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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02742766




Registration number
NCT02742766
Ethics application status
Date submitted
10/03/2016
Date registered
19/04/2016
Date last updated
15/01/2019

Titles & IDs
Public title
Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects
Scientific title
A Phase I, Randomized, Placebo-Controlled, Double-Blind (Sponsor Unblind), Three Part Study to Evaluate the Safety, Tolerability, Preliminary PK and PD of Single and Repeat Oral Doses of GSK3008356 in Healthy Subjects and Obese Subjects
Secondary ID [1] 0 0
204856
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Volunteers 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - GSK3008356
Treatment: Drugs - Placebo

Experimental: Part 1 - GSK3008356 single dose and multiple doses - Healthy subjects will receive GSK3008356 in morning as single dose or multiple doses of 5 milligrams (mg), 10 mg, 30 mg,45 mg, 75 mg, 90 mg, 125, 180 mg, 200 mg, 250 mg total daily dose or matching placebo in eleven sequential cohorts while receiving a standard fat meal. The initial dosing for the first cohort will be staggered so that 2 subjects will be dosed as sentinel subjects. Provided there are no safety concerns, the remainder of the subjects scheduled for the cohort may be dosed. Eight subjects will be enrolled in each cohort.

Experimental: Part 2 - GSK3008356 14 day repeat dose - Healthy subjects will receive GSK3008356 or matching placebo, as 14 daily doses in the three sequential cohorts. Subjects in cohort 1 will receive their daily dose in morning, while subjects in cohort 2 and cohort 3 will receive their daily dose in evening. In all the three cohorts, Day 1 and day 14 dosing will occur while receiving a standard fat meal in morning. Eight subjects will be enrolled in each cohort.

Experimental: Part 3 - GSK3008356 28 day repeat dose - Obese subjects will receive GSK3008356 or matching placebo, as 28 daily doses in the three parallel cohorts. Cohort 1 will evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Cohorts 2 and 3 will evaluate 2 dose strengths (1 per cohort) of GSK3008356 (or matching placebo) administered in the evening. Ten subjects will be enrolled in each cohort.


Treatment: Drugs: GSK3008356
This intervention is available as 0.5, 1, 5, and 25 mg white oral tablet. The formulation will be used to administer dose of 5 mg, 10 mg, 30 mg, 45 mg, 75 mg, 90 mg, 125 mg, 180 mg, 200 mg, and 250 mg total daily dose during the study.

