ANZCTR - Registration

Registration number

NCT02742766

Ethics application status

Date submitted

10/03/2016

Date registered

19/04/2016

Date last updated

24/07/2019

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]

204856

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Healthy Volunteers

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]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Part 1: Number of Participants With Abnormal Findings in Physical Examinations

Timepoint [1]

Up to Day 8

Primary outcome [2]

Part 1: Number of Participants With Vital Signs of Potential Clinical Concern

Timepoint [2]

Up to Day 8

Primary outcome [3]

Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern

Timepoint [3]

Up to Day 4

Primary outcome [4]

Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring

Timepoint [4]

Day 1

Primary outcome [5]

Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern

Timepoint [5]

Up to Day 8

Primary outcome [6]

Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

Timepoint [6]

Up to Day 8

Primary outcome [7]

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

Timepoint [7]

Up to Day 22

Primary outcome [8]

Part 2: Number of Participants With Vital Signs of Potential Clinical Concern

Timepoint [8]

Up to Day 22

Primary outcome [9]

Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern

Timepoint [9]

Up to Day 17

Primary outcome [10]

Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring

Timepoint [10]

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

Primary outcome [11]

Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern

Timepoint [11]

Up to Day 22

Primary outcome [12]

Part 2: Number of Participants With AE and SAE

Timepoint [12]

Up to Day 22

Primary outcome [13]

Part 3: Number of Participants With Abnormal Findings in Physical Examination

Timepoint [13]

Up to Day 36

Primary outcome [14]

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

Timepoint [14]

Up to Day 36

Primary outcome [15]

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

Timepoint [15]

Up to Day 31

Primary outcome [16]

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

Timepoint [16]

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

Primary outcome [17]

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

Timepoint [17]

Up to Day 36

Primary outcome [18]

Part 3: Number of Participants With AE and SAE

Timepoint [18]

Up to Day 36

Secondary outcome [1]

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])

Timepoint [1]

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]

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

Timepoint [2]

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]

Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356

Timepoint [3]

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]

Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356

Timepoint [4]

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

Secondary outcome [5]

Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356

Timepoint [5]

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

Secondary outcome [6]

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

Timepoint [6]

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]

Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax

Timepoint [7]

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]

Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356

Timepoint [8]

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

Secondary outcome [9]

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

Timepoint [9]

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]

Part 2: Cmax of GSK3008356 on Day 1 and Day 14

Timepoint [10]

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]

Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14

Timepoint [11]

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]

Part 2: Ae of GSK3008356 on Day 14

Timepoint [12]

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

Secondary outcome [13]

Part 2: CLr of GSK3008356 on Day 14

Timepoint [13]

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

Secondary outcome [14]

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

Timepoint [14]

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]

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

Timepoint [15]

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]

Part 2: Observed Accumulation Ratio of GSK3008356

Timepoint [16]

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]

Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing

Timepoint [17]

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

Secondary outcome [18]

Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356

Timepoint [18]

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]

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

Timepoint [19]

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]

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

Timepoint [20]

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]

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

Timepoint [21]

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]

Part 3: t1/2 of GSK3008356 on Day 28

Timepoint [22]

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]

Part 3: Ae of GSK3008356 on Day 28

Timepoint [23]

Day 28 in each cohort

Secondary outcome [24]

Part 3: CLr of GSK3008356 on Day 28

Timepoint [24]

Day 28 in each cohort

Secondary outcome [25]

Part 3: Dose Proportionality of GSK3008356

Timepoint [25]

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]

Part 3: Observed Accumulation Ratio of GSK3008356

Timepoint [26]

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]

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

Timepoint [27]

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]

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

Timepoint [28]

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

Sex

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

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

Actual

14/03/2016

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

16/06/2017

Sample size

Target

Accrual to date

Final

104

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

GSK Investigational Site - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Primary sponsor type

Commercial sector/Industry

Name

GlaxoSmithKline

Country

Other collaborator category [1]

Other

Name [1]

Nucleus Network Ltd

Country [1]

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/ct2/show/NCT02742766

Public notes

Contacts

Principal investigator

Name

GSK Clinical Trials

Address

GlaxoSmithKline

Country

Phone

Email

Contact person for public queries

Name

Address

Country

Phone

Email

Contact person for scientific queries

Trial Review

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02742766