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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02742766
Recruitment Status : Completed
First Posted : April 19, 2016
Results First Posted : January 15, 2019
Last Update Posted : July 24, 2019
Sponsor:
Collaborator:
Nucleus Network Ltd
Information provided by (Responsible Party):
GlaxoSmithKline

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.

Condition or disease Intervention/treatment Phase
Healthy Volunteers Drug: GSK3008356 Drug: Placebo Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 104 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : March 14, 2016
Actual Primary Completion Date : June 16, 2017
Actual Study Completion Date : June 16, 2017

Arm Intervention/treatment
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.
Drug: 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.

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

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.
Drug: 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.

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

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.
Drug: 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.

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




Primary Outcome Measures :
  1. Part 1: Number of Participants With Abnormal Findings in Physical Examinations [ Time Frame: Up to Day 8 ]
    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.

  2. Part 1: Number of Participants With Vital Signs of Potential Clinical Concern [ Time Frame: Up to Day 8 ]
    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.

  3. Part 1: Number of Participants With 12-lead Electrocardiogram (ECG) Values of Potential Clinical Concern [ Time Frame: Up to Day 4 ]
    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.

  4. Part 1: Number of Participants With Clinically Significant Findings During Cardiac Monitoring [ Time Frame: Day 1 ]
    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.

  5. Part 1: Number of Participants With Laboratory Values of Potential Clinical Concern [ Time Frame: Up to Day 8 ]
    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.

  6. Part 1: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [ Time Frame: Up to Day 8 ]
    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.

  7. Part 2: Number of Participants With Abnormal Findings in Physical Examination [ Time Frame: Up to Day 22 ]
    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.

  8. Part 2: Number of Participants With Vital Signs of Potential Clinical Concern [ Time Frame: Up to Day 22 ]
    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.

  9. Part 2: Number of Participants With 12-lead ECG Values of Potential Clinical Concern [ Time Frame: Up to Day 17 ]
    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.

  10. Part 2: Number of Participants With Clinically Significant Findings During Cardiac Monitoring [ Time Frame: Day 1 (Pre-dose to 4 hours post dose) ]
    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.

  11. Part 2: Number of Participants With Laboratory Values of Potential Clinical Concern [ Time Frame: Up to Day 22 ]
    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).

  12. Part 2: Number of Participants With AE and SAE [ Time Frame: Up to Day 22 ]
    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.

  13. Part 3: Number of Participants With Abnormal Findings in Physical Examination [ Time Frame: Up to Day 36 ]
    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.

  14. Part 3: Number of Participants With Vital Signs of Potential Clinical Concern [ Time Frame: Up to Day 36 ]
    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.

  15. Part 3: Number of Participants With 12-lead ECG Values of Potential Clinical Concern [ Time Frame: Up to Day 31 ]
    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.

  16. Part 3: Number of Participants With Clinically Significant Findings During Cardiac Monitoring [ Time Frame: Day 1 (Pre-dose to 4 hours post-dose) ]
    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.

  17. Part 3: Number of Participants With Laboratory Values of Potential Clinical Concern [ Time Frame: Up to Day 36 ]
    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.

  18. Part 3: Number of Participants With AE and SAE [ Time Frame: Up to Day 36 ]
    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.


Secondary Outcome Measures :
  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]) [ Time Frame: 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 ]
    Blood samples for pharmacokinetic (PK) analysis of GSK3008356 were collected at the indicated time points.

  2. Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3008356 [ Time Frame: 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 ]
    Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.

  3. Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of GSK3008356 and Apparent Terminal Half-life (t1/2) of GSK3008356 [ Time Frame: 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 ]
    Blood samples for PK analysis of GSK3008356 were collected at the indicated time points.

  4. Part 1: Cumulative Amount of Unchanged Drug Excreted Into the Urine (Ae) of GSK3008356 [ Time Frame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours ]
    Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.

  5. Part 1: Renal Clearance of Drug From Plasma (CLr) of GSK3008356 [ Time Frame: Pre-dose and over the post-dose intervals 0 to 12 hours and 12 to 24 hours ]
    Urine samples for PK analysis of GSK3008356 were collected at the indicated time points.