Treatment: Drugs: Placebo
This intervention is available as white oral tablet. The formulation will be used as a matching placebo for GSK3008356 during the study.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Part 1: Number of Participants With Abnormal Findings in Physical Examinations - A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 1 are presented.
Timepoint [1] 0 0
Up to Day 8
Primary outcome [2] 0 0
Part 1: Number of Participants With Vital Signs of Potential Clinical Concern - Vital signs included systolic and diastolic blood pressure and pulse rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring.
Timepoint [2] 0 0
Up to Day 8
Primary outcome [3] 0 0
Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern - Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QT interval corrected by Fridericia's formula (QTcF). Number of participants with 12-lead ECG values of potential clinical concern in Part 1 are presented.
Timepoint [3] 0 0
Up to Day 4
Primary outcome [4] 0 0
Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring - Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 1 are presented.
Timepoint [4] 0 0
Day 1
Primary outcome [5] 0 0
Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern - Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells (RBC) and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination of urine (WBC, RBC and casts) within 120 minutes of collection.
Timepoint [5] 0 0
Up to Day 8
Primary outcome [6] 0 0
Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) - AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function.
Timepoint [6] 0 0
Up to Day 8
Primary outcome [7] 0 0
Part 2: Number of Participants With Abnormal Findings in Physical Examination - A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 2 are presented.
Timepoint [7] 0 0
Up to Day 22
Primary outcome [8] 0 0
Part 2: Number of Participants With Vital Signs of Potential Clinical Concern - Vital signs included systolic and diastolic blood pressure and pulse and was measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring.
Timepoint [8] 0 0
Up to Day 22
Primary outcome [9] 0 0
Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern - Single 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals, and QTcF. Number of participants with 12-lead ECG values of potential clinical concern in Part 2 are presented.
Timepoint [9] 0 0
Up to Day 17
Primary outcome [10] 0 0
Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring - Continuous lead II cardiac telemetry or cardiac monitoring was performed on Day 1. Number of participants with clinically significant findings during cardiac monitoring in Part 2 are presented.
Timepoint [10] 0 0
Day 1 (Pre-dose to 4 hours post dose)
Primary outcome [11] 0 0
Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern - Hematology parameters included hematocrit, hemoglobin, platelets, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, red blood cells and reticulocytes. Clinical chemistry parameters included blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transferase, alkaline phosphatase, uric acid, total protein, total and direct bilirubin, albumin, calcium, bile acids, chloride, creatinine, glucose (fasting/non-fasting), potassium, sodium and total carbon dioxide/bicarbonate. Urinalysis included specific gravity, potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick and microscopic examination (within 120 minutes of collection).
Timepoint [11] 0 0
Up to Day 22
Primary outcome [12] 0 0
Part 2: Number of Participants With AE and SAE - AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function.
Timepoint [12] 0 0
Up to Day 22
Primary outcome [13] 0 0
Part 3: Number of Participants With Abnormal Findings in Physical Examination - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [13] 0 0
Up to Day 36
Primary outcome [14] 0 0
Part 3: Number of Participants With Vital Signs of Potential Clinical Concern - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [14] 0 0
Up to Day 36
Primary outcome [15] 0 0
Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [15] 0 0
Up to Day 31
Primary outcome [16] 0 0
Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [16] 0 0
Day 1 (Pre-dose to 4 hours post-dose)
Primary outcome [17] 0 0
Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [17] 0 0
Up to Day 36
Primary outcome [18] 0 0
Part 3: Number of Participants With AE and SAE - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [18] 0 0
Up to Day 36
Secondary outcome [1] 0 0
Part 1: Area Under the Concentration-time Curve (AUC) Extrapolated to Infinity (AUC[0 to Inf]), AUC From Time Zero to the Time of the Last Quantifiable Concentration (AUC[0 to t]) and AUC From Time Zero to 24 Hour (AUC[0 to 24]) - Blood samples for pharmacokinetic (PK) analysis of GSK3008356 were collected at the indicated time points.
Timepoint [1] 0 0
Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Secondary outcome [2] 0 0
Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 - Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Timepoint [2] 0 0
Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose
Secondary outcome [3] 0 0
Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 - Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Timepoint [3] 0 0
Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post dose on Day 1 and 36, 48, and 72 hours post-dose
Secondary outcome [4] 0 0
Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 - Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.
Timepoint [4] 0 0
Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
Secondary outcome [5] 0 0
Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 - Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.
Timepoint [5] 0 0
Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
Secondary outcome [6] 0 0
Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg Versus (vs.) 200 mg After Single Dose Administration and Multiple Dose Administration (100 mg t0, t4 and 100 mg t0, t16) Based on AUC - Dose proportionality was assessed from the AUC (0 to t) and AUC (0 to inf) obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of AUC with the logarithmic transformation of dose as the single covariate in the linear regression. Point estimates and 90% confidence interval are presented.
Timepoint [6] 0 0
Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Secondary outcome [7] 0 0
Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax - Dose proportionality was assessed from the Cmax obtained from multiple cohorts in Part 1. The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. For Cmax, only a single dose group from Cohort 1 to Cohort 6 was considered since other cohorts are multiple dosing where Cmax is so different from that of single dose group. Data for Cohort A5 vs. Cohort A1 is presented, Point estimates and 90% confidence interval are presented.
Timepoint [7] 0 0
Pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18, 24 hours post-dose on Day 1 and 36, 48, and 72 hours post-dose
Secondary outcome [8] 0 0
Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 - Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected triglyceride value (Day 1) at each nominal sampling time point was defined as the corresponding post dose value by adding the following value: Part 1 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2). Mean triglyceride levels are presented.
Timepoint [8] 0 0
Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose
Secondary outcome [9] 0 0
Part 2: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to the End of Dosing Interval (AUC[0 to Tau]) of GSK3008356 on Day 1 and Day 14 - Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Timepoint [9] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Secondary outcome [10] 0 0
Part 2: Cmax of GSK3008356 on Day 1 and Day 14 - Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Timepoint [10] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Secondary outcome [11] 0 0
Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 - Blood samples for PK analysis of GSK3008356 were collected at the indicated time points. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Timepoint [11] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Secondary outcome [12] 0 0
Part 2: Ae of GSK3008356 on Day 14 - Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.
Timepoint [12] 0 0
Pre-dose and 24 hours post-dose on Day 14
Secondary outcome [13] 0 0
Part 2: CLr of GSK3008356 on Day 14 - Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.
Timepoint [13] 0 0
Pre-dose and 24 hours post-dose on Day 14
Secondary outcome [14] 0 0
Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on AUC - Dose proportionality was assessed from Day 1 and Day 14 AUC (0 to tau) obtained from multiple cohorts in Part 2. The dose proportionality was assessed using a power model on logarithmic transformation of AUC, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented.
Timepoint [14] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Secondary outcome [15] 0 0
Part 2: Dose Proportionality of GSK3008356 for Dose 1 mg BID vs 10 mg BID and 3 mg BID After Repeat Dose Administration Based on Cmax - The dose proportionality was assessed using a power model on logarithmic transformation of Cmax, with the logarithmic transformation of dose as the single covariate in the linear regression. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose. Point estimates and 90% confidence interval are presented for Day 1 and Day 14 of Part 2.
Timepoint [15] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post-dose
Secondary outcome [16] 0 0
Part 2: Observed Accumulation Ratio of GSK3008356 - Observed accumulation ratio based on AUC(0- tau) is (Ro), and based on Cmax is (RCmax). Ro was calculated as the ratio [AUC0-tau on the final day (Day 14)]/[ AUC0-tau on Day 1] and Rcmax was calculated as the ratio [Cmax on the final day (Day 14)]/[Cmax on Day 1]. Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.
Timepoint [16] 0 0
Day 1 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24 hours post-dose, pre-dose Day 4, 5, 6, 12 and 13 and Day 14 pre-dose, and 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 18 and 24, 36, 48 and 72 hours post dose
Secondary outcome [17] 0 0
Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing - Ctrough is the observed concentration at the end of a dosing interval, immediately before next administration. Due to the cancellation of Part 2, Cohort B1, there are no PK parameters available on Day 14 for that dose.
Timepoint [17] 0 0
Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14
Secondary outcome [18] 0 0
Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 - Preliminary pharmacodynamics of GSK3008356 was evaluated by assessing the postprandial triglyceride levels at the indicated time points. Corrected TG value (Day 1 and Day 14) at each nominal sampling time point defined as the corresponding post dose value by adding the following value: Part 2 Day 1 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 1 (1 hour + 2 hour)/2); Part 2 Day 14 Correction: (Day -1 (1 hour + 2 hour)/2) - (Day 14 (1 hour + 2 hour)/2). Mean triglyceride levels are presented.
Timepoint [18] 0 0
Day 1 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose) and Day 14 (1, 2, 3, 4, 5, 6, 7, 8, 9 and 12 hours post-dose)
Secondary outcome [19] 0 0
Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [19] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [20] 0 0
Part 3: Cmax of GSK3008356 on Day 1 and Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [20] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [21] 0 0
Part 3: Tmax of GSK3008356 on Day 1 and Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [21] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Day 1 and Day 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [22] 0 0
Part 3: t1/2 of GSK3008356 on Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [22] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, 24, 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [23] 0 0
Part 3: Ae of GSK3008356 on Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [23] 0 0
Day 28 in each cohort
Secondary outcome [24] 0 0
Part 3: CLr of GSK3008356 on Day 28 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [24] 0 0
Day 28 in each cohort
Secondary outcome [25] 0 0
Part 3: Dose Proportionality of GSK3008356 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [25] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [26] 0 0
Part 3: Observed Accumulation Ratio of GSK3008356 - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [26] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [27] 0 0
Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [27] 0 0
Pre-dose, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8 (only in cohort 1), 12, 14 (only in cohorts 2 and 3), 18, and 24 hours post-dose on Days 1 and 28 and additionally 36, 48, and 72 hours post-dose on Day 28
Secondary outcome [28] 0 0
Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants - Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.
Timepoint [28] 0 0
Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3

