A Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Administering Multiple Oral Doses of GSK1292263 Alone and With Atorvastatin

NCT01218204 | Completed Phase 2 Results

• 1 other identifier: 113779
• Study Type: interventional
• Target: 287
• Locations: 1 country
• Sites: 21

Brief Summary

This study investigates the safety, pharmacokinetics and effects of GSK1292263 when taken alone or when co-dosed with atorvastatin to subjects with dyslipidemia.

Conditions

Dyslipidaemias; Dyslipidemias

Keywords

Pharmacodynamics; Lipids; Dyslipidemia; Safety; GSK1292263; Ezetimibe; Statin; Pharmacokinetics; Tolerability; Atorvastatin

Outcome Measures

Primary Outcomes (41)

• Number of Participants With Any Adverse Events (AEs) and Serious Adverse Events (SAEs)- Part A

  An AE is defined as any untoward medical occurrence in a 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. An SAE is defined as 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 an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

  Up to Day 26

• Number of Participants With Any AEs and SAEs- Part B (Washout)

  An AE is defined as any untoward medical occurrence in a 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. An SAE is defined as 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 an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

  Up to Day 28

• Number of Participants With Any AEs and SAEs- Part B (Run-in)

  An AE is defined as any untoward medical occurrence in a 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. An SAE is defined as 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 an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

  Up to Day 28

• Number of Participants With Any AEs and SAEs- Part B (Pooled Treatment Arm)

  An AE is defined as any untoward medical occurrence in a 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. An SAE is defined as 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 an important medical events that jeopardize the participants or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition, or a drug-induced liver injury.

  Up to Day 26

• Number of Participants With Abnormal- Clinically Significant Electrocardiogram (ECG) Findings- Part A

  Single ECGs were taken after admission on Day -1 and at Follow-up (up to Day 26). On Days 1, 7, and 14 single ECGS were taken pre-breakfast (fasting) and at 1, 3, 6, 8, 14 and 24 hours post-dose. ECGs were taken in supine position. Additional ECGs were taken at the discretion of the investigator as needed based on symptoms or ECG findings. No value found to be abnormal clinically significant in Part A of the study.

  Up to Day 26

• Number of Participants With Abnormal Clinically Significant ECG Findings- Part B (Washout)

  ECGs were taken at Screening, and on Day1 and Day 28. Single assessments were made. ECGs were taken in supine position. Additional ECGs were taken at the discretion of the investigator as needed based on symptoms or ECG findings.

  Up to Day 28

• Number of Participants With Abnormal Clinically Significant ECG Findings- Part B (Run-in)

  ECGs were taken on Day 28. Single assessments were made. ECGs were taken in supine position. Additional ECGs were taken at the discretion of the investigator as needed based on symptoms or ECG findings. No data found to be abnormal clinically significant in run-in phase.

  Day 28

• Number of Participants With Abnormal Clinically Significant ECG Findings- Part B (Pooled Treatment Arm)

  Single ECGs were taken after admission on Day -2, and pre-breakfast on Days -1, 4, 10, and at Follow-up. On Days 1, 7, and 14 single ECGS were taken pre-breakfast (fasting) and at 1, 3, 6, 8, 14 and 24 hours post-dose. ECGs were taken in supine position. Additional ECGs were taken at the discretion of the investigator as needed based on symptoms or ECG findings. The data was found to be abnormal clinically significant in treatment phase.

  Up to Day 26

• Number of Participants With Vital Signs of Potential Clinical Importance (PCI)- Part A

  Assessment of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate was performed after admission on Day -1 and at Follow-up. On Days 1, 7 and 14, they were taken at pre-dose, 1, 3, 6, 8, 14 and 24 hours after the morning dose. At each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Data for only those parameters are presented for which findings are of PCI either high or low.

  Up to Day 26

• Number of Participants With Vital Signs of PCI- Part B (Washout)

  Assessment of vital signs including SBP, DBP heart rate was performed at Screening, on Days 1, 14 and 28 in the morning. At each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Data for only those parameters are presented for which findings are of PCI either high or low.

  Up to day 28

• Number of Participants With Vital Signs of Potential Clinical Importance- Part B (Run-in)

  Assessment of vital signs including SBP, DBP and heart rate was performed on Days 1, 14 and 28 in the morning. At each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Data for only those parameters are presented for which findings are of PCI either high or low.

