Clinical trial NCT02742766: Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects
Official 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Volunteers
Keywords: Dose escalation study
Safety
Pharmacodynamics
Pharmacokinetics
GSK3008356
Tolerability
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Nucleus Network Ltd
First posted: 2016-04-19
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Part 1: Number of Participants With Abnormal Findings in Physical Examinations
timeFrame: Up to Day 8
measure: Part 1: Number of Participants With Vital Signs of Potential Clinical Concern
timeFrame: Up to Day 8
measure: Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern
timeFrame: Up to Day 4
measure: Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
timeFrame: Day 1
measure: Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern
timeFrame: Up to Day 8
measure: Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to Day 8
measure: Part 2: Number of Participants With Abnormal Findings in Physical Examination
timeFrame: Up to Day 22
measure: Part 2: Number of Participants With Vital Signs of Potential Clinical Concern
timeFrame: Up to Day 22
measure: Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern
timeFrame: Up to Day 17
measure: Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
timeFrame: Day 1 (Pre-dose to 4 hours post dose)
measure: Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern
timeFrame: Up to Day 22
measure: Part 2: Number of Participants With AE and SAE
timeFrame: Up to Day 22
measure: Part 3: Number of Participants With Abnormal Findings in Physical Examination
timeFrame: Up to Day 36
measure: Part 3: Number of Participants With Vital Signs of Potential Clinical Concern
timeFrame: Up to Day 36
measure: Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern
timeFrame: Up to Day 31
measure: Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring
timeFrame: Day 1 (Pre-dose to 4 hours post-dose)
measure: Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern
timeFrame: Up to Day 36
measure: Part 3: Number of Participants With AE and SAE
timeFrame: Up to Day 36
Secondary outcomes:
measure: 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])
timeFrame: 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
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356
timeFrame: 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
measure: Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356
timeFrame: 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
measure: Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356
timeFrame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
measure: Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356
timeFrame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours
measure: 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
timeFrame: 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
measure: Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax
timeFrame: 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
measure: Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356
timeFrame: Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose
measure: 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
timeFrame: 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
measure: Part 2: Cmax of GSK3008356 on Day 1 and Day 14
timeFrame: 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
measure: Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14
timeFrame: 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
measure: Part 2: Ae of GSK3008356 on Day 14
timeFrame: Pre-dose and 24 hours post-dose on Day 14
measure: Part 2: CLr of GSK3008356 on Day 14
timeFrame: Pre-dose and 24 hours post-dose on Day 14
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Part 2: Observed Accumulation Ratio of GSK3008356
timeFrame: 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
measure: Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing
timeFrame: Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14
measure: Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356
timeFrame: 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)
measure: Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28
timeFrame: 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
measure: Part 3: Cmax of GSK3008356 on Day 1 and Day 28
timeFrame: 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
measure: Part 3: Tmax of GSK3008356 on Day 1 and Day 28
timeFrame: 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
measure: Part 3: t1/2 of GSK3008356 on Day 28
timeFrame: 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
measure: Part 3: Ae of GSK3008356 on Day 28
timeFrame: Day 28 in each cohort
measure: Part 3: CLr of GSK3008356 on Day 28
timeFrame: Day 28 in each cohort
measure: Part 3: Dose Proportionality of GSK3008356
timeFrame: 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
measure: Part 3: Observed Accumulation Ratio of GSK3008356
timeFrame: 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
measure: Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing
timeFrame: 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
measure: Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants
timeFrame: Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3
Other outcomes:
Locations:
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.