Eligibility
Key inclusion criteria
- Between 18 and 65 years of age inclusive, at the time of signing the informed consent.

- For Part 1 and Part 2: Healthy as determined by the investigator or medically
qualified designee based on a medical evaluation including medical history, physical
examination, laboratory tests and cardiac monitoring.

- For Part 3: Obese subjects may have chronic disease not specifically excluded and not
requiring chronic medication for treatment and are otherwise healthy as determined by
the investigator or medically qualified designee based on a medical evaluation
including medical history, physical examination, laboratory tests and cardiac
monitoring. A subject with a clinical abnormality or laboratory parameter(s) which
is/are not specifically listed in the inclusion or exclusion criteria, outside the
reference range for the population being studied may be included only if the
investigator in consultation with the Medical Monitor agree and document that the
finding is unlikely to introduce additional risk factors and will not interfere with
the study procedures.

- Body weight >=50 kilograms (kg)

- For Part 1 and Part 2 body mass index (BMI) 19-25 kilogram per meter square
(inclusive)

- For Part 3 BMI >=30 kilogram per meter square

- Males or Females of non-childbearing potential as follows: Male subjects with female
partners of child bearing potential must comply with the following contraception
requirements from the time of first dose of study medication until at least five
half-lives of study medication after the last dose of study medication.

1. Vasectomy with documentation of azoospermia.

2. Male condom plus partner use of one of the following contraceptive options:
Contraceptive subdermal implant; Intrauterine device or intrauterine system; Oral
Contraceptive, either combined or progestogen alone; Injectable progestogen;
Contraceptive vaginal ring; Percutaneous contraceptive patches

- Males or Females of non-childbearing potential as follows: A female subject is
eligible to participate if she is not pregnant (as confirmed by a negative serum human
chorionic gonadotrophin [hCG] test), not lactating, and the following condition
applies:

Non-reproductive potential defined as: Pre-menopausal females with one of the following:
Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with
follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral
Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable
cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40
milli-international units per milliliter (MlU/ml) and estradiol < 40 picograms (pg) per ml
(<147 picomoles per liter (pmol/L) is confirmatory. Females on hormone replacement therapy
(HRT) and whose menopausal status is in doubt will not be allowed.

The investigator is responsible for ensuring that subjects understand how to properly use
these methods of contraception.

- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the consent form and in this protocol.
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Alanine aminotransferase (ALT) and bilirubin >1.5 times upper limit of normal
(isolated bilirubin >1.5 times upper limit of normal is acceptable if bilirubin is
fractionated and direct bilirubin <35%).

- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones)

- QTcF >450 millisecond (msec)

- Current or chronic history of gastrointestinal illness or conditions interfering with
normal gastrointestinal anatomy or motility. Examples include gastrointestinal bypass
surgery, cholecystectomy, partial or total gastrectomy, small bowel resection,
vagotomy, malabsorption, Crohn's disease, ulcerative colitis, irritable bowel syndrome
(IBS), or celiac sprue.

- 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 drug, unless in the opinion of the Investigator and GlaxoSmithKline
(GSK) Medical Monitor the medication will not interfere with the study procedures or
compromise subject safety. By exception, subject may take acetaminophen (<=2 grams per
day) up to 48 hours prior to the first dose of study drug.

- Subjects should refrain from consumption of red wine, Seville oranges, grapefruit or
grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit
juices from 7 days prior to the first dose of study medication until after the final
dose.

- History of regular alcohol consumption within 6 months of the study defined as an
average weekly intake of >14 standard drinks. One standard drink is equivalent to 10
grams of alcohol: 285 milliliter (mL) of beer, 100 mL of wine or 30 mL of 40% alcohol
by volume distilled spirits.

- For Part 1 and Part 2, urinary cotinine levels indicative of smoking or history or
regular use of tobacco- or nicotine-containing products within 3 months prior to
screening.

- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation.

- Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
result at screening or within 3 months prior to first dose of study treatment. For
potent immunosuppressive agents, subjects with presence of hepatitis B core antibody
(HBcAb) should also be excluded.

- A positive pre-study drug/alcohol screen.

- A positive test for human immunodeficiency virus (HIV) antibody.

- Where participation in the study would result in donation of blood or blood products
in excess of 750 mL within 90 day period.

- 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 chemical entities within 12 months prior to the first
dosing day.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
GSK Investigational Site - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Nucleus Network Ltd
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
This study is a phase I, randomized, placebo-controlled, double-blind (sponsor unblind),
three part study. The primary objective of the study is to characterize the safety, and
tolerability of GSK3008356 single dose, 14 daily repeat doses in healthy subjects and 28
daily repeat doses in obese subjects. The study has three parts. Part 1, will be a single and
multiple-dose, dose-rising study in healthy subjects. Part 2, will be a 14-day, repeat-dose,
dose-rising study in healthy subjects, and part 3 will be a 28-day, repeat-dose study in
obese subjects. For Parts 1 and 2, data from prior doses cohorts will be available prior to
escalation decisions. Data from Parts 1 and 2 will be available prior to initiation of the
three parallel cohorts in Part 3. A dose escalation meeting will be held to review these data
and document the decision to proceed as planned or make any alterations in dosing, if
indicated. Part 1, Part 2 and Part 3 study will have approximately 88, 24 and 30 subjects,
respectively.
Trial website
https://clinicaltrials.gov/show/NCT02742766
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications