A Randomized, Double Blind, Dose Escalation, Fusion, First Time in Human Study to Assess the Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Single and Repeat Doses of GSK2336805 in Healthy Volunteers and Single Doses in Chronically Infected Hepatitis C Subjects
Overview
- Phase
- Phase 1
- Intervention
- GSK2336805 10mg
- Conditions
- Hepatitis C
- Sponsor
- GlaxoSmithKline
- Enrollment
- 58
- Locations
- 1
- Primary Endpoint
- GSK2336805 safety parameters : adverse events
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
This study is a three Part, Phase 1, randomized, dose-escalation, fusion, placebo-controlled, double-blind study to determine the safety, tolerability and Pharmacokinetic (PK) profile of GSK2336805 in healthy subjects and the safety, tolerability, PK, and antiviral profile of GSK2336805 in subjects chronically infected with HCV: i. Single doses in healthy subjects and the effect of food on GSK2336805 PK (Part 1). ii. Repeat doses in healthy subjects (Part 2) iii. Single doses in chronically infected HCV positive subjects (Part 3).
Investigators
Eligibility Criteria
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.
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.
Arms & Interventions
Part 1: Single Dose Escalation in Healthy Subjects
The doses currently planned are 10, 30mg, 100mg, 200mg
Intervention: GSK2336805 10mg
Part 1: Single Dose Escalation in Healthy Subjects
The doses currently planned are 10, 30mg, 100mg, 200mg
Intervention: GSK2336805 30mg
Part 1: Single Dose Escalation in Healthy Subjects
The doses currently planned are 10, 30mg, 100mg, 200mg
Intervention: GSK2236805 100mg
Part 1: Single Dose Escalation in Healthy Subjects
The doses currently planned are 10, 30mg, 100mg, 200mg
Intervention: GSK2236805 200mg
Part 2: Repeat Dose Escalation in Healthy Subjects
The first planned dose is currently 10mg QD and the planned maximum dose is 100mg QD
Intervention: GSK2236805 10mg
Part 2: Repeat Dose Escalation in Healthy Subjects
The first planned dose is currently 10mg QD and the planned maximum dose is 100mg QD
Intervention: GSK2236805 dose to be determined up to 100mg
Part 3: Single Dose Escalation in HCV Infected Subjects
The planned doses for Part 3 are 5mg, 30mg, and 100 mg.
Intervention: GSK2236805 5mg
Part 3: Single Dose Escalation in HCV Infected Subjects
The planned doses for Part 3 are 5mg, 30mg, and 100 mg.
Intervention: GSK2236805 30mg
Part 3: Single Dose Escalation in HCV Infected Subjects
The planned doses for Part 3 are 5mg, 30mg, and 100 mg.
Intervention: GSK2236805 100mg
Outcomes
Primary Outcomes
GSK2336805 safety parameters : adverse events
Time Frame: Part 1 change from baseline for 14 days; Part 2 change from baseline for 24 days; Part 3 change from baseline for 16 days
GSK2336805 safety parameters: telemetry
Time Frame: Part 1 change from baseline for 14 days; Part 2 change from baseline for 24 days; Part 3 change from baseline for 16 days
GSK2336805 safety parameters: absolute values and changes over time of hematology, clinical chemistry, urinalysis
Time Frame: Part 1 change from baseline for 14 days; Part 2 change from baseline for 24 days; Part 3 change from baseline for 16 days
GSK2336805 safety parameters: vital signs (blood pressure, heart rate)
Time Frame: Part 1 change from baseline for 14 days; Part 2 change from baseline for 24 days; Part 3 change from baseline for 16 days
GSK2336805 safety parameters: electrocardiogram (ECG) parameters
Time Frame: Part 1 change from baseline for 14 days; Part 2 change from baseline for 24 days; Part 3 change from baseline for 16 days
GSK2336805 PK parameters following single dose administration: area under the plasma concentration curve from time zero (pre-dose) extrapolated to infinite time (AUC(0-infinity)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: area under the plasma concentration curve over the dosing interval AUC(0-tau))
