Clinical trial NCT01648140: Dose Ranging of GSK2336805 in Combination Therapy
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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C, Chronic
Keywords: Genotype 4
GSK2336805
pegylated interferon
telaprevir
Genotype 1
chronic hepatitis C
ribavirin
NS5A inhibitor
hepatitis C virus (HCV) infection
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2012-07-24
Enrollment: 286
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 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Achieving eRVR
timeFrame: Week 4 and Week 12
measure: Number of Participants With Any Adverse Events (AEs) and Any Serious Adverse Events (SAEs) up to Week 12
timeFrame: From the start of study treatment up to Week 12
measure: Mean Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) up to 12-week treatment period
measure: Mean Change From Baseline in Heart Rate at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Day 2, Weeks 1, 2, 4, 6, 8, and 12
measure: 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
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Hemoglobin at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Hematocrit at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Albumin at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: 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
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Direct Bilirubin, Total Bilirubin and Creatinine at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: 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
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Mean Change From Baseline in Creatinine Clearance at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1, 2, 4, 6, 8 and 12
measure: Number of Participants With Shift From Baseline in Urinalysis Data up to Week 12
timeFrame: Baseline (Week 0), Weeks 2 and 12
measure: Mean Change From Baseline in Electrocardiographic (ECG) Heart Rate Values at the Indicated Time Points up to Week 12
timeFrame: Baseline (Week 0) and Weeks 1 and 12
measure: 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
timeFrame: Baseline (Week 0) and Weeks 1 and 12
Secondary outcomes:
measure: Number of Participants With Any AEs and Any SAEs After Week 12
timeFrame: From Week 12 up to PT Week 24 FU
measure: 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)
timeFrame: From the start of the treatment up to PT FU Week 24
measure: Mean GSK2336805 Plasma Concentrations on Day 1, Day 2, Week 4, and Week 12
timeFrame: Day 1, Day 2, Week 4, and Week 12
measure: Maximum Plasma Concentration (Cmax) and Concentration at the End of the Dosing Interval (Ctau) of GSK2336805 at Week 4
timeFrame: Week 4 (24 h post dose)
measure: Time of Maximal Plasma Concentration (Tmax) of GSK2336805 at Week 4
timeFrame: Week 4 (24 h post dose)
measure: Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) at Week 4
timeFrame: Week 4 (24 h post dose)
measure: Apparent Clearance (CL/F) at Week 4
timeFrame: Week 4 (24 h post dose)
measure: Apparent Volume of Distribution (Vz/F) at Week 4
timeFrame: Week 4 (24 h post dose)
measure: 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
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Red Blood Cell Count at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Hemoglobin at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Hematocrit at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Mean Corpuscle Volume at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Albumin at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in ALP, ALT, AST, CK and GGT at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Total Bilirubin and Creatinine at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in SBP and DBP at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Heart Rate at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in ECG Heart Rate Values at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in PR Interval, QRS Duration, Uncorrected QT Interval, QTcB, QTcF Values at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Chloride, Bicarbonate, Glucose, Potassium, Sodium, Inorganic Phosphorus and Urea/BUN at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Mean Change From Baseline in Creatinine Clearance at the Indicated Time Points After Week 12
timeFrame: Baseline (Week 0) and Weeks 18, 24, 30, 36, 42, 48 and PT FU Week 4
measure: Correlation of Individual GSK2336805 Dose With Week 4 Plasma AUC(0-tau) Versus eRVR Status
timeFrame: Week 4 and Week 12
measure: Correlation of Individual GSK2336805 Dose With Week 4 Plasma Cmax, Ctau, C0 Versus eRVR Status
timeFrame: Week 4 and Week 12
measure: Correlation of Individual GSK2336805 Dose With Week 4 Plasma AUC(0-tau) Versus RVR Status
timeFrame: Week 4
measure: Correlation of Individual GSK2336805 Dose With Week 4 Plasma Cmax, Ctau, C0 Versus RVR Status
timeFrame: Week 4
measure: Correlation of Individual GSK2336805 Dose With Pre-dose Plasma Concentration at Week 4 and Week 12 Versus eRVR Status
timeFrame: Week 4 and Week 12
measure: Correlation GSK2336805 Pre-dose Plasma Concentration on Day 2 Versus Reduction in HCV RNA on Day 2
timeFrame: Day 2
Other outcomes:
Locations:
city: Dothan
country: United States
facility: GSK Investigational Site
state: Alabama
city: Anaheim
country: United States
facility: GSK Investigational Site
state: California
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: DeLand
country: United States
facility: GSK Investigational Site
state: Florida
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: Columbus
country: United States
facility: GSK Investigational Site
state: Georgia
city: Savannah
country: United States
facility: GSK Investigational Site
state: Georgia
city: Baltimore
country: United States
facility: GSK Investigational Site
state: Maryland
city: Brockton
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Springfield
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Asheville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Fayetteville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Jenkintown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Annandale
country: United States
facility: GSK Investigational Site
state: Virginia
city: Norfolk
country: United States
facility: GSK Investigational Site
state: Virginia
city: Brussels
country: Belgium
facility: GSK Investigational Site
city: Liege
country: Belgium
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Sofia
country: Bulgaria
facility: GSK Investigational Site
city: Varna
country: Bulgaria
facility: GSK Investigational Site
city: Lyon Cedex 04
country: France
facility: GSK Investigational Site
city: Paris Cedex 13
country: France
facility: GSK Investigational Site
city: Pessac Cedex
country: France
facility: GSK Investigational Site
city: Freiburg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Heidelberg
country: Germany
facility: GSK Investigational Site
state: Baden-Wuerttemberg
city: Wuerzburg
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Ponce
country: Puerto Rico
facility: GSK Investigational Site
city: San Juan
country: Puerto Rico
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Protocol contains no citations