Atherosclerosis
Conditions
Keywords
SB-480848, Dyslipidaemia
Brief summary
The primary objective of this study is to examine the effects of SB-480848 on plasma lipoprotein associated phospholipase A2 (Lp-PLA2) activity in dyslipidemic patients during a 4-week treatment with SB-480848.
Interventions
DRUGSB480848 40mg EC Tablet
1 tablet once a day
DRUGSB480848 80mg EC Tablet
1 tablet once a day
DRUGSB480848 160mg EC Tablet
1 tablet once a day
DRUGSB480848 Placebo Tablet
1 tablet once a day
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Dyslipidemic subject who is currently undergoing statin therapy and no change in lipid-lowering therapy or dose during the 4 week prior to randomization
Exclusion criteria
1. Recent (i.e.,\<6 months prior to screening) CV event and/or vascular procedure defined as: A)ST-elevation MI or non-ST-elevation MI B)Unstable angina C)Coronary revascularization \[(percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)\] D)Stroke of any etiology E)Peripheral arterial disease with critical limb ischemia (resting pain or ischemic skin lesions, either ulcers or gangrene) F)Resuscitated cardiac arrest 2. Planned CABG or planned PCI or planned major non-cardiac surgery within study period 3. No measurable Lp-PLA2 activity in plasma (\<10 nmol/min/mL) at screening 4. Change in a lipid-lowering medication, regimen or dosage during the 4 week prior to randomization 5. Poorly controlled dyslipidemia (LDL-c \>=160 mg/dL) at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity | Baseline (Week 0, Visit 2) and Week 4 | Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Change from Baseline was calculated as the post-Baseline (Week 4) assessment value minus the Baseline assessment value. If either value was missing, then the change from Baseline was set to be missing. The natural logarithm (log) was used for transformation in Lp-PLA2 activity. In case of zero values, an offset of 0.0001 was added to the zero values to ensure that the log transformation was successfully applied. The log transformation was conducted on the original value and then taken the change from Baseline on that log original value, calculated as log (post-Baseline value \[week 4\]) minus log (Baseline value). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Baseline (Week 0, Visit 2) up to Follow-up (up to Week 7) | Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Percentage inhibition of Lp-PLA2 activity relative to a Baseline value was calculated as: 100 multiplied by (post-Baseline values (Week 1, 2, 4 and Follow-up-Baseline value) divided by \[Baseline value\]). |
| Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Baseline (Week 0, Visit 2), Week 1, Week 2 and Follow-up ( Week 7) | Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Change from Baseline was calculated as the post-Baseline (Week 1, Week 2 and Follow-up) assessment values minus the Baseline assessment value. If either value was missing, then the change from Baseline was set to be missing. The log was used for transformation in Lp-PLA2 activity. In case of zero values, an offset of 0.0001 was added to the zero values to ensure that the log transformation was successfully applied. The log transformation was conducted on the original value and then taken change from Baseline on that log original value, calculated as log (post-Baseline \[Week 1, Week 2 and Follow-up\] values) minus log (Baseline value). |
Countries
Japan
Participant flow
Recruitment details
The study was planned in 100 dyslipidemic male or female participants, aged 20 to 80 years, undergoing statin therapy and no change in lipid-lowering medication or dose during the 4 weeks prior to randomization from 26 August 2008 to 16 January 2009 at 7 centers in Japan.
