Please select the eligibility criteria that correspond to the clinical trial below.
Title: Double-Blind, Randomized, Placebo-Controlled Study to Assess Safety, Efficacy, and Pharmacokinetics (PK) of GSK2336805 in Combination With Peginterferon and Ribavirin in Treatment-naive Chronic Hepatitis C Subjects With Hepatitis C Virus Genotypes 1 or 4
Brief Summary: GSK2336805 is a hepatitis C virus (HCV) NS5A inhibitor being developed for the treatment of chronic hepatitis C (CHC). This study will assess the safety, antiviral activity, and pharmacokinetics of GSK2336805 alone and in combination with peginterferon alfa 2a and ribavirin in subjects with chronic hepatitis C (CHC).


Options:
A: Key Inclusion Criteria:

* Documented chronic genotype 1 or genotype 4 HCV infection
* Naïve to all HCV antiviral treatment(s)
* Agree to IL28B genotyping
* A body mass index \>18 kg/m2 but not exceeding 36 kg/m2
* Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic. 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 two forms of effective contraception between them during treatment and during the 24 weeks after treatment ends
* Otherwise healthy as determined by the medical history, physical examination, ECG findings, and clinical laboratory measurements performed at Screening

Key Exclusion Criteria:

* Positive test at Screening for hepatitis B surface antigen (HBsAg) or anti-human immunodeficiency virus antibody
* History of any other clinically significant chronic liver disease
* 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 ECG corrected QT interval value greater than 450 ms and/or clinically significant ECG findings
* A personal or family history of Torsade de Pointes findings
* Pregnant or nursing women
* Males with a female partner who is pregnant
* Abnormal hematological and biochemical parameters as specified in the protocol
* History of major organ transplantation with an existing functional graft
* Thyroid dysfunction not adequately controlled
* Subjects with a history of suicide attempt or hospitalization for depression in the past 5 years and/or any current (within 6 months) severe or poorly controlled psychiatric disorder
* History or current evidence of immunologic disorder; pulmonary, cardiac, or pulmonary disease; seizure disorder; cancer or history of malignancy that in the opinion of the investigator makes the subject unsuitable for the study
* Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration
B: Inclusion Criteria:

* Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECG, including no cardiac, pulmonary, hepatic, biliary (except Gilbert's disease, gastrointestinal, or renal (defined as serum creatinine \>1.5 mg/dL or a calculated creatinine clearance (CrCl)\<50 mL/min), disorders, or cancer within the past 5 years (except localized or in situ cancer of the skin). A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GSK Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. A single repeat laboratory evaluation is allowed for eligibility determination.
* Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
* A female is eligible to enter and participate in this study if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation, bilateral oophorectomy, hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea.
* Male subjects must agree to use one of the contraception methods listed in the protocol.
* Body weight greater than or equal to 50 kg (110 lbs.) for men and greater than or equal to 45 kg (99 lbs.) for women. For Part 1, body mass index (BMI) between 18.5-32 kg/m2 inclusive will be allowed. For Part 3, BMI between 18.5-35.0 kg/m2 inclusive will be allowed.
* For healthy subjects in Part 1 and Part 2, Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), alkaline phosphatase, bilirubin, and creatinine less than the upper limits of normal (ULN) (isolated bilirubin \<2.0xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
* QTcB or QTcF \< 450 msec; or QTc \<480 msec in subjects with Bundle Branch Block.
* The subject's systolic blood pressure is inside the range of 90-140 mmHg, or diastolic blood pressure is inside the range of 45-90 mmHg or heart rate is inside the range of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male subjects.
* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions and is likely to complete the study as planned.
* The following are Supplemental inclusion criteria for Part 3: HCV positive subjects: Treatment naive chronically infected genotype 1 HCV patients, defined as infection for \>6 months and no prior HCV therapy.
* An HCV RNA viral load of greater than 100,000 IU/mL using a COBAS TaqMan HCV test and HCV genotype 1a or 1b as assessed by VERSANT HCV genotyping LiPA 2.0 (Bayer Healthcare, Berkeley, California), or by direct Deoxyribonucleic acid (DNA) sequencing of the NS5B gene Hepatitis C virus infection of mixed genotype excluded. HCV subjects with mixed genotypes are not eligible for the study.
* ALT greater than or equal to 3x ULN is allowed.
* Liver biopsy within two years prior to screening indicating the absence of cirrhosis.

