Cachexia
Conditions
Keywords
safety, pharmacokinetics, FTIH, SARM
Brief summary
This study is the first administration of GSK2849466 in humans. This will be a single centre, randomized, double-blind, placebo-controlled study, to investigate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GSK2849466, given as single and repeat oral doses up to 14 days to healthy male subjects. Part A will be a randomized placebo controlled and 4-way crossover study. It will include two cohorts of 8 subjects each. In each cohort there will be 4 study periods each approximately of 1 week including 6 days of washout. Each subject will receive a total of 3 active doses as ascending single oral dose of GSK2849466 and 1 placebo dose during the course of their participation in the study. The first (bridging dose) dose provided to subjects in Cohort 2 will be the same as the last dose provided to subjects in Cohort 1. The single doses of GSK2849466 planned in Part A of this study are: 0.01, 0.03, 0.1, and 0.3 milligram (mg) in Cohort 1 and 0.3, 1, 3, and 10 mg in Cohort 2. In cohorts 1 and 2 all available safety, tolerability, and PK data will be reviewed prior to each dose escalation. The dosing schedule in Part A may be adjusted to expand a cohort or to add an additional cohort(s) in order to further evaluate additional doses or repeat evaluation of a dose level already studied. Part B will be a randomized placebo controlled, parallel group study. It will include three cohorts of 12 subjects each. Each subject will receive repeat doses of GSK2849466 over 14 days. The doses chosen for Part B will be based on the safety, tolerability, and PK data from Part A. Subjects in Cohort 4 (and/or an another cohort \[s\] as determined based on Part A PK data) will be dosed in the fasted state on Days 1 and 14 and in the fed state on Day 7 when subjects will receive a standard meal 30 minutes prior to dosing. Part B will provide sufficient safety and tolerability data to bridge to longer duration studies. The study duration, including screening and follow-up, is not expected to exceed 70 days for subjects in the study.
Interventions
DRUGGSK2849466
GSK2849466 will be available as capsules of dose strengths 0.01, 0.1, 1.0, and 2.5 mg.
DRUGPlacebo
Matching placebo capsules will be available.
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Males between 18 and 50 years of age (inclusive), at the time of signing the informed consent form. * Body weight \>=50 kilogram (kg) and Body Mass Index (BMI) within the range 19 - 32 kg/meter (m)\^2 (inclusive), where BMI = (weight in kg)/(height in meters)\^2. * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. 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 GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. * Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in the Lifestyle Section of the protocol. This criterion must be followed through the completion of the follow-up visit. * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Average corrected QT interval using Fridericia's formulas (QTcF) \<450 milliseconds (msec); or QTcF \<480 msec in subjects with Bundle Branch Block.
Exclusion criteria
* Subjects with a history of clinically significant endocrine, gastrointestinal, hepatic, cardiovascular, neurological, hematological, immunological, renal, respiratory, or genitourinary abnormalities or diseases. * Subjects with a history at any time in the past of coronary artery disease, congestive heart failure, angina, myocardial infarction, any cardiac surgery, valvular heart disease, clinically significant arrhythmia, dyspnea, pulmonary edema, stroke, or transient ischemic attack. * ECG
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in clinical monitoring of blood pressure | 14 days | Safety and tolerability parameters will include blood pressure readings at Baseline and at end of the study. |
| Safety and tolerability of single ascending doses GSK2849466 as assessed by number of subjects with adverse events (AE)s | 28 days | Safety and tolerability parameters will include recording of AEs, throughout the study. |
| Safety and tolerability of repeat doses of GSK2849466 as assessed by number of subjects with AEs | 14 days | Safety and tolerability parameters will include recording of AEs, throughout the study. |
| Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in electrocardiogram (ECG) readings | 28 days | Safety and tolerability parameter will include the ECG readings at Baseline and at end of the study. |
| Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in ECG readings | 14 days | Safety and tolerability parameter will include the ECG readings at Baseline and at end of the study. |
| Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in clinical monitoring of blood pressure | 28 days | Safety and tolerability parameters will include blood pressure readings at Baseline and at end of the study. |
| Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in heart rate | 28 days | Safety and tolerability parameters will include heart rate at Baseline and at end of the study. |
| Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in heart rate | 14 days | Safety and tolerability parameters will include heart rate at Baseline and at end of the study. |
| Safety and tolerability of GSK2849466 as assessed by change from Baseline in cardiac telemetry | Part A-Day 1 continuous at least 12 hours post-dose of each dosing session; Part B-Day 1, 4, 7, 10 and 14 continuous at least 8 hours post-dose | Safety and tolerability parameters will include cardiac telemetry recording at Baseline and at end of the study. |
| Safety and tolerability of single ascending doses of GSK2849466 as assessed by change from Baseline in laboratory assessments | 28 days | Safety and tolerability parameters will include laboratory values at Baseline and at end of the study. |
| Safety and tolerability of repeat doses of GSK2849466 as assessed by change from Baseline in laboratory assessments | 14 days | Safety and tolerability parameters will include laboratory values at Baseline and at end of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) and AUC from zero to infinity (AUC(0-inf)) following single doses of GSK2849466 | 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose. | The AUC(0-t) and AUC(0-inf) for GSK2849466 will be assessed following single doses of GSK2849466. |
| Maximum concentration (Cmax) following single doses of GSK2849466 | 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose. | The Cmax of GSK2849466 will be assessed following single doses of GSK2849466. |
| Time to maximum observed plasma drug concentration (Tmax) following single doses of GSK2849466 | 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose. | The Tmax for GSK2849466 will be assessed following single doses of GSK2849466. |
| Terminal half-life (t1/2) following single doses of GSK2849466 | 2 days of each treatment period in Part A: Day 1-0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hours post dose; Day 2-24 hours post Day 1 dose. | The t1/2 for GSK2849466 will be assessed following single doses of GSK2849466. |
| The AUC(0-t), AUC(0-inf)) and AUC from time zero to the end of the dosing interval at steady state AUC(0-tau) following repeat doses of GSK2849466 | Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7. | The AUC(0-t), AUC(0-inf) and AUC(0-tau) following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study. |
| The Cmax following repeat doses of GSK2849466 | Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7. | The Cmax following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study. |
| The Tmax following repeat doses of GSK2849466 | Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7. | The Tmax following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study. |
| The t1/2 following repeat doses of GSK2849466 | Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7. | The t1/2 following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study. |
| The estimation of an accumulation ratio following repeat doses of GSK2849466 | Part B (all cohorts): Day 1, 2, 14, 15(24 hours serial sampling); Day 4, 5, 6, 7 (pre dose sampling). Part B (Cohort 4): Day 7 and 8 (24 hours serial sampling) and no PK samples on Day 8 if fasted on Day 7. | The estimation of an accumulation ratio following repeat doses of GSK2849466 with and without food (Cohort 4 and/or another cohort(s) as determined based on Part A PK data) will be assessed in Part B of the study. |
Countries
United States
Outcome results
None listed