  Up to day 28

• Number of Participants With Vital Signs of Potential Clinical Importance- Part B (Pooled Treatment Arm)

  Assessment of vital signs including SBP, DBP and heart rate was performed after admission on Day-2, and pre-breakfast on Days -1, 4, and 10 in a fasting state early in the morning (prior to dosing), and at Follow-up. On Days 1, 7 and 14, they were also be taken at 1, 3, 6, 9, 12 and 24 hours after the morning dose. At each time point, assessment was performed after resting in a supine or semi-supine position for at least 10 minutes. Data for only those parameters are presented for which findings are of PCI either high or low.

  Up to Day 26

• Number of Participants With Abnormal Hematology Value of PCI- Part A

  Blood samples were collected fasting on Day -1, and prior to breakfast (early in the morning, fasting) on Days 2, 4, 7, 11 and on Day 15 prior to checkout (24 hours post last-dose), and at Follow-up. When this resulted in multiple samples at the same time point, only one sample was collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Data for only those parameters (Hematocrit, Hemoglobin and Total neutrophils) are presented for which findings are of PCI either high or low.

  Up to Day 26

• Number of Participants With Abnormal Hematology Value of PCI- Part B (Washout)

  Blood samples were collected at screening, and on Days 1 (first day of washout), 14 and 28 prior to breakfast (early in the morning, fasting). Data for only those parameters (White blood cells \[WBC\], Total neutrophils, Hematocrit and Lymphocytes) are presented for which findings are of PCI either high or low.

  Up to Day 28

• Number of Participants With Abnormal Hematology Value of PCI- Part B (Run-in)

  Blood samples were collected on Day 14 and 28 prior to breakfast (early in the morning, fasting). Data for only those parameters (Lymphocytes) are presented for which findings are of PCI either high or low.

  Days 14 and 28

• Number of Participants With Abnormal Hematology Value of PCI- Part B (Pooled Treatment Arm)

  Blood samples were collected fasting on Day -2, and prior to breakfast (early in the morning, fasting) on Days 2 (pre-dose), 4, 7, 10, 13 and on Day 15 prior to checkout (24hrs post-dose), and at Follow-up. When this resulted in multiple samples at the same time point, only one sample was collected (example, when 24hrs post dose = pre-dose (time 0) for the next dose). Data for only those parameters (Platelet count, Total neutrophils and Lymphocytes) are presented for which findings are of PCI either high or low.

  Up to Day 26

• Number of Participants With Abnormal Clinical Chemistry Value of PCI- Part A

  Samples were collected fasting on Day -1, and prior to breakfast (early in the morning, fasting) on Days 2, 4, 7, 11 and on Day 15 prior to checkout (24 hours post last-dose), and at Follow-up. When this resulted in multiple samples at the same time point, only one sample was collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). No parameter was found to have any value of PCI.

  Up to Day 26

• Number of Participants With Abnormal Clinical Chemistry Value of PCI- Part B (Washout)

  Samples were collected at screening, and on Days1 (first day of washout), 14 and 28 prior to breakfast (early in the morning, fasting). Data for only those parameters (Inorganic phosphorus, Sodium, Alanine aminotransferase \[ALT\], Potassium, Creatinine, Calcium, magnesium, Glucose, Total Bilirubin, Carbon dioxide/bicarbonate \[CO2/HCO3\] and Aspartate aminotransferase \[AST\]) are presented for which findings are of PCI either high or low.

  Up to Day 28

• Number of Participants With Abnormal Clinical Chemistry Value of PCI- Part B (run-in)

  Samples were collected on Day 14 and 28 prior to breakfast (early in the morning, fasting). Data for only those parameters (Glucose, Magnesium, ALT, AST, Calcium, Inorganic phosphorus and Total bilirubin) are presented for which findings are of PCI either high or low.

  Days 14 and 28

• Number of Participants With Abnormal Clinical Chemistry Value of PCI- Part B (Pooled Treatment Arm)

  Samples were collected fasting on Day -2, and prior to breakfast (early in the morning, fasting) on Days 2 (pre-dose), 4, 7, 10, 13 and on Day 15 prior to checkout (24 hours post-dose), and at Follow-up. When this resulted in multiple samples at the same time point, only one sample was collected (example, when 24 hours post dose = pre-dose (time 0) for the next dose). Data for only those parameters (Glucose, Total bilirubin, Albumin, Magnesium, CO2/HCO3, Calcium, ALT, AST, Inorganic phosphorus, Potassium and Sodium) are presented for which findings are of PCI either high or low.

  Up to Day 26

• Maximum Observed Concentration (Cmax) of GSK1292263- Part A

  Serial blood samples for the determination of the PK for GSK1292263 on Days 1 and 14 were collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (no 48 hour sample on Day 1).

