Safety, Tolerability and Preliminary Pharmacokinetics (PK) and Pharmacodynamics (PD) of Single and Repeat Oral Doses of GSK3008356 in Healthy and Obese Subjects

NCT02742766 | Completed Phase 1 Results

• 1 other identifier: 204856
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

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.

Conditions

Healthy Volunteers

Keywords

Dose escalation study; Safety; Pharmacodynamics; Pharmacokinetics; GSK3008356; Tolerability

Outcome Measures

Primary Outcomes (18)

• 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

  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.

  Up to Day 8

• 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.

  Up to Day 8

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

  A complete physical examination included assessment of the cardiovascular, respiratory, gastrointestinal, dermatologic and neurological systems, height, and weight. Height was measured and recorded only at screening. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). Weight was recorded with the brief physical exam, but was not part of the brief physical exam. Number of participants with abnormal findings in physical examinations in Part 2 are presented.

  Up to Day 22

• 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.

  Up to Day 22

• 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.

  Up to Day 17

• 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.

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

• 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).

  Up to Day 22

• Part 2: Number of Participants With AE and SAE

  AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e., lack of efficacy), abuse or misuse. SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or is associated with liver injury and impaired liver function.

  Up to Day 22

• 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.

  Up to Day 36

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

  Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.

  Up to Day 36

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

  Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.

  Up to Day 31

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

  Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.

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

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

  Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.

  Up to Day 36

• Part 3: Number of Participants With AE and SAE

  Part 3 was planned as a 28-day, repeat dose study in obese participants; however, since a tolerable dose with sufficient pharmacodynamic effects was not identified, this portion of the study was not conducted.

  Up to Day 36

Secondary Outcomes (28)

• 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])

  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

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

  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

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

  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

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

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

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

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

Study Arms (3)

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

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.

Part 1 - GSK3008356 single dose and multiple doses; Part 2 - GSK3008356 14 day repeat dose; Part 3 - GSK3008356 28 day repeat dose

Placebo DRUG

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

Part 1 - GSK3008356 single dose and multiple doses; Part 2 - GSK3008356 14 day repeat dose; Part 3 - GSK3008356 28 day repeat dose

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Vasectomy with documentation of azoospermia.
• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Nucleus Network Ltd: collaborator

Study Sites (1)

GSK Investigational Site

Melbourne, Victoria, 3004, Australia

Location

Related Publications (1)

• 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.

  PMID: 30950565 BACKGROUND

MeSH Terms

Interventions

GSK3008356

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 10, 2016
• First Posted: April 19, 2016
• Study Start: March 14, 2016
• Primary Completion: June 16, 2017
• Study Completion: June 16, 2017
• Last Updated: July 24, 2019
• Results First Posted: January 15, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

AU (1)