Exclusion Criteria:

* Unwillingness or inability to follow the procedures outlined in the protocol.
* A positive pre-study test for Human Immunodeficiency Virus (HIV) antibody or Hepatitis B surface antigen.
* For healthy subjects in Parts 1 and 2, a positive Hepatitis C antibody result within 3 months of screening. Chronic HCV infected subjects in Part 3 will have a positive HCV antibody and a positive HCV RNA.
* Pregnant females as determined by positive serum or urine Human chorionic gonadotropin (hCG) test at screening or prior to dosing.
* Subject is mentally or legally incapacitated.
* Has a history of regular alcohol consumption averaging: \>7 drinks/week for women or \>14 drinks/week for men within 6 months of the screening visit.
* Unwilling to abstain from alcohol for 48 hours prior to the start of dosing until collection of the final pharmacokinetic sample during each treatment period.
* For healthy subjects in Parts 1 and 2, history of regular use of tobacco- or nicotine-containing products within 3 months of the screening visit or indication of tobacco use as evidenced by a positive urine cotinine test at screening. For chronic HCV infected subjects in Part 3, history of regular use of tobacco- or nicotine-containing products is allowed; however, use of tobacco is not allowed on days of PK draws nor at the study site.
* Consumption of red wine, seville oranges, grapefruit or grapefruit juice, pummelos, satsuma, ugli, tangerine, and tangelo, exotic citrus fruits, grapefruit hybrids or fruit juices from 5 days prior to the first dose of study medication.
* The subject has a positive pre-study drug screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids, phencyclidine (PCP), and benzodiazepines. Unwilling to refrain from the use of illicit drugs and adhere to other protocol-stated restrictions while participating in the study.
* Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
* The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
* Exposure to more than four new investigational entities within 12 months prior to the first dosing day.
* History or presence of allergy or intolerance to the study drugs or their components or drugs of their class, or a history of drug or other allergy that, in the opinion of the physician responsible, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
* Holter monitoring shows one or more of the following: Any symptomatic arrhythmia (except isolated extra systoles); Sustained cardiac arrhythmias (such as atrial fibrillation or flutter, sustained ventricular tachycardia (SVT) (\>10 consecutive beats)); Non-sustained or sustained ventricular tachycardia (defined as \>3 consecutive ventricular ectopic beats); Any conduction abnormality (including but not specific to left or right complete bundle branch block, atrioventricular (AV) block \[2nd degree or higher in an awake subject\], Wolff-Parkinson-White syndrome (WPW) syndrome, other pre-excitation syndromes); Symptomatic sinus pause or sinus pause \>3 seconds - unless patient is straining, vomiting, or having some other type of hypervagal response; 300 or more supraventricular ectopic beats in 24 hours; 250 or more ventricular ectopic beats in 24 hours; Ischemia, diagnosed by a sequence of EKG changes that include flat or down sloping ST-segment depression \>0.1 mV, with a gradual onset and offset that lasts for a minimum period of 1 minute. Each episode of ischemia must be separated by a minimum duration of at least 1 minute, during which the ST segment returns back to baseline (1x1x1 rule)
C: Inclusion Criteria:

* Chronically infected with HCV genotype 1
* Treatment naive or treatment non-responders or treatment intolerant
* HCV RNA viral load of ≥10\*5\* IU/mL
* BMI 18 to 35 kg/m²

Exclusion Criteria:

* Any significant acute or chronic medical illness which is not stable or is not controlled with medication and not consistent with HCV infection
* Major surgery within 4 weeks of study drug administration and any gastrointestinal surgery that could impact the absorption of study drug
* Co-infection with HIV or HBV
D: Inclusion Criteria:

* Patient must have had a liver biopsy before screening (or between the screening and baseline visit), unless patient cannot undergo such a procedure or has evidence of portal hypertension not associated with cirrhosis. For patients who had a liver biopsy performed more than 2 years prior to screening or without a biopsy (because of a contraindication or portal hypertension), a non-invasive staging assessment needs to be available. Non-invasive staging assessments include FibroScan, MR-Elastography, or FibroTest/FibroSure and must not be older than 6 months prior to screening
* Chronicity of hepatitis C virus (HCV) infection, as confirmed by one or both of the following: presence of anti-HCV antibody and/or HCV ribonucleic acid (RNA) at least 6 months prior to the screening visit and/or presence of fibrosis on biopsy
* Genotype 1 HCV infection with plasma HCV RNA of \>10,000 IU/mL (both confirmed at screening)
* Patient must have had at least 1 documented previous course of treatment with PegINFα-2a or PegINFα-2b in combination with ribavirin (RBV) (at least 12 weeks for null responder and 20 weeks for partial responder)

Exclusion Criteria:

* Hepatic decompensation (impaired functioning of the liver), as indicated by significant laboratory abnormalities or other active diseases
* Infection with Human Immunodeficiency Virus (HIV) or non genotype 1 hepatitis C
* Liver disease not related to hepatitis C infection
* Previous chronic hepatitis C treatment, other than PegIFN and RBV

Answer: A