| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10019752 |
| E.1.2 | Term | Hepatitis C virus (HCV) |
| E.1.2 | System Organ Class | 100000004848 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objectives of this study are:
• To evaluate the 12-week safety and tolerability of 40 and 60 mg of GSK2336805 when given in combination with pegylated interferon alfa-2a (PEG) and ribavirin (RIBA).
• To evaluate 12-week antiviral activity of 40 and 60 mg of GSK2336805 when given in combination with PEG and RIBA as measured by eRVR (defined as undetectable plasma HCV RNA at Weeks 4 and 12) |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are:
• To evaluate the safety and tolerability of 40 and 60 mg of GSK2336805 when given in combination with PEG (pegylated interferon alfa-2a) and RIBA (ribavirin) for 12 weeks, followed by either 12 or 36 weeks of combination therapy with PEG and RIBA based on RGT
• To describe GSK2336805 plasma pharmacokinetics at 40- and 60-mg dose levels when given in combination with PEG and RIBA
• To compare very rapid virologic response (vRVR) rates defined as undetectable plasma HCV RNA 2 weeks after initiation of therapy) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
2. Is male or female aged 18 to 70 years, inclusive, at Screening.
3. Has chronic genotype 1 or genotype 4 (as assessed by VERSANT HCV Genotype assay 2.0 (LiPA); Siemens Healthcare Diagnostics, Deerfield, Illinois) HCV infection documented by at least 1 measurement of serum HCV RNA ≥100,000 IU/mL measured during Screening by the COBAS High Pure/COBAS
TaqMan HCV Test v2.0 (Roche Molecular Diagnostics, Pleasanton, California) 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 CHC disease, such as the presence of fibrosis).
4. Is naïve to all HCV antiviral treatment(s), including, but not limited to, immunomodulatory and nucleoside/nucleotide treatments for chronic HCV infection.
5. Agrees to IL28B genotyping.
6. Is a subject, who, in the opinion of the investigator, is an appropriate candidate for PEG/RIBA/protease inhibitor combination therapy for genotype 1 subjects and PEG/RIBA combination therapy for genotype 4 subjects.
7. Has a body mass index >18 kg/m2 but not exceeding 36 kg/m2.
8. Has 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 ≤3, Metavir ≤2, Ishak ≤4, or Batts and Ludwig ≤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).
9. For all fertile males and females, must use 2 forms of effective contraception (as defined in inclusion criterion #10) between them during treatment and during the 24 weeks after treatment ends.
10. For females, is eligible to enter and participate in the study if she is of
• Nonchildbearing potential (i.e., physiologically incapable of becoming pregnant) including any female who
• Has had a hysterectomy
• Has had a bilateral oophorectomy (ovariectomy)
• Has had a bilateral tubal ligation
• Is postmenopausal (demonstrate total cessation of menses for greater than 1 year)
• 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
11. Is otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening.
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
1. Has positive test at Screening for hepatitis B surface antigen (HBsAg) or antihuman immunodeficiency virus antibody.
2. Has a 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) (Note: Subjects with Gilbert’s syndrome who otherwise meet all inclusion/exclusion criteria are eligible.)
3. Has a history of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease.
4. Has positive results on urine screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription).
5. Has a history of alcohol/drug abuse or dependence within 6 months of the study start (unless participating in a controlled rehabilitation program).
6. Has screening ECG corrected QT (QTc) interval value >450 ms and/or clinically significant ECG findings.
7. Has personal or family history of torsade de pointes findings.
8. Is pregnant or nursing.
9. Is male with a female partner who is pregnant.
10. Has 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 ≥1.5 × the upper limit of normal (ULN)
• Estimated creatinine clearance ≤50 mL/min (as calculated using the Cockcroft-Gault formula)
• ALT, AST, or alkaline phosphatase ≥5 × ULN
• Total bilirubin ≥2.0 × ULN (except subjects with Gilbert's syndrome)
• Albumin ≤3.0 g/dL
• Platelet count ≤90,000/mm3
11. Has history of major organ transplantation with an existing functional graft.
12. Has thyroid dysfunction not adequately controlled.
13. Has a history of any one of the following:
• Suicide attempt or hospitalization for depression in the past 5 years
• Any current (within 6 months) severe or poorly controlled psychiatric disorder
• The following subjects are eligible for study participation but must be assessed
and followed (if recommended) by a mental health professional:
• Subjects who have had a severe or poorly controlled psychiatric disorder more than 6 months ago but less than 5 years ago
14. Has a 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.
15. Has been 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.
16. Has participated in a clinical study with an investigational drug, biologic, or device within 3 months prior to the first dose administration.
17. Has a history of a known allergy to antiviral medications, including telaprevir, PEG, or RIBA, or any excipient in the investigational product or history of drug or other allergy that, in the opinion of the investigator, contradicts participation.
18. Requires prohibited medications. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Assessment of 12-week safety and tolerability as measured by the nature and frequency of AEs and absolute values and changes over time from predose
values for hematology, clinical chemistry, urinalysis, vital sign measurements (blood pressure, heart rate), and ECG parameters
• Proportion of subjects achieving eRVR (extended rapid virological response) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• To evaluate the safety and tolerability of 40 and 60 mg of GSK2336805 when given in combination with PEG and RIBA for 12 weeks, followed by either 12 or 36 weeks of combination therapy with PEG and RIBA based on RGT (response guided treatment)
• To describe GSK2336805 plasma pharmacokinetics at 40- and 60-mg dose levels when given in combination with PEG and RIBA
• To compare very rapid virologic response (vRVR) rates defined as undetectable plasma HCV RNA 2 weeks after initiation of therapy)
• To compare RVR rates (defined as undetectable plasma HCV RNA 4 week after initiation of therapy)
• To compare complete early virologic response (cEVR) rates (defined as undetectable plasma HCV RNA 12 weeks after initiation of therapy)
• To compare 12-week sustained virologic response (SVR12) rates (defined as undetectable plasma HCV RNA 12 weeks after completion of all therapy)
• To compare the 24-week sustained virologic response (SVR24) rates (defined as undetectable plasma HCV RNA 24 weeks after completion of all therapy)
• To compare SVR rates among subjects who receive a total of 24 weeks of therapy (12 weeks of GSK2336805 and PEG + RIBA followed by 12 weeks of PEG + RIBA) versus those who receive the current SoC (PEG + RIBA and telaprevir based on label recommendations)
• To evaluate the potential of HCV to develop resistance against GSK2336805 by repeated sequencing of HCV strains
• To further characterize the antiviral activity and safety of GSK2336805 in subjects with chronic genotype 4 HCV infection (Note: for the final reporting, the data from this cohort may be combined with the data from the cohort of genotype 1 subjects as appropriate)
• To describe exposure-response relationships of GSK2336805 (e.g., the relationship between GSK2336805 dose or plasma exposure and measures of virologic response) when given in combination with PEG + RIBA
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 4, 12, 24, 48, 60, and 72 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Puerto Rico |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Subject’s Last Visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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