. * History or current evidence of immunologic disorder; cardiac or pulmonary disease; seizure disorder; or cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study. * Treated with herbal or natural remedies with antiviral activity within 30 days of the baseline visit or has a history of having received any systemic antineoplastic or immunomodulatory treatment (including mycophenolate mofetil, thymosin alpha, supraphysiologic doses of steroids \>10 mg/day and radiation) within 6 months of the baseline visit or expects that such treatment will be needed at any time during the study. * Participated in a clinical study with an investigational drug, biologic, or device within 3 months prior to the first dose administration. * History of a known allergy to antiviral medications, including telaprevir, pegylated interferon alpha-2a (PEG), ribavirin (RIBA), or any excipient in the investigational product or history of drug or other allergy that, in the opinion of the investigator, contradicts participation. * Requires prohibited medications

Locations (34)

GSK Investigational Site

Dothan, Alabama, United States

GSK Investigational Site

Anaheim, California, United States

GSK Investigational Site

Los Angeles, California, United States

GSK Investigational Site

DeLand, Florida, United States

GSK Investigational Site

Orlando, Florida, United States

Outcomes

Primary Outcomes

Number of Participants Achieving eRVR

eRVR is defined as plasma HCV ribonucleic acid (RNA) \<lower limit of quantification (LLOQ) and target not detected at Weeks 4 and 12. Participants who discontinued prior to Week 12 assessments or had missing HCV RNA values at Weeks 4 and 12 were treated as non-responders.

Time frame: Week 4 and Week 12

Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) up to Week 12

An AE is 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. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, or disease(new or exacerbated) temporally associated with the use of a medicinal product. A SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Time frame: From the start of study treatment up to Week 12

Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points up to Week 12

Blood pressure measurements were taken to observe vital signs and included SBP and DBP at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and Post-treatment (PT) Follow Up (FU) Weeks 4, 12 and 24. Change from Baseline in SBP and DBP is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) up to 12-week treatment period

Mean Change From Baseline in Heart Rate at the Indicated Time Points up to Week 12

Vital sign monitoring included heart rate, measured at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4, 12 and 24. Change from Baseline in heart rate is summarized for each post-Baseline assessment upto Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Day 2, Weeks 1, 2, 4, 6, 8, and 12

Mean Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the basophils, eosinophils, lymphocytes, total neutrophils, platelet count and white blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of red blood cell count at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the red blood cell count values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of hemoglobin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hemoglobin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Hematocrit at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of hematocrit at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the hematocrit values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of mean corpuscle volume at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the mean corpuscle volume values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Albumin at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of albumin at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the albumin values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Creatine Kinase (CK) and Gamma Glutamyl Transferase (GGT) at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of ALP, ALT, AST, CK and GGT at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4 Change from Baseline in the ALP, ALT, AST, CK and GGT values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Direct Bilirubin, Total Bilirubin and Creatinine at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of direct bilirubin, total bilirubin and creatinine at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the direct bilirubin, total bilirubin and creatinine values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Chloride, Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus and Urea/Blood Urea Nitrogen (BUN) at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of Chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. Change from Baseline in the chloride, bicarbonate, glucose, potassium, sodium, inorganic phosphorus and urea/BUN values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Mean Change From Baseline in Creatinine Clearance at the Indicated Time Points up to Week 12

Blood samples were collected for the measurement of Creatinine Clearance at the Baseline, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Weeks 4. It is estimated by Cockcroft-Gault Equation. Change from Baseline in the Creatinine Clearance values are summarized for each post-Baseline assessment until Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12

Number of Participants With Shift From Baseline in Urinalysis Data up to Week 12

Urine samples were collected for urinalysis at Baseline, Weeks 2, 12, 18, 24, 48 and PT FU Weeks 4. Number of participants with shift from Baseline in urinalysis to normal (NL), abnormal (ANL) and missing (MIS) data up to Week 12 are summarized. Urine bilirubin (UBIL), urine glucose (UGLU), urine ketones (UKET), urine leukocyte esterase test (ULET) for detecting WBC, urine nitrite (UNIT), urine occult blood (UOB) were performed with dipstick method. Urine microscopy (UM) is performed to detect bacteria (BAC), red blood cells (RBC) and white blood cells (WBC). Other urinalysis parameter included urine pH (UpH) and urine specific gravity (USG). Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0), Weeks 2 and 12

Mean Change From Baseline in Electrocardiographic (ECG) Heart Rate Values at the Indicated Time Points up to Week 12

The ECG parameter heart rate was measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG heart rate is summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1 and 12

Mean Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval and QT Interval Corrected Bazett's Formula (QTcB), QT Interval Corrected Using Fridericia's Formula (QTcF) Values at the Indicated Time Points up to Week 12

The ECG parameters including PR interval, QRS duration, uncorrected QT interval, QTcB, QTcF were measured at Baseline, Weeks 1 and 12. Change from Baseline in ECG parameters are summarized for each post-Baseline assessment up to Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.

Time frame: Baseline (Week 0) and Weeks 1 and 12

Secondary Outcomes

Number of Participants With Any AEs and Any SAEs After Week 12

An AE is 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. An AE can therefore be any unfavorable and unintended sign(including an abnormal laboratory finding), symptom, or disease(new or exacerbated) temporally associated with the use of a medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect, important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Time frame: From Week 12 up to PT Week 24 FU

Number of Participants Achieving Very Rapid Virologic Response (vRVR), Rapid Virologic Response (RVR), Complete Early Virologic Response (cEVR), Sustained Virologic Response 12 and 24 (SVR12 and SVR24) With Response Guided Treatment (RGT)

Blood samples for the determination of HCV RNA levels were collected at Screening and Baseline, every study visit during the Treatment Period, and at PT FU Weeks 4, 12, and 24. vRVR is defined as plasma HCV RNA \<LLOQ and target not detected 2 weeks after initiation of therapy. RVR is defined as plasma HCV RNA \<LLOQ and target not detected 4 weeks after initiation of therapy. cEVR is defined as plasma HCV RNA \<LLOQ and target not detected 12 weeks after initiation of therapy. SVR12 is defined as plasma HCV RNA \<LLOQ and target not detected 12 weeks after completion of all therapy. SVR24 is defined as plasma HCV RNA \<LLOQ and target not detected 24 weeks after completion of all therapy. SVR24 with RGT are participants who achieved both SVR24 and eRVR.

Time frame: From the start of the treatment up to PT FU Week 24

Mean GSK2336805 Plasma Concentrations on Day 1, Day 2, Week 4, and Week 12

Plasma pharmacokinetic (PK) samples were collected for all participants on Day 1 (0 hour \[h\]-1h, 1h-4h, 4h-8h, 8h-20h), Day 2 (Predose \[20-28h\]), Week 4 (Predose \[20-28h\], 0h-1h, 1h-4h, 4h-8h, 8h-20h, 20h-28h) and Week 12 (Predose \[20-28h\]). PK Population is comprised of all participants who received GSK2336805 and underwent plasma PK sampling (intensive or sparse) during the study.

Time frame: Day 1, Day 2, Week 4, and Week 12

Mean Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Total Neutrophils, Platelet Count and White Blood Cell Count at the Indicated Time Points After Week 12

Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelet count and white blood cell count at the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT Week 4. Change from Baseline in the basophils, eosinophils, lymphocytes, total neutrophils platelet count and white blood cell count values are summarized for each post-Baseline assessment after Week 12. Change from Baseline was calculated as the individual post-Baseline value minus the Baseline value. Baseline value is defined as the last Pre-treatment value observed.