This is a First in Human (FIH), double-blinded, parallel-group, randomised, placebo-controlled study designed to evaluate the safety, tolerability, PK and PD of single and multiple ascending oral doses of GS-248 in healthy subjects.
Part I (SAD); In the SAD part of the study, single oral doses of GS-248 will be administered in 6 sequential cohorts, each consisting of 8 subjects randomised to receive either GS 248 or placebo in a 3:1 ratio. The first 2 subjects in each cohort will be dosed in a sentinel fashion; 1 subject will receive GS-248 and the other will receive placebo as randomised. The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs, safety laboratory and ECG will be checked at regular intervals. Part II (MAD); The MAD part of the study will explore multiple ascending dosing of GS-248 administered for 10 days. The proposed starting dose is 25 mg/day. However, the starting dose as well as subsequent dose levels may be adjusted based on safety and PK evaluation in previous cohorts. GS-248 will be administered in 4 sequential cohorts, each of 8 subjects randomised to receive either GS 248 or placebo in a 3:1 ratio. The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs, safety laboratory and ECG will be checked at regular intervals.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
72
CTC Clinical Trial Consultants AB
Uppsala, Sweden
Number of Treatment Related Adverse Events
AEs were assessed as 'unlikely', 'possibly' or 'probably' related to the IMP. 'Possibly' and 'probably' were categorized as treatment related.
Time frame: AEs were collected from the start of IMP administration until the end-of-study visit of each part, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD).
Clinically Significant Changes in ECG
Single 12-lead ECG was recorded in supine position after 10 minutes of rest using an ECG machine. Heart rate and PQ/PR, QRS, QT and QTcF intervals were recorded. Ambulatory ECG telemetry was used for cardiac surveillance up to 24 h after IMP administration in the SAD part of the study.
Time frame: 12-lead ECG was measured at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).
Clinically Significant Changes in Vital Signs
Systolic and diastolic blood pressure and pulse were measured in supine position after 10 minutes of rest. Body temperature was measured orally using a digital thermometer.
Time frame: Vital signs was checked at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD).
Clinically Significant Changes in Safety Laboratory Parameters
Blood samples for analysis of clinical chemistry, haematology and coagulation parameters.
Time frame: Blood samples were collected at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).
Clinically Significant Changes in Physical Examination
A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities.
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Time frame: Physical examination was performed at pre-defined timepoints from the screening visit until the end-of- study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD).
Cmax:
Maximum plasma concentration.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD Day 1-3 (first dose) and Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
Tmax:
Time to Cmax.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD: Day 1-3 (first dose) Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
T½:
Terminal elimination half-life
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
AUC0-t:
Area under the concentration time curve from the time of dosing to the time of the last observation.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
AUC 0-inf
Area under the curve from time 0 to infinity.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose
AUCss
Area under the plasma concentration curve during a dosing interval at steady state.
Time frame: MAD: Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
Clearance (CL)/F:
Apparent total body clearance following extravascular administration.
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
Vz/F:
Apparent volume of distribution following extravascular administration
Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.
Accumulation Ratio AUC 0-ss
Time frame: MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.