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Dose Ranging of GSK2336805 in Combination Therapy (HAI115879)

Primary Purpose

Hepatitis C, Chronic

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

GSK2336805 40 mg

GSK2336805 60 mg

Pegylated interferon alpha-2a

Ribavirin

Telaprevir

About this trial

This is an interventional treatment trial for Hepatitis C, Chronic focused on measuring Genotype 4, GSK2336805, pegylated interferon, telaprevir, Genotype 1, chronic hepatitis C, ribavirin, NS5A inhibitor, hepatitis C virus (HCV) infection

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Active Comparator

Experimental

Arm Label

T40

T60

PRT

Arm Description

Hepatitis C virus (HCV) genotype 1 GSK2336805 40 mg, pegylated interferon alpha-2a, and ribavirin arm

Hepatitis C virus (HCV) genotype 1 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Hepatitis C virus (HCV) genotype 1 Telaprevir, pegylated interferon alpha-2a, and ribavirin arm

Hepatitis C virus (HCV) genotype 4 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Outcomes

Primary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

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.

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.

Maximum Plasma Concentration (Cmax) and Concentration at the End of the Dosing Interval (Ctau) of GSK2336805 at Week 4

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7, 24 hours post-dose.

Time of Maximal Plasma Concentration (Tmax) of GSK2336805 at Week 4

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7, 24 hours postdose.

Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) at Week 4

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7 and 24 hours postdose.

Apparent Clearance (CL/F) at Week 4

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7 and 24 hours postdose. CL/F was calculated as dose divided by AUC(0-tau).

Apparent Volume of Distribution (Vz/F) at Week 4

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7 and 24 hours postdose. Vz/F was calculated as dose divided by (AUC[0-tau] lambda z) where lambda z is the terminal phase rate constant.

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.

Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points After 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 Week 4. Change from Baseline in the red 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.

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

Blood samples were collected for the measurement of hemoglobin at the the Baseline, Day 2, 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 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.

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

Blood samples were collected for the measurement of hematocrit at the the Baseline, Day 2, 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 after Week 12. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. 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.

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

Blood samples were collected for the measurement of mean corpuscle volume at the the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the mean corpuscle volume 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.

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

Blood samples were collected for the measurement of albumin at the the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the albumin 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.

Mean Change From Baseline in ALP, ALT, AST, CK and GGT at the Indicated Time Points After Week 12

Blood samples were collected for the measurement of ALP, ALT, AST, CK and GGT at the the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the ALP, ALT, AST, CK and GGT 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.

Mean Change From Baseline in Total Bilirubin and Creatinine at the Indicated Time Points After Week 12

Blood samples were collected for the measurement of total bilirubin and creatinine at the the Baseline, Day 2, Weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 36, 42, 48 and PT FU Week 4. Change from Baseline in the direct bilirubin, total bilirubin and creatinine values are summarized for each post-Baseline assessment afterl 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.

Mean Change From Baseline in SBP and DBP at the Indicated Time Points After 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 PT FU Weeks 4. As defined in the Reporting Analysis Plan (RAP) for this protocol, the supplemental final data package generated for this study after Week 12 only provided graphical displays of vital signs (e.g., change from baseline for heart rate and blood pressure) to facilitate clinical interpretation and data summarization. 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. All abnormal values and statistical summary tables were not available after week 12.

Mean Change From Baseline in Heart Rate at the Indicated Time Points After 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. As defined in the Reporting Analysis Plan (RAP) for this protocol, the supplemental final data package generated for this study after Week 12 only provided graphical displays of vital signs (e.g., change from Baseline for heart rate and blood pressure) to facilitate clinical interpretation and data summarization. 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. All abnormal values and statistical summary tables were not available after week 12.

Mean Change From Baseline in ECG Heart Rate Values at the Indicated Time Points After Week 12

The ECG data was only collected "Perform as needed", therefore, no such summary table was generated. 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.

Mean Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QTcB, QTcF Values at the Indicated Time Points After Week 12

Mean Change From Baseline in Chloride, Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus and Urea/BUN at the Indicated Time Points After 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 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.

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

Blood samples were collected for the measurement of estimated creatinine clearance by Cockcroft-Gault formula 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 estimated creatinine clearance 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.

Correlation of Individual GSK2336805 Dose With Week 4 Plasma AUC(0-tau) Versus eRVR Status

Correlation of individual GSK2336805 40 mg and 60 mg with Week 4 plasma AUC(0-tau) versus eRVR Status (eRVR and no eRVE) was performed. eRVR is defined as plasma HCV RNA <LLOQ and target not detected at Weeks 4 and 12. AUC (0-tau) is area under the concentration-time curve over the dosing interval. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected pharmacokinetic parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Correlation of Individual GSK2336805 Dose With Week 4 Plasma Cmax, Ctau, C0 Versus eRVR Status

Correlation of Individual GSK2336805 40 mg and 60 mg dose with Week 4 maximum plasma concentration (Cmax), pre-dose concentration (C0), concentration at the end of the dosing interval (Ctau) versus eRVR status (eRVR and no eRVR) was performed. eRVR is defined as plasma HCV RNA <LLOQ and target not detected at Weeks 4 and 12. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected PK parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Correlation of Individual GSK2336805 Dose With Week 4 Plasma AUC(0-tau) Versus RVR Status

Correlation of individual GSK2336805 40 mg and 60 mg with Week 4 plasma AUC(0-tau) versus eRVR Status (RVR and no eVE) was performed. RVR is defined as plasma HCV RNA <LLOQ and target not detected 4 weeks after initiation of therapy. AUC (0-tau) is area under the concentration-time curve over the dosing interval. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected PK parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Correlation of Individual GSK2336805 Dose With Week 4 Plasma Cmax, Ctau, C0 Versus RVR Status

