Dose Ranging of GSK2336805 in Combination Therapy (HAI115879)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
PPD
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01648140
First received: July 12, 2012
Last updated: June 5, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Hepatitis C, Chronic
Drug: GSK2336805 40 mg
Drug: GSK2336805 60 mg
Drug: Pegylated interferon alpha-2a
Drug: Ribavirin
Drug: Telaprevir
Phase 2

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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Frequency of adverse events and absolute values. [ Time Frame: 12-week treatment period ] [ Designated as safety issue: Yes ]
    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.

  • Antiviral activity of 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alpha-2a and ribavirin. [ Time Frame: 12-week treatment period ] [ Designated as safety issue: No ]
    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).

  • Changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements and electrocardiograms. [ Time Frame: 12-week treatment period ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • GSK2336805 plasma pharmacokinetics [ Time Frame: Baseline and week 4 treatment period ] [ Designated as safety issue: No ]
    Describe GSK2336805 plasma pharmacokinetics at 40 and 60 mg dose levels when given in combination with pegylated interferon alpha-2a and ribavirin.

  • Very rapid virologic response (vRVR) [ Time Frame: 2 weeks after start of treatment period ] [ Designated as safety issue: No ]
    Compare very rapid virologic response (vRVR) rates defined as undetectable plasma HCV RNA 2 weeks after initiation of therapy.

  • Rapid virologic response (RVR) [ Time Frame: 4 weeks after start of treatment period ] [ Designated as safety issue: No ]
    Compare rapid virologic response (RVR) rates defined as undetectable plasma HCV RNA 4 weeks after initiation of therapy.

  • Complete early virologic response (cEVR) [ Time Frame: 12 weeks after start of treatment period ] [ Designated as safety issue: No ]
    Compare complete early virologic response (cEVR) rates defined as undetectable plasma HCV RNA 12 weeks after initiation of therapy.

  • Sustained virologic response (SVR12) [ Time Frame: 12 weeks after start of treatment period ] [ Designated as safety issue: No ]
    Compare 12-week sustained virologic response (SVR12) rates defined as undetectable plasma HCV RNA 12 weeks after completion of all therapy.

  • Sustained virologic response (SVR24) [ Time Frame: 24 weeks after start of treatment period ] [ Designated as safety issue: No ]
    Compare the 24-week sustained virologic response (SVR24) rates defined as undetectable plasma HCV RNA 24 weeks after completion of all therapy.

  • Sustained virologic response rates between GSK2336805 and standard of care [ Time Frame: 24 weeks after start of treatment period ] [ Designated as safety issue: No ]
    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).

  • Resistance against GSK2336805 [ Time Frame: 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. ] [ Designated as safety issue: No ]
    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.

  • Antiviral activity and safety of 60 mg of GSK2336805 in subjects with genotype 4 hepatitis C virus (HCV) infection [ Time Frame: 24-week or 48-week treatment period ] [ Designated as safety issue: Yes ]
    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).

  • GSK2336805 exposure-response relationships [ Time Frame: 24-week or 48-week treatment period ] [ Designated as safety issue: No ]
    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.

  • Frequency of adverse events and absolute values [ Time Frame: 24-week or 48-week treatment period ] [ Designated as safety issue: Yes ]
    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.

  • Changes over time from predose values for hematology, clinical chemistry, urinalysis, vital sign measurements and electrocardiograms [ Time Frame: 24-week or 48-week treatment period ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 115
Study Start Date: August 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: T40
Hepatitis C virus (HCV) genotype 1 GSK2336805 40 mg, pegylated interferon alpha-2a, and ribavirin arm
Drug: GSK2336805 40 mg
20 mg tablet, round, 10-mm diameter, white to off-white, no markings
Other Name: GSK2336805 40 mg
Drug: Pegylated interferon alpha-2a
180 microgram per 0.5 mL prefilled syringe for single use
Other Name: Pegasys
Drug: 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
Other Name: Ribasphere
Experimental: T60
Hepatitis C virus (HCV) genotype 1 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm
Drug: GSK2336805 60 mg
30 mg tablet, round, 10-mm diameter, white to off-white, no markings
Other Name: GSK2336805 60 mg
Drug: Pegylated interferon alpha-2a
180 microgram per 0.5 mL prefilled syringe for single use
Other Name: Pegasys
Drug: 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
Other Name: Ribasphere
Active Comparator: PRT
Hepatitis C virus (HCV) genotype 1 Telaprevir, pegylated interferon alpha-2a, and ribavirin arm
Drug: Pegylated interferon alpha-2a
180 microgram per 0.5 mL prefilled syringe for single use
Other Name: Pegasys
Drug: 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
Other Name: Ribasphere
Drug: Telaprevir
375 mg film-coated tablet
Other Names:
  • Incivek (United States)
  • Incivo (European Union)
Experimental: G4
Hepatitis C virus (HCV) genotype 4 GSK2336805 60 mg, pegylated interferon alpha-2a, and ribavirin arm
Drug: GSK2336805 60 mg
30 mg tablet, round, 10-mm diameter, white to off-white, no markings
Other Name: GSK2336805 60 mg
Drug: Pegylated interferon alpha-2a
180 microgram per 0.5 mL prefilled syringe for single use
Other Name: Pegasys
Drug: 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
Other Name: Ribasphere

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

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01648140

  Show 39 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
PPD
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01648140     History of Changes
Other Study ID Numbers: 115879
Study First Received: July 12, 2012
Last Updated: June 5, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Genotype 4
GSK2336805
pegylated interferon
telaprevir
Genotype 1
chronic hepatitis C
ribavirin
NS5A inhibitor
hepatitis C virus (HCV) infection

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Interferon-alpha
Interferons
Ribavirin
Peginterferon alfa-2a
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 28, 2014