Dose Ranging of GSK2336805 in Combination Therapy

Hepatitis C, Chronic Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01648140
• Other study ID #: 115879
• Status: Completed
• Phase: Phase 2
• First received: July 12, 2012
• Last updated: November 28, 2016
• Start date: August 2012
• Est. completion date: July 2014

Study information

• Verified date: November 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 286
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• GSK2336805 40 mg
20 mg tablet, round, 10-mm diameter, white to off-white, no markings
• GSK2336805 60 mg
30 mg tablet, round, 10-mm diameter, white to off-white, no markings
• Pegylated interferon alpha-2a
180 microgram per 0.5 mL prefilled syringe for single use
• Ribavirin
200-mg tablet, capsule-shaped, light blue, film-coated, and debossed with "200" on 1 side and the logo "3RP" on the other side
• Telaprevir
375 mg film-coated tablet

Locations

Country	Name	City	State
Belgium	GSK Investigational Site	Brussels
Belgium	GSK Investigational Site	Liege
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Sofia
Bulgaria	GSK Investigational Site	Varna
France	GSK Investigational Site	Lyon Cedex 04
France	GSK Investigational Site	Paris Cedex 13
France	GSK Investigational Site	Pessac Cedex
Germany	GSK Investigational Site	Berlin
Germany	GSK Investigational Site	Freiburg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Wuerzburg	Bayern
Puerto Rico	GSK Investigational Site	Ponce
Puerto Rico	GSK Investigational Site	San Juan
United States	GSK Investigational Site	Anaheim	California
United States	GSK Investigational Site	Annandale	Virginia
United States	GSK Investigational Site	Asheville	North Carolina
United States	GSK Investigational Site	Baltimore	Maryland
United States	GSK Investigational Site	Brockton	Massachusetts
United States	GSK Investigational Site	Columbus	Georgia
United States	GSK Investigational Site	DeLand	Florida
United States	GSK Investigational Site	Dothan	Alabama
United States	GSK Investigational Site	Fayetteville	North Carolina
United States	GSK Investigational Site	Houston	Texas
United States	GSK Investigational Site	Jenkintown	Pennsylvania
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Los Angeles	California
United States	GSK Investigational Site	New York	New York
United States	GSK Investigational Site	Norfolk	Virginia
United States	GSK Investigational Site	Orlando	Florida
United States	GSK Investigational Site	Savannah	Georgia
United States	GSK Investigational Site	Springfield	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
GlaxoSmithKline	PPD

Countries where clinical trial is conducted

United States,  Belgium,  Bulgaria,  France,  Germany,  Puerto Rico, 

References & Publications (1)

Protocol contains no citations

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of adverse events and absolute values.	Assessment of 12-week safety in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin as measured by the nature and frequency of adverse events and absolute values.	12-week treatment period	Yes
Primary	Antiviral activity of 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin.	Evaluate 12-week antiviral activity of 40 and 60 mg of GSK2336805 as measured by extended rapid virologic response (defined as undetectable plasma HCV RNA at Weeks 4 and 12).	12-week treatment period	No
Primary	Changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements and electrocardiograms.	Assessment of 12-week tolerability in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin as measured by changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements (blood pressure, heart rate), and ECG parameters.	12-week treatment period	Yes
Secondary	GSK2336805 plasma pharmacokinetics	Describe GSK2336805 plasma pharmacokinetics at 40 and 60 mg dose levels when given in combination with pegylated interferon alpha-2a and ribavirin.	Baseline and week 4 treatment period	No
Secondary	Very rapid virologic response (vRVR)	Compare very rapid virologic response (vRVR) rates defined as undetectable plasma HCV RNA 2 weeks after initiation of therapy.	2 weeks after start of treatment period	No
Secondary	Rapid virologic response (RVR)	Compare rapid virologic response (RVR) rates defined as undetectable plasma HCV RNA 4 weeks after initiation of therapy.	4 weeks after start of treatment period	No
Secondary	Complete early virologic response (cEVR)	Compare complete early virologic response (cEVR) rates defined as undetectable plasma HCV RNA 12 weeks after initiation of therapy.	12 weeks after start of treatment period	No
Secondary	Sustained virologic response (SVR12)	Compare 12-week sustained virologic response (SVR12) rates defined as undetectable plasma HCV RNA 12 weeks after completion of all therapy.	12 weeks after start of treatment period	No
Secondary	Sustained virologic response (SVR24)	Compare the 24-week sustained virologic response (SVR24) rates defined as undetectable plasma HCV RNA 24 weeks after completion of all therapy.	24 weeks after start of treatment period	No
Secondary	Sustained virologic response rates between GSK2336805 and standard of care	Compare sustained virologic response (SVR) rates among subjects who receive a total of 24 weeks of therapy (12 weeks of GSK2336805 and pegylated interferon alpha-2a and ribavirin followed by 12 weeks of pegylated interferon alpha-2a and ribavirin) versus those who receive the current standard of care (pegylated interferon alpha-2a, ribavirin and telaprevir based on label recommendations).	24 weeks after start of treatment period	No
Secondary	Resistance against GSK2336805	Evaluate the potential of hepatitis C virus to develop resistance against GSK2336805 by repeated sequencing of HCV strains. Analysis of the viral genotyping samples will be dependent on the subject's HCV viral load data. All study participants in a GSK2336805 treatment group will have genotypic analysis performed on the baseline sample. Samples from non-responders and subjects who rebound on GSK2336805 treatment will be subject to further genotypic analysis at nadir and at several time points after nadir.	Baseline (all subjects in GSK2336805 treatment group) and depending on subject's HCV viral load data also at weeks 1, 2, 4, 6, 8, 12, 18, 24, 30, 42, 48, Post-treatment Weeks 4, 12, and 24.	No
Secondary	Antiviral activity and safety of 60 mg of GSK2336805 in subjects with genotype 4 hepatitis C virus (HCV) infection	Further characterize the antiviral activity and safety of 60 mg of GSK2336805 in subjects with chronic genotype 4 hepatitis C virus (HCV) infection. GSK2336805 (60 mg) will be given in combination with pegylated interferon alpha-2a and ribavirin for 12 weeks, followed by pegylated interferon alpha-2a and ribavirin alone for either 12 or 36 weeks (based on the achievement of extended rapid virologic response).	24-week or 48-week treatment period	Yes
Secondary	GSK2336805 exposure-response relationships	Describe exposure-response relationships of GSK2336805 for example the relationship between GSK2336805 dose or plasma exposure and measures of virologic response when given in combination with pegylated interferon alpha-2a and ribavirin.	24-week or 48-week treatment period	No
Secondary	Frequency of adverse events and absolute values	Evaluate 12-week safety in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin followed by either 12 or 36 weeks of combination therapy with pegylated interferon alpha-2a and ribavirin based on response guided treatment (RGT) as measured by the nature and frequency of adverse events and absolute values.	24-week or 48-week treatment period	Yes
Secondary	Changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements and electrocardiograms	Evaluate 12-week tolerability in subjects dosed with 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin followed by either 12 or 36 weeks of combination therapy with pegylated interferon alpha-2a and ribavirin based on response guided treatment (RGT) as measured by changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements (blood pressure, heart rate), and ECG parameters.	24-week or 48-week treatment period	Yes

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