  On Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Cmax of GSK1292263- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of GSK1292263 were taken on Days 1 and 14. For monotherapy arms, serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1 and 14. Blood samples for PK were collected on Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hours PK sample was collected on Day 16).

  On Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. On Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Time of Occurrence of Cmax (Tmax) and Terminal Phase Half-life (t1/2) GSK1292263- Part A

  Serial blood samples for the determination of the PK for GSK1292263, on Days 1 and 14 were collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (no 48 hour sample on Day 1).

  On Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Lag Time Before Observation of Drug Concentrations in Sampled Matrix (Tlag) of GSK1292263- Part A

  Serial blood samples for the determination of the PK for GSK1292263 on Days 1 were collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (no 48h sample on Day 1).

  On Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Tmax and t1/2 of GSK1292263- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of GSK1292263 were taken on Days 1 and 14. For monotherapy arms, serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1 and 14. Blood samples for PK were collected on Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hours PK sample was collected on Day 16).

  On Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. On Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Tlag of GSK1292263- Part B (Pooled Treatment Arm)

  Blood samples for PK were collected on Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose.

  On Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose.

• Area Under the Concentration-time Curve From Time Zero (Pre-dose) to 24 Hours [AUC(0-24)] of GSK1292263- Part A

  Serial blood samples for the determination of the PK for GSK1292263, on Days 1 and 14 were collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (no 48 hour sample on Day 1).

  On Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• AUC(0-24) of GSK1292263- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of GSK1292263 were taken on Days 1 and 14. For monotherapy arms, serial blood samples for the determination of the PK of GSK1292263 were collected on Days 1 and 14. Blood samples for PK were collected on Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hours PK sample was collected on Day 16).

  On Day 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. On Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Trough Concentration of GSK1292263

  Trough samples for GSK1292263 PK (all treatment arms) were planned to be collected early in the morning on Days 13, 14, 15 and 16 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48h PK sample was collected on Day 16). (pre-dose for Days 13 and 14; trough Day 15 = 24h post last dose; trough Day 16 = 48h post last dose).

  On Days 13, 14, 15 and 16 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Cmax of Atorvastatin- Part A

  Serial blood samples for the determination of the PK for atorvastatin on Day -1 was collected at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose (24 hour sample Day -1 = 0 hour sample Day 1). Serial blood samples for the determination of the PK for atorvastatin on Days 1 and 14 will be collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose (no 48h sample on Day 1).

  On Day -1 at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose. on Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose.

• Cmax of Atorvastatin- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of atorvastatin were collected on Day -1 and for atorvastatin on Days 1 and 14. Blood samples for PK were collected on Days -1 (co-dosing arms only) and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hour PK sample was collected on Day 16).

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Tmax of Atorvastatin- Part A

  Serial blood samples for the determination of the PK for atorvastatin on Day -1 was collected at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose (24 hour sample Day -1 = 0 hour sample Day 1). Serial blood samples for the determination of the PK for atorvastatin on Days 1 and 14 will be collected at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose (no 48h sample on Day 1).

  On Day -1 at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose. on Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose.

• Tmax of Atorvastatin- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of atorvastatin were collected on Day -1 and for atorvastatin on Days 1 and 14. Blood samples for PK were collected on Days -1 (co-dosing arms only) and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hour PK sample was collected on Day 16).

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• AUC (0-24) of Atorvastatin- Part A

  For co-dosing arms, serial blood samples for the determination of the PK of atorvastatin were collected on Day -1 and for atorvastatin on Days 1 and 14. Blood samples for PK were collected on Days -1 (co-dosing arms only) and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hour PK sample was collected on Day 16).

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• AUC (0-24) of Atorvastatin- Part B (Pooled Treatment Arm)

  For co-dosing arms, serial blood samples for the determination of the PK of atorvastatin were collected on Day -1 and for atorvastatin on Days 1 and 14. Blood samples for PK were collected on Days -1 (co-dosing arms only) and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hour PK sample was collected on Day 16).

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Trough Concentration of Atorvastatin

  For co-dosing arms, serial blood samples for the determination of the PK of atorvastatin were planned to be collected on Day -1 and for atorvastatin on Days 1 and 14. Blood samples for PK were planned to be collected on Days -1 (co-dosing arms only) and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. Blood samples for PK were planned to be collected on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose (48 hour PK sample was planned to be collected on Day 16).

