Safety, Tolerability and Preliminary Pharmacokinetics (PK... | NCT02742766

Name	Class
Nucleus Network Ltd	OTHER

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Part 1 - GSK3008356 single dose and multiple doses	Experimental	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.	Drug: GSK3008356 Drug: Placebo
Part 2 - GSK3008356 14 day repeat dose	Experimental	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.	Drug: GSK3008356 Drug: Placebo
Part 3 - GSK3008356 28 day repeat dose	Experimental	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.	Drug: GSK3008356 Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
GSK3008356	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	Up to Day 8
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.	Up to Day 8
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.	Up to Day 4
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.	Day 1
Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern

Secondary Outcomes

Measure	Description	Time Frame
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.	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

Eligibility Module

Eligibility Criteria

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.

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.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Melbourne	Victoria	3004	Australia

PubMed Identifier	Type	Citation	Retractions
30950565	Background	Okour M, Gress A, Zhu X, Rieman D, Lickliter JD, Brigandi RA. First-in-Human Pharmacokinetics and Safety Study of GSK3008356, a Selective DGAT1 Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Nov;8(8):1088-1099. doi: 10.1002/cpdd.691. Epub 2019 Apr 5.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
FG001	Part 1-Cohort A1: GSK3008356 5 mg

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 7, 2017	Jun 21, 2018

Arm/Group Information

ID	Title	Description
BG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
BG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG003	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG004	Part 1-Cohort A4: GSK3008356 75 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 75 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG005	Part 1-Cohort A5: GSK3008356 200 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG006	Part 1-Cohort A6: GSK3008356 125 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 125 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
BG007	Part 1-Cohort A7: GSK3008356 100 mg BID (0 h, 4 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 4 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.
BG008	Part 1-Cohort A8: GSK3008356 100 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 16 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.
BG009	Part 1-Cohort A9: GSK3008356 200 mg Evening Dose	Participants in this arm were planned to receive a single evening dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the evening dose; but this arm was cancelled.
BG010	Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 90 mg such that a 10 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.
BG011	Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 45 mg such that a 5 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.
BG012	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
BG013	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
BG014	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
BG015	Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 6 mg such that a 3 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
BG016	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
BG017	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
BG018	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
BG019	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

Safety Population comprised of all participants who received at least one dose of study medication.

Posted

Number

Participants

Up to Day 8

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG003	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG004	Part 1-Cohort A4: GSK3008356 75 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 75 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG005	Part 1-Cohort A5: GSK3008356 200 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG006	Part 1-Cohort A6: GSK3008356 125 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 125 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG007	Part 1-Cohort A7: GSK3008356 100 mg (0 h, 4 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 4 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.
OG008	Part 1-Cohort A8: GSK3008356 100 mg (0 h, 16 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 16 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.
OG009	Part 1-Cohort A9: GSK3008356 200 mg Evening Dose	Participants in this arm were planned to receive a single evening dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the evening dose; but this arm was cancelled.
OG010	Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 90 mg such that a 10 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.
OG011	Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 45 mg such that a 5 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.

Units	Counts
Participants	OG00020 OG0016 OG0026 OG003

Title

Denominators

Categories

Title	Measurements
	OG0002 OG0011 OG0020 OG003

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 8

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 4

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Number

Participants

Day 1

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG003

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 8

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 8

ID	Title	Description
OG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.
OG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

Part 2: Number of Participants With Abnormal Findings in Physical Examination

Safety Population.

Posted

Number

Participants

Up to Day 22

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 22

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Number

Participants

Up to Day 17

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Number

Participants

Day 1 (Pre-dose to 4 hours post dose)

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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).

Safety Population.

Posted

Number

Participants

Up to Day 22

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

Part 2: Number of Participants With AE and SAE

Safety Population.

Posted

Number

Participants

Up to Day 22

ID	Title	Description
OG000	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Primary

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.

Safety Population.

Posted

Up to Day 36

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Primary

Part 3: Number of Participants With Vital Signs of Potential Clinical Concern

Safety Population.

Posted

Up to Day 36

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Primary

Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern

Safety Population.

Posted

Up to Day 31

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Primary

Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring

Safety Population.

Posted

Day 1 (Pre-dose to 4 hours post-dose)

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Primary

Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern

Safety Population.