  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 [ Time Frame: 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 ]
    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.

  7. Part 1: Dose Proportionality of GSK3008356 for Dose 5 mg vs. 200 mg After Single Dose Administration Based on Cmax [ Time Frame: 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 ]
    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.

  8. Part 1: Postprandial Triglyceride Levels Following a Single Dose and Multiple Doses of GSK3008356 [ Time Frame: Day 1 at 1,2,3,4,5,6,7,8,9,12 hours post-dose ]
    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.

  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 [ Time Frame: 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 ]
    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.

  10. Part 2: Cmax of GSK3008356 on Day 1 and Day 14 [ Time Frame: 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 ]
    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.

  11. Part 2: t1/2 and Tmax of GSK3008356 on Day 1 and Day 14 [ Time Frame: 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 ]
    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.

  12. Part 2: Ae of GSK3008356 on Day 14 [ Time Frame: Pre-dose and 24 hours post-dose on Day 14 ]
    Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.

  13. Part 2: CLr of GSK3008356 on Day 14 [ Time Frame: Pre-dose and 24 hours post-dose on Day 14 ]
    Urine samples (urine concentrations or volumes) were not collected for the Part 2 of the study.

  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 [ Time Frame: 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 ]
    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.

  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 [ Time Frame: 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 ]
    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.

  16. Part 2: Observed Accumulation Ratio of GSK3008356 [ Time Frame: 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 ]
    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.

  17. Part 2: Trough Plasma Concentrations (Ctrough) to Assess Steady State of GSK3008356 Following 14-day Repeat Dosing [ Time Frame: Pre-dose on Days 2, 4, 5, 6, 12, 13, 14 and the 24 hours post-dose on Day 14 ]
    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.

  18. Part 2: Postprandial Triglyceride Levels Following 14-day Repeat Dosing of GSK3008356 [ Time Frame: 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) ]
    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.

  19. Part 3: AUC (0-tau) of GSK3008356 on Day 1 and Day 28 [ Time Frame: 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 ]
    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.

  20. Part 3: Cmax of GSK3008356 on Day 1 and Day 28 [ Time Frame: 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 ]
    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.

  21. Part 3: Tmax of GSK3008356 on Day 1 and Day 28 [ Time Frame: 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 ]
    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.

  22. Part 3: t1/2 of GSK3008356 on Day 28 [ Time Frame: 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 ]
    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.

  23. Part 3: Ae of GSK3008356 on Day 28 [ Time Frame: Day 28 in each cohort ]
    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.

  24. Part 3: CLr of GSK3008356 on Day 28 [ Time Frame: Day 28 in each cohort ]
    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.

  25. Part 3: Dose Proportionality of GSK3008356 [ Time Frame: 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 ]
    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.

  26. Part 3: Observed Accumulation Ratio of GSK3008356 [ Time Frame: 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 ]
    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.

  27. Part 3: Ctrough to Assess Steady State of GSK3008356 Following 28-day Repeat Dosing [ Time Frame: 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 ]
    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.

  28. Part 3: Postprandial Triglyceride Levels Following 28-day Repeat Dosing of GSK3008356 in Obese Participants [ Time Frame: Day -1, Day 1, and Day 28 in cohort 1, and Day 1, Day 2, and Day 28 in cohorts 2 and 3 ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02742766


Locations
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Australia, Victoria
GSK Investigational Site
Melbourne, Victoria, Australia, 3004
Sponsors and Collaborators
GlaxoSmithKline
Nucleus Network Ltd
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Study Protocol  [PDF] February 7, 2017
Statistical Analysis Plan  [PDF] August 3, 2017

Publications:
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02742766    
Other Study ID Numbers: 204856
First Posted: April 19, 2016    Key Record Dates
Results First Posted: January 15, 2019
Last Update Posted: July 24, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.
URL: https://www.clinicalstudydatarequest.com/SearchAllPostings.aspx?searchparam=204856
Keywords provided by GlaxoSmithKline:
Dose escalation study
Safety
Pharmacodynamics
Pharmacokinetics
GSK3008356
Tolerability