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: maximum observed concentration (Cmax)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: time to maximum observed concentration (tmax)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: observed concentration at 24h post-dose (C24)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: terminal half-life (t1/2)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: lag time (tlag)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following single dose administration: apparent clearance (CL/F)
Time Frame: Part 1 up to 48 hours; Part 2 for 7 and 14 days; Part 3 for 48 hours
GSK2336805 PK parameters following repeat dose administration:AUC(0-tau)
Time Frame: Day 7 and Day 14
GSK2336805 PK parameters following repeat dose administration: Pre-dose (trough) concentration at the end of the dosing interval Ctau
Time Frame: Day 7 and Day 14
GSK2336805 PK parameters following repeat dose administration: CL/F
Time Frame: Day 7 and Day 14
GSK2336805 PK parameters following single dose in HCV infected subjects: AUC(0-infinity) or AUC(0 - tau)
Time Frame: for 48 hours
GSK2336805 PK parameters following single dose in HCV infected subjects: Cmax
Time Frame: for 48 hours
GSK2336805 PK parameters following single dose in HCV infected subjects: C24
Time Frame: for 48 hours
GSK2336805 PK parameters following single dose in HCV infected subjects: tmax
Time Frame: for 48 hours
GSK2336805 PK parameters following single dose in HCV infected subjects: tlag
Time Frame: for 48 hours
GSK2336805 PK parameters following single dose in HCV infected subjects: CL/F
Time Frame: for 48 hours
HCV Ribonucleic acid (RNA) viral load reduction from baseline during the 24hr and post-dosing following a single dose of GSK2336805 in HCV subjects
Time Frame: at baseline, 24 hours, and for 16 days
HCV RNA change from baseline to nadir (maximum change) in HCV subjects
Time Frame: baseline, and for 16 days
Time course of HCV viral load at baseline, after dosing with GSK2336805, and for greater than or equal to 2 weeks after GSK2336805 dosing (Part 3)
Time Frame: baseline and up to 16 days
GSK2336805 PK parameters following repeat dose administration: Cmax
Time Frame: Day 7 and Day 14
GSK2336805 PK parameters following repeat dose administration: tmax
Time Frame: Day 7 and Day 14
GSK2336805 PK parameters following repeat dose administration: t1/2,
Time Frame: Day 7 and day 14
Secondary Outcomes
- GSK2336805 PK parameters: AUC(0-τ), Cτ, and Cmax following repeat administration(for 7 days)
- GSK2336805 PK parameters: AUC(0-infinity), AUC(0-t), Cmax, and C24 following single dose administration(48 hours)
- GSK2336805 PK parameters: AUC(0-infinity) or AUC (0 - tau) following single dose administration of a given dose of GSK2336805 with and without moderate fat/calorie meal (Part 1)(48 hours)
- GSK2336805 PK parameters: Cmax following single dose administration of a given dose of GSK2336805 with and without moderate fat/calorie meal (Part 1)(48 hours)
- GSK2336805 PK parameters: tmax following single dose administration of a given dose of GSK2336805 with and without moderate fat/calorie meal (Part 1)(48 hours)
- GSK2336805 PK parameters: tlag following single dose administration of a given dose of GSK2336805 with and without moderate fat/calorie meal (Part 1)(48 hours)
- GSK2336805 AUC(0-tau) on Day 7 compared to AUC(0-24) on Day 1 to estimate accumulation ratio (R) and GSK2336805 AUC(0-tau) on Day 7 compared to AUC(0-infinity) on Day 1(Day 1 and Day 7)
- Pre-dose concentrations (Ctau) on Day 2 through 7 to assess the achievement of steady state of GSK2336805 following repeat administration (Part 2)(Day 2 through Day 7)
- Correlation between concentration and various safety parameters, if appropriate(16 days)
- Sequence analysis of the viral quasispecies as appropriate (Part 3).(16 days)
- GSK2336805 AUC(0-tau) on Day 14 compared to AUC(0-24) on Day 1 to estimate accumulation ratio (R) and GSK2336805 AUC(0-tau) on Day 14 compared to AUC(0-inf) on Day 1(14 days)
- Pre-dose concentrations (Ctau) on Day 2 through 14 to assess the achievement of steady state of GSK2336805 following repeat administration (Part 2 Cohort E)(Day 2 and Day 14)