Posted

Up to Day 36

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Primary

Part 3: Number of Participants With AE and SAE

Safety Population.

Posted

Up to Day 36

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Secondary

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.

PK Parameter Population comprised of all participants in the PK Concentration Population (participants for whom a PK sample was obtained and analyzed) who received at least one active dose of GSK3008356 and provided PK parameters. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours*nanograms/milliliters

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

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002

Secondary

Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356

Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.

PK Parameter Population.

Posted

Geometric Mean

Geometric Coefficient of Variation

Nanograms per milliliters

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

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population.

Posted

Mean

Standard Deviation

Hours

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

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population.

Posted

Mean

Standard Deviation

Nanograms*10^5

Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG003

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Milliliters per hour

Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population.

Posted

Number

90% Confidence Interval

Slope of log dose

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

ID	Title	Description
OG000	GSK3008356 5 mg, 200 mg, 100 mg 0 h, 4 h and 100 mg 0 h, 16 h	Participants received a single dose of either 5 mg or 200 mg or multiple doses of 100 mg at either 0 h and 4 h or t0 and 16 h via oral route on Day 1 of Part 1.

Units	Counts
Participants	OG000

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Number

90% Confidence Interval

Slope of log dose

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

ID	Title	Description
OG000	GSK3008356 5 mg and 200 mg	Participants received a single dose of either 5 mg or 200 mg via oral route on Day 1 of Part 1.

Units	Counts
Participants	OG000

Secondary

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.

Pharmacodynamic (PD) Population comprised of participants in the Safety population for whom at least one postprandial triglyceride sample was obtained and analyzed at Baseline and post Baseline. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Millimoles/Liters

Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose

ID	Title	Description
OG000	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours*nanograms/milliliters

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

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

Geometric Coefficient of Variation

Nanograms/milliliters

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Hours

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

Part 2: Ae of GSK3008356 on Day 14

Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.

PK Parameter Population.

Posted

Pre-dose and 24 hours post-dose on Day 14

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 6 mg such that a 3 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

Part 2: CLr of GSK3008356 on Day 14

Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.

PK Parameter Population.

Posted

Pre-dose and 24 hours post-dose on Day 14

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002	Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 6 mg such that a 3 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population. Only those parameters available at the specified time points were analyzed.

Posted

Number

90% Confidence Interval

Slope of log dose

ID	Title	Description
OG000	GSK3008356 1 mg BID or 3 mg BID or 10 mg BID	Participants received multiple doses of either 1 mg BID or 3 mg BID or 10 mg BID of GSK3008356 via oral route on Day 1 and Day 14 of Part 2.

Units	Counts
Participants

Secondary

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.

PK Parameter Population.

Posted

Number

90% Confidence Interval

Slope of log dose

ID	Title	Description
OG000	GSK3008356 1 mg BID or 3 mg BID or 10 mg BID	Participants received multiple doses of either 1 mg BID or 3 mg BID or 10 mg BID of GSK3008356 via oral route on Day 1 and Day 14 of Part 2.

Units	Counts
Participants	OG000

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Geometric Mean

Geometric Coefficient of Variation

Ratio

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

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.

PK Parameter Population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Nanograms/Milliliters

Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG002

Secondary

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.

PD Population. Only those participants available at the specified time points were analyzed.

Posted

Mean

Standard Deviation

Millimoles/Liter

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)

ID	Title	Description
OG000	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.
OG001	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.

Secondary

Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Secondary

Part 3: Cmax of GSK3008356 on Day 1 and Day 28

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Secondary

Part 3: Tmax of GSK3008356 on Day 1 and Day 28

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Secondary

Part 3: t1/2 of GSK3008356 on Day 28

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Secondary

Part 3: Ae of GSK3008356 on Day 28

PK Parameter Population.

Posted

Day 28 in each cohort

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Secondary

Part 3: CLr of GSK3008356 on Day 28

PK Parameter Population.

Posted

Day 28 in each cohort

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.

Secondary

Part 3: Dose Proportionality of GSK3008356

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Cohort 1 to Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 administered as morning doses.

Units	Counts
Participants	OG000

Secondary

Part 3: Observed Accumulation Ratio of GSK3008356

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Secondary

Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing

PK Parameter Population.

Posted

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

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Secondary

Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants

PD Population.

