Hepatitis C, Chronic
Conditions
Keywords
chronic hepatitis C (CHC), Hepatitis C virus (HCV), NS5B, pharmacokinetics, GSK2878175, safety, FTIH, healthy subjects
Brief summary
GSK2878175 is a site IV NS5B non-nucleoside inhibitor (NNI) being developed for the treatment of chronic HCV infection. This study represents the first administration of GSK2878175 in humans to define safety, tolerability, and pharmacokinetics (PK) following single and repeat doses of GSK2878175 in healthy subjects. This is a Phase 1, randomized, single-blind, placebo-controlled, dose escalation study to determine the safety, tolerability, and PK profile of GSK2878175 in single (Part 1) and repeat doses (Part 2) in healthy subjects. In addition the study will explore the effect of a moderate (30%) fat meal on single dose PK endpoints in healthy subjects.
Interventions
DRUGGSK2878175
Round tablets (5.0mg) given once daily single and repeated (to 7 days), Oral dose.
DRUGPlacebo
Visually matching GSK2878175
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* 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. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and ECGs. There should be no evidence of cardiac, pulmonary, hepatic, biliary, gastrointestinal, or renal 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 parameter(s) which is/are not specifically listed in the inclusion or
Exclusion criteria
and are reported as outside of the normal reference range for healthy volunteers may be included only if the Investigator considers the finding is unlikely to introduce additional risk to the subject and will not interfere with the study procedures. * Body weight \>50 Kilograms(kg) (110 pounds) for men and \>45kg (99pounds) women and a body mass index (BMI) between 18.5-32 kg/meter\^2 inclusive will be allowed. * Male or female between 18 and 55 years of age inclusive, at the time of signing the informed consent. * A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy \[for this definition, documented refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records\]; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 milli international unit \[MlU\]/milliliter \[mL\] and estradiol \<40 picogram \[pg\]/mL \[\<147 picomoles /litre\] is confirmatory\].. * Male subjects with female partners of child-bearing potential must agree to use contraception method. This criterion must be followed from the time of the first dose of study medication until the follow up visit.his criterion must be followed from the time of the first dose of study medication until the follow up visit (7 to 14 days post last dose). * Aspartate Amino Transferase (AST), Alanine Amino Transferase (ALT), alkaline phosphatase, bilirubin, and creatinine less than the upper limits of normal. TSH within normal reference range. At the discretion of the principle investigator (PI) or sub-PI, these values may be repeated once. * White blood cell count (including neutrophil counts), hemoglobin, platelets and reticulocytes greater than the lower limits of normal. At the discretion of the PI or sub-PI, these values may be repeated once. * The subject's systolic blood pressure is inside the range of 90-140 millimeters of mercury (mmHg,) and diastolic blood pressure is inside the range of 45-90 mmHg. Heart rate is inside the range of 50-100 beat per minute (bpm) for female subjects or 45-100 bpm for male subjects.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as assessed by the collection of adverse events (AEs). | Screening to 7-14 days post last-dose | AEs will be collected from the start of Study Treatment and until 7-14 days post last-dose (at follow up). |
| Safety as assessed by hematology, clinical chemistry, urinalysis, vital signs, electrocardiogram (ECG) intervals, ECG rhythm telemetry, pulmonary function tests, respiratory rate and lung auscultation. | Pre-dose to 7-14 days post last-dose | Absolute values and changes over time of hematology, clinical chemistry, urinalysis, vital signs (blood pressure \[BP\], FSH/Estradiol (Women), Urine β-hCG (Women) temperature, and heart rate), 12 LED ECG, and Holter monitoring, ECG intervals, ECG rhythm, and telemetry will be measured. Telemetry is the continuous monitoring of a subject's heart rate and rhythm from a remote location. Pulmonary function testing includes a group of tests that measure how well the lung is functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite of pharmacokinetics (PK) parameters following single dose administration of GSK2878175. | Part 1 and Day 1for Part 2 | PK parameters include: area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC \[0-infinity\]), area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC \[0-t\]), maximum observed concentration (Cmax), time to maximum observed concentration (tmax), observed concentration at 24hour post-dose (C24), lag time before observation of drug concentrations in sampled matrix (tlag), terminal half-life (t1/2), apparent oral clearance (CL/F). |
| Composite of PK parameters following repeat dose administration of GSK2878175. | on Part 2 Day 7 | PK parameters include: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval),tmax, tlag, t1/2, CL/F |
| Dose proportionality of GSK2878175 PK parameters following single and repeat administration | Pre-dose, Day1 and Day 7 | GSK2878175 PK parameters: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval),tmax, tlag, t1/2 |
| The effect of a moderate fat/caloric meal on the relative bioavailability of a given single dose of GSK2878175 | Pre-dose, Day1 | GSK2878175 PK parameters: AUC (0-infinity), AUC (0-t), Cmax, and Ctau (Pre-dose trough concentration at the end of the dosing interval), tmax, tlag, t1/2, with and without moderate fat/calorie meal (Part 1). |
| Estimate GSK2878175 accumulation and time invariance | Pre-dose, Day1 and Day 7 | GSK2878175 AUC(0 t), Cmax, and Ctau on the last day of dosing compared to AUC(0-24), Cmax, and C24 on Day 1 to estimate accumulation ratio (R) and GSK2878175 AUC(0 t) on the last day of dosing compared to AUC(0 infinity) on Day 1 to evaluate time invariance (Part 2) |
| To assess attainment of steady state following repeat administration | Pre-dose, Day 1 and Day 7 | Pre-dose concentrations on Day 3 through 7 and Ctau on Day 7 to assess the achievement of steady state of GSK2878175 following repeat administration (Part 2). |
| To describe exposure-response relationships for various safety parameters, if appropriate. | Pre-dose, Day1 and Day 7 | Correlation between PK parameters and various safety parameters, if appropriate |
Countries
Australia
Outcome results
None listed