Correlation of Individual GSK2336805 40 mg and 60 mg dose with Week 4 maximum plasma concentration (Cmax), pre-dose concentration (C0), concentration at the end of the dosing interval (Ctau) versus RVR status (RVR and no RVR) was performed. RVR is defined as plasma HCV RNA <LLOQ and target not detected 4 weeks after initiation of therapy. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected PK parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Correlation of Individual GSK2336805 Dose With Pre-dose Plasma Concentration at Week 4 and Week 12 Versus eRVR Status

Correlation of individual GSK2336805 dose with pre-dose plasma concentration at Week 4 and Week 12 versus eRVR status was performed. eRVR is defined as plasma HCV RNA <LLOQ and target not detected at Weeks 4 and 12. The PK/Pharmacodynamic (PD) analysis population comprised of all participants with available PD measures (e.g., safety and/or efficacy data) and with evaluable GSK2336805 plasma concentration data considered suitable for investigation of relationship with the PD measures. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected PK parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Correlation GSK2336805 Pre-dose Plasma Concentration on Day 2 Versus Reduction in HCV RNA on Day 2

Correlation GSK2336805 pre-dose plasma concentration (ng/mL) on Day 2 versus reduction in HCV RNA (log IU/mL) on Day 2 was performed. As defined in the RAP for this protocol, correlations between GSK2336805 dose, and selected PK parameters and virological outcomes was analyzed only with graphical presentations to facilitate clinical interpretation and data summarization. These data were also provided in by-participant data listings. Therefore, no statistical summary tables are available.

Full Information

NCT ID

NCT01648140

First Posted

July 12, 2012

Last Updated

April 25, 2017

Sponsor

GlaxoSmithKline

Collaborators

PPD

1. Study Identification

Unique Protocol Identification Number

NCT01648140

Brief Title

Dose Ranging of GSK2336805 in Combination Therapy

Acronym

HAI115879

Official Title

A Phase II Multicenter, Parallel-Group, Randomized, Dose-Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Following 12 Weeks of Oral Administration of GSK2336805 With Pegylated Interferon and Ribavirin in Treatment-Naïve Subjects With Chronic Genotype 1 or 4 Hepatitis C Infection

Study Type

Interventional

2. Study Status

Record Verification Date

November 2016

Overall Recruitment Status

Completed

Study Start Date

August 1, 2012 (undefined)

Primary Completion Date

July 1, 2014 (Actual)

Study Completion Date

July 16, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

Collaborators

PPD

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis C, Chronic

Keywords

Genotype 4, GSK2336805, pegylated interferon, telaprevir, Genotype 1, chronic hepatitis C, ribavirin, NS5A inhibitor, hepatitis C virus (HCV) infection

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

286 (Actual)

8. Arms, Groups, and Interventions

Arm Title

T40

Arm Type

Experimental

Arm Description

Hepatitis C virus (HCV) genotype 1 GSK2336805 40 mg, pegylated interferon alpha-2a, and ribavirin arm

Arm Title

T60

Arm Type

Experimental

Arm Description

Hepatitis C virus (HCV) genotype 1 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Arm Title

PRT

Arm Type

Active Comparator

Arm Description

Hepatitis C virus (HCV) genotype 1 Telaprevir, pegylated interferon alpha-2a, and ribavirin arm

Arm Title

Arm Type

Experimental

Arm Description

Hepatitis C virus (HCV) genotype 4 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm

Intervention Type

Drug

Intervention Name(s)

GSK2336805 40 mg

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

GSK2336805 60 mg

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Pegylated interferon alpha-2a

Other Intervention Name(s)

Pegasys

Intervention Description

180 microgram per 0.5 mL prefilled syringe for single use

Intervention Type

Drug

Intervention Name(s)

Ribavirin

Other Intervention Name(s)

Ribasphere

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Telaprevir

Other Intervention Name(s)

Incivek (United States), Incivo (European Union)

Intervention Description

375 mg film-coated tablet

Primary Outcome Measure Information:

Title

Number of Participants Achieving eRVR

Description

Time Frame

Week 4 and Week 12

Title

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

Description

Time Frame

From the start of study treatment up to Week 12

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

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

Title

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

Description

Time Frame

Baseline (Week 0), Weeks 2 and 12

Title

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

Description

Time Frame

Baseline (Week 0) and Weeks 1 and 12

Title

Description

Time Frame

Baseline (Week 0) and Weeks 1 and 12

Secondary Outcome Measure Information:

Title

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

Description

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

Title

Description

Time Frame

From the start of the treatment up to PT FU Week 24

Title

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

Description

Time Frame

Day 1, Day 2, Week 4, and Week 12

Title

Maximum Plasma Concentration (Cmax) and Concentration at the End of the Dosing Interval (Ctau) of GSK2336805 at Week 4

Description

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7, 24 hours post-dose.

Time Frame

Week 4 (24 h post dose)

Title

Time of Maximal Plasma Concentration (Tmax) of GSK2336805 at Week 4

Description

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7, 24 hours postdose.

Time Frame

Week 4 (24 h post dose)

Title

Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) at Week 4

Description

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7 and 24 hours postdose.

Time Frame

Week 4 (24 h post dose)

Title

Apparent Clearance (CL/F) at Week 4

Description

Blood samples for PK analysis of GSK2336805 was obtained on Week 4+1 day at predose and at 1, 2, 4, 7 and 24 hours postdose. CL/F was calculated as dose divided by AUC(0-tau).

Time Frame

Week 4 (24 h post dose)

Title

Apparent Volume of Distribution (Vz/F) at Week 4

Description

Time Frame

Week 4 (24 h post dose)

Title

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

Description

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.

Time Frame