Posted

Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3

ID	Title	Description
OG000	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG001	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.
OG002	Part 3: Obese Participants Cohort 3

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part 1- Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (as either single or multiple doses) along with a 30% fat by calorie meal approximately 2 hours after the morning dose for a single day.	20	20	0	20
EG001	Part 1-Cohort A1: GSK3008356 5 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 5 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	1	6
EG002	Part 1-Cohort A2: GSK3008356 10 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 10 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	0	6
EG003	Part 1-Cohort A3: GSK3008356 30 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 30 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	1	6
EG004	Part 1-Cohort A4: GSK3008356 75 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 75 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	1	6
EG005	Part 1-Cohort A5: GSK3008356 200 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	3	6
EG006	Part 1-Cohort A6: GSK3008356 125 mg	Eligible participants received a single morning dose of GSK3008356 tablets via oral route (total dose of 125 mg) along with a 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	3	6
EG007	Part 1-Cohort A7: GSK3008356 100 mg BID (0 h, 4 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 4 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.	6	6	3	6
EG008	Part 1-Cohort A8: GSK3008356 100 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets via oral route (total dose of 200 mg such that one 100 mg dose was administered at 0 h and 16 h) along with a 30% fat by calorie meal approximately 2 hours after the morning dose in a single day.	6	6	3	6
EG009	Part 1-Cohort A9: GSK3008356 200 mg Evening Dose	Participants in this arm were planned to receive a single evening dose of GSK3008356 tablets via oral route (total dose of 200 mg) along with a 30% fat by calorie meal approximately 2 hours after the evening dose; but this arm was cancelled.	0	0	0	0
EG010	Part 1-Cohort A10: GSK3008356 10 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 90 mg such that a 10 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.	6	6	0	6
EG011	Part 1-Cohort A11: GSK3008356 5 mg q1h x 9 Doses	Eligible participants received GSK3008356 tablets via oral route (total dose of 45 mg such that a 5 mg dose was administered q1h for a total of 9 doses) along with a 30% fat by calorie meal approximately 2 hours after the first morning dose in a single day.	6	6	3	6
EG012	Part 2-Placebo	Eligible participants received GSK3008356 matching placebo tablets via oral route (repeat doses) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	2	6
EG013	Part 2-Cohort B1: GSK3008356 10 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 20 mg such that a 10 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	5	6
EG014	Part 2-Cohort B2: GSK3008356 1 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 2 mg such that a 1 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	3	6
EG015	Part 2-Cohort B3: GSK3008356 3 mg BID (0 h, 16 h)	Eligible participants received GSK3008356 tablets BID via oral route (total daily dose of 6 mg such that a 3 mg dose was administered at 0 h and 16 h) for a period of 14 days. Day 1 and Day 14 dosing occurred while receiving a standard 30% fat by calorie meal approximately 2 hours after the morning dose.	6	6	3	6
EG016	Part 3: Obese Participants Cohort 1	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as morning doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.	0	0	0	0
EG017	Part 3: Obese Participants Cohort 2	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.	0	0	0	0
EG018	Part 3: Obese Participants Cohort 3	Participants in this arm were planned to receive 28 daily doses so as to evaluate 1 dose strength of GSK3008356 (or matching placebo) administered as evening doses. Part 3 was not conducted since a tolerable dose with sufficient pharmacodynamic effects was not identified in Part 2 due to gastrointestinal issues.	0	0	0	0

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0010 affected6 at risk EG0020 affected6 at risk EG0030 affected6 at risk EG0041 affected6 at risk EG0053 affected6 at risk EG0060 affected6 at risk EG0071 affected6 at risk EG0081 affected6 at risk EG0090 affected0 at risk EG0100 affected6 at risk EG0111 affected6 at risk EG0121 affected6 at risk EG0135 affected6 at risk EG0143 affected6 at risk EG0151 affected6 at risk EG0160 affected0 at risk EG0170 affected0 at risk EG0180 affected0 at risk
Vomiting	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0010 affected6 at risk EG0020 affected6 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0010 affected6 at risk EG0020 affected6 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0010 affected6 at risk EG0020 affected6 at risk EG003
Headache	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0010 affected6 at risk EG0020 affected6 at risk EG003
Dizziness	Nervous system disorders	MedDRA 19.0	Systematic Assessment	EG0000 affected20 at risk EG0011 affected6 at risk EG0020 affected6 at risk EG003