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Percent Change From Baseline for Lipid Metabolism: Apolipoprotein A1 and Apolipoprotein B100 at Day 14

  Blood samples were collected fasting on Days 1 (pre-dose), 7 and 15 prior to checkout (24 hours post-dose), and at Follow-up. When this results in multiple samples at the same time point, only one sample will be collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Baseline was the closest scheduled value prior to dosing. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value is missing, the change from Baseline was set to missing as well. Percent change from Baseline was calculated as the change from Baseline divided by the Baseline value then multiplied by 100.

  Baseline and Day 14

• Percent Change From Baseline in Lipid Metabolism: Apolipoprotein E at Day 14 (24 Hours)

  Blood samples were collected fasting on Days 1 (pre-dose), 7 and 15 prior to checkout (24 hours post-dose), and at Follow-up. When this results in multiple samples at the same time point, only one sample will be collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Baseline was the closest scheduled value prior to dosing. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value is missing, the change from Baseline was set to missing as well. Percent change from Baseline was calculated as the change from Baseline divided by the Baseline value then multiplied by 100.

  Baseline and Day 14

• Percent Change From Baseline in Lipid Metabolism: High Density Lipids Cholesterol (HDLc), Low Density Lipids Cholesterol (LDLc), Tryglycerides, Non-HDLc and Total Cholesterol at Day 14 (24 Hours)

  Blood samples were collected fasting on Days 1 (pre-dose), 7 and 15 prior to checkout (24 hours post-dose), and at Follow-up. When this results in multiple samples at the same time point, only one sample will be collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Baseline was the closest scheduled value prior to dosing. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value is missing, the change from Baseline was set to missing as well. Percent change from Baseline was calculated as the change from Baseline divided by the Baseline value then multiplied by 100.

  Baseline and Day 14

• Percent Change From Baseline in Lipid Metabolism: LDL/HDL Ratio at Day 14 (24 Hours)

  Blood samples were collected fasting on Days 1 (pre-dose), 7 and 15 prior to checkout (24 hours post-dose), and at Follow-up. When this results in multiple samples at the same time point, only one sample will be collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Baseline was the closest scheduled value prior to dosing. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value is missing, the change from Baseline was set to missing as well. Percent change from Baseline was calculated as the change from Baseline divided by the Baseline value then multiplied by 100.

  Baseline and Day 14

• Weighted Mean Area Under Concentration Curve From 0 to 24 Hours (AUC [0-24]) Change From Baseline for Triglycerides at Day 14

  Blood samples were collected fasting on Days 1 (pre-dose), 7 and 15 prior to checkout (24 hours post-dose), and at Follow-up. When this results in multiple samples at the same time point, only one sample will be collected (example, when 24 hours post-dose = pre-dose (time 0) for the next dose). Baseline was Day -1 value. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. If either the Baseline or post-randomization value is missing, the change from Baseline was set to missing as well. Percent change from Baseline was calculated as the change from Baseline divided by the Baseline value then multiplied by 100.

  Baseline and Day 14

Secondary Outcomes (7)

• Cmax of Atorvastatin Metabolite (2-Hydroxyatorvastatin)- Part A

  On Day -1 at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose. on Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose.

• Cmax of Atorvastatin Metabolite (2-Hydroxyatorvastatin)- Part B (Pooled Treatment Arm)

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose. on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• Tmax of Atorvastatin Metabolite (2-Hydroxyatorvastatin)- Part A

  On Day -1 at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose. on Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose.

• Tmax of Atorvastatin Metabolite (2-Hydroxyatorvastatin)- Part B (Pooled Treatment Arm)

  On Days -1 and 1 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, and 24 hours post-morning dose and on Day 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hours post-morning dose

• AUC (0-24) of Atorvastatin Metabolite (2-Hydroxyatorvastatin)- Part A

  On Day -1 at immediately pre-morning dose=pre-breakfast (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14 and 24 hours post-morning dose. on Days 1 and 14 at immediately pre-morning dose (time 0), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 14, 24 and 48 hour post-morning dose.

Study Arms (16)

Part A Run-in

OTHER

Subjects on stable 40mg atorvastatin \> 4 weeks may raise their dose to 80mg for 2 weeks in order to qualify for Part A.

Drug: 80mg atorvastatin

Part A Co-Dosing 800mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 800mg GSK1292263

Part B Washout

OTHER

Washout for 4 weeks

Other: Washout

Part B Run-in 10mg atorvastatin

ACTIVE COMPARATOR

Dosing for 4 weeks

Drug: 10mg atorvastatin

Part B Run-in 80mg atorvastatin

ACTIVE COMPARATOR

Dosing for 4 weeks

Drug: 80mg atorvastatin

Part B Co-Dosing 10mg atorvastatin + 100mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 10mg atorvastatin

Part B Co-Dosing 10mg atorvastatin + 300mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 300mg GSK1292263

Part B Co-Dosing 10mg atorvastatin + 800mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 10mg atorvastatin; Drug: 800mg GSK1292263

Part B Co-Dosing 10mg atorvastatin + 10mg ezetimibe

EXPERIMENTAL

Dosing for 14 days

Drug: 10mg atorvastatin; Drug: 10mg ezetimibe

Part B Dosing 100mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 100mg GSK1292263

Part B Dosing 300mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 300mg GSK1292263

Part B Dosing 800mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 800mg GSK1292263

Part B Dosing Placebo GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: GSK1292263 Placebo

Part B Co-Dosing 80mg atorvastatin + 800mg GSK1292263

EXPERIMENTAL

Dosing for 14 days

Drug: 80mg atorvastatin

Part B Co-dosing 80mg atorvastatin + Placebo (GSK1292263)

EXPERIMENTAL

Dosing for 14 days

Drug: GSK1292263 Placebo

Part B Co-Dosing 10mg atorvastatin + Placebo (GSK1292263)

EXPERIMENTAL

Dosing for 14 days

Drug: 10mg atorvastatin

Interventions

10mg atorvastatin DRUG

10mg

Also known as: Lipitor

Part B Co-Dosing 10mg atorvastatin + 100mg GSK1292263; Part B Co-Dosing 10mg atorvastatin + 10mg ezetimibe; Part B Co-Dosing 10mg atorvastatin + 800mg GSK1292263; Part B Co-Dosing 10mg atorvastatin + Placebo (GSK1292263); Part B Run-in 10mg atorvastatin

80mg atorvastatin DRUG

80mg

Also known as: Lipitor

Part A Run-in; Part B Co-Dosing 80mg atorvastatin + 800mg GSK1292263; Part B Run-in 80mg atorvastatin

GSK1292263 Placebo DRUG

Placebo

Part B Co-dosing 80mg atorvastatin + Placebo (GSK1292263); Part B Dosing Placebo GSK1292263

100mg GSK1292263 DRUG

100mg

Part B Dosing 100mg GSK1292263

300mg GSK1292263 DRUG

300mg

Part B Co-Dosing 10mg atorvastatin + 300mg GSK1292263; Part B Dosing 300mg GSK1292263

800mg GSK1292263 DRUG

800mg

Part A Co-Dosing 800mg GSK1292263; Part B Co-Dosing 10mg atorvastatin + 800mg GSK1292263; Part B Dosing 800mg GSK1292263

10mg ezetimibe DRUG

10mg

Also known as: Zetia

Part B Co-Dosing 10mg atorvastatin + 10mg ezetimibe

Washout OTHER

No interventions - washout period

Part B Washout

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy adult males and females of non-child-bearing-potential, aged 18-75 years who is capable of giving informed consent.
• A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 MlU/ml and estradiol \<40 pg/ml (\<140 pmol/L) is confirmatory in the absence of a clear post-menopausal history.
• Females on hormone replacement therapy (HRT) must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study.
• Male subjects must agree to use one of the contraception methods listed in the protocol. This criterion must be followed from the time of the first dose of study medication until seven days following the last dose.
• Body weight \> 50 kg (110 pounds) and body mass index (BMI) between 19.0 and 39.0 (inclusive).
• Part A: (i) Subjects who are on 80mg or 40mg atorvastatin for \>= 4 weeks and are tolerating the drug well, or (ii) Subjects not on lipid-modifying therapy who have a fasting low density lipoprotein cholesterol (LDLc) \>= 130mg/dL.
• In Part B at Screening: Subjects who are on statins or Vytorin treatment for \>= 4 weeks.
• Part B at the end of the 4 week washout: Subjects who have a fasting LDL cholesterol of \>=120mg/dL and \<=180mg/dL and fasting triglycerides of \>=100mg/dL and \<=400mg/dL.
• Part B at the end of the 4 week run-in on atorvastatin: Subjects who are tolerating well atorvastatin 10mg or 80mg (as determined by the Investigator).
• Part B: Subjects must be willing to discontinue statins or Vytorin for the duration of the study.
• Liver enzymes, AST and ALT \< 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin =\< 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%). Subjects with Gilbert's syndrome are allowed to participate in the study.
• Average QTcB or QTcF \< 450msec; or QTc \< 480msec in subjects with right bundle branch block.

You may not qualify if:

• A medical history of the following:
• Clinical or angiographic cardiovascular disease, including history or current evidence of coronary heart disease, heart failure, cerebrovascular disease (including stroke and transient ischemic attack \[mini-stroke\]), peripheral vascular disease. Subjects pending diagnostic procedures for any of those conditions at the time of screening will not be eligible for participation.
• Homozygous familial hypercholesterolemia or family history of familial hypercholesterolemia (Part B only). Note: Subjects with heterozygous familial hypercholesterolemia on 80mg atorvastatin who are tolerating this drug well and fulfill the other eligibility criteria may participate in Part A only.
• History of recurrent or unexplained muscle aches (e.g., fibromyalgia), myopathy or myositis, whether or not it is related to treatment with statins or other lipid modifying drugs.
• Renal impairment as defined by a calculated glomerular filtration rate \< 60 mL/min
• History of diabetes mellitus, or history of post-prandial and/or random blood glucose \> 200 mg/dl or fasting glucose \> 125 mg/dL or currently taking diabetes medications to manage fasting glucose levels (e.g., thiazolidinediones, sulfonylureas, insulin, metformin).
• History of pancreatitis within 10 years of screening.
• Any concurrent serious illness (e.g., severe chronic obstructive pulmonary disease, sleep apnea, history of malignancy other than skin cancer within 5 years of initial diagnosis or with evidence of recurrence) that may interfere with a subject from completing the study.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
• Active peptic ulcer disease and/or history of peptic ulcer disease or gastrointestinal bleeding within 12 months prior to screening.
• History of kidney stones within 10 years of screening.
• History of uncorrected thyroid dysfunction or an abnormal thyroid function test assessed by thyroid stimulating hormone (TSH) at Screening. (NOTE: subjects with hypothyroidism on a stable dose of thyroid replacement therapy for at least 3 months prior to screening and who have a screening TSH within the normal range may participate.)
• Symptomatic cholelithiasis or obstructive or inflammatory gallbladder disease within 3 months prior to screening.
• Gastrointestinal disease that could affect fat or bile acid absorption, or the pharmacokinetics or pharmacodynamics of the study drugs, including inflammatory bowel disease, chronic diarrhea, Crohn's disease or malabsorption syndromes within the past year.
• Gastrointestinal surgery that may affect the pharmacokinetics or pharmacodynamics of the study drugs.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (21)

GSK Investigational Site

Anniston, Alabama, 36207, United States

Location

GSK Investigational Site

Chula Vista, California, 91910, United States

Location

GSK Investigational Site

Stockton, California, 95204, United States

Location

GSK Investigational Site

Jacksonville, Florida, 32216, United States

Location

GSK Investigational Site

Miami, Florida, 33169, United States

Location

GSK Investigational Site

Miami, Florida, 33183, United States

Location

GSK Investigational Site

Port Orange, Florida, 32127, United States

Location

GSK Investigational Site

St. Petersburg, Florida, 33709, United States

Location

GSK Investigational Site

Chicago, Illinois, 60607, United States

Location

GSK Investigational Site

Chicago, Illinois, 60610, United States

Location

GSK Investigational Site

Louisville, Kentucky, 40213, United States

Location

GSK Investigational Site

Kalamazoo, Michigan, 49007, United States

Location

GSK Investigational Site

Minneapolis, Minnesota, 55430, United States

Location

GSK Investigational Site

Berlin, New Jersey, 08009, United States

Location

GSK Investigational Site

Cincinnati, Ohio, 45246, United States

Location

GSK Investigational Site

Oklahoma City, Oklahoma, 73112, United States

Location

GSK Investigational Site

Eugene, Oregon, 97404, United States

Location

GSK Investigational Site

Spartanburg, South Carolina, 29303, United States

Location

GSK Investigational Site

San Antonio, Texas, 78205, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

Location

GSK Investigational Site

Renton, Washington, 98057, United States

Location

MeSH Terms

Conditions

Dyslipidemias

Interventions

Atorvastatin; (1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate; Ezetimibe; WASH protein, Drosophila

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Azetidines; Azetines

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

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 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2010
• First Posted: October 11, 2010
• Study Start: September 14, 2010
• Primary Completion: June 29, 2011
• Study Completion: June 29, 2011
• Last Updated: July 16, 2019
• Results First Posted: November 8, 2017

Record last verified: 2019-06

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

US (21)