Pre-assignment details
Out of 116 participants screened, 9 were screen failures; 107 participants were randomized in a ratio of 1:1:1:1, to receive placebo or any 1 of the 3 doses of SB-480848 (40 milligram \[mg\], 80 mg, 160 mg), prior to which they continued their statin therapy with no change in lipid-lowering medication or dose during 4 weeks of Run-in period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received oral dose of matching placebo tablet once daily, after breakfast in the morning for 4 weeks of treatment period. | 25 |
| SB-480848 40 mg Participants received oral dose of SB-480848 40 mg enteric-coated tablet once daily, after breakfast in the morning for 4 weeks of treatment period. | 28 |
| SB-480848 80 mg Participants received oral dose of SB-480848 80 mg enteric-coated tablet once daily, after breakfast in the morning for 4 weeks of treatment period. | 28 |
| SB-480848 160 mg Participants received oral dose of SB-480848 160 mg enteric-coated tablet once daily, after breakfast in the morning for 4 weeks of treatment period. | 26 |
| Total | 107 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | SB-480848 160 mg | SB-480848 80 mg | SB-480848 40 mg |
|---|---|---|---|---|---|
| Age, Continuous | 59.5 Years STANDARD_DEVIATION 11.71 | 59.0 Years STANDARD_DEVIATION 10.34 | 58.3 Years STANDARD_DEVIATION 10.48 | 58.3 Years STANDARD_DEVIATION 9.54 | 59.8 Years STANDARD_DEVIATION 10.17 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 107 Participants | 26 Participants | 28 Participants | 28 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 17 Participants | 65 Participants | 13 Participants | 18 Participants | 17 Participants |
| Sex: Female, Male Male | 8 Participants | 42 Participants | 13 Participants | 10 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 28 | 0 / 28 | 0 / 26 |
| other Total, other adverse events | 8 / 25 | 12 / 28 | 13 / 28 | 13 / 26 |
| serious Total, serious adverse events | 0 / 25 | 1 / 28 | 0 / 28 | 0 / 26 |
Outcome results
Primary
Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity
Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Change from Baseline was calculated as the post-Baseline (Week 4) assessment value minus the Baseline assessment value. If either value was missing, then the change from Baseline was set to be missing. The natural logarithm (log) was used for transformation in Lp-PLA2 activity. In case of zero values, an offset of 0.0001 was added to the zero values to ensure that the log transformation was successfully applied. The log transformation was conducted on the original value and then taken the change from Baseline on that log original value, calculated as log (post-Baseline value \[week 4\]) minus log (Baseline value).
Time frame: Baseline (Week 0, Visit 2) and Week 4
Population: Full Analysis Set (FAS) Population was defined as all randomized participants who received at least one dose of study medication during treatment period and who had at least one evaluable assessment of Lp-PLA2 activity after randomization. Missing values during treatment period, except for Baseline were imputed by last observed response (LOCF).
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity | 0.961 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 8.5 |
| SB-480848 40 mg | Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity | 0.494 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 24.6 |
| SB-480848 80 mg | Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity | 0.404 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 21.5 |
| SB-480848 160 mg | Change From Baseline to Week 4 in Plasma Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Activity | 0.313 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 24.7 |
p-value: <0.00195% CI: [0.449, 0.59]ANCOVA
p-value: <0.00195% CI: [0.367, 0.483]ANCOVA
p-value: <0.00195% CI: [0.284, 0.375]ANCOVA
Secondary
Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up
Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Change from Baseline was calculated as the post-Baseline (Week 1, Week 2 and Follow-up) assessment values minus the Baseline assessment value. If either value was missing, then the change from Baseline was set to be missing. The log was used for transformation in Lp-PLA2 activity. In case of zero values, an offset of 0.0001 was added to the zero values to ensure that the log transformation was successfully applied. The log transformation was conducted on the original value and then taken change from Baseline on that log original value, calculated as log (post-Baseline \[Week 1, Week 2 and Follow-up\] values) minus log (Baseline value).
Time frame: Baseline (Week 0, Visit 2), Week 1, Week 2 and Follow-up ( Week 7)
Population: FAS Population with LOCF analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 2 | 0.977 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 8.4 |
| Placebo | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 7 (Follow-up) | 0.964 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 9.6 |
| Placebo | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 1 | 0.957 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 7.4 |
| SB-480848 40 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 1 | 0.495 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 30.9 |
| SB-480848 40 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 7 (Follow-up) | 0.917 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 11.6 |
| SB-480848 40 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 2 | 0.499 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 20.9 |
| SB-480848 80 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 2 | 0.403 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 19 |
| SB-480848 80 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 1 | 0.430 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 24.1 |
| SB-480848 80 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 7 (Follow-up) | 0.902 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 9.8 |
| SB-480848 160 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 1 | 0.332 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 22.5 |
| SB-480848 160 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 7 (Follow-up) | 0.860 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 12.1 |
| SB-480848 160 mg | Change From Baseline in Lp-PLA2 Activity at Week 1, 2 and Follow-up | Week 2 | 0.313 Log(millimole per milliliter per minute) | Geometric Coefficient of Variation 28.3 |
Secondary
Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time
Blood sample for Lp-PLA2 activity was collected before administration of study medication on the sampling day. Participants were instructed to visit without meal and study medication in the morning. The study medication was administered with food following test. Baseline value was defined as the assessment done on Week 0 (Visit 2). Percentage inhibition of Lp-PLA2 activity relative to a Baseline value was calculated as: 100 multiplied by (post-Baseline values (Week 1, 2, 4 and Follow-up-Baseline value) divided by \[Baseline value\]).
Time frame: Baseline (Week 0, Visit 2) up to Follow-up (up to Week 7)
Population: FAS Population with LOCF analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 2 | -1.96 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 8.147 |
| Placebo | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 7 (Follow-up) | -3.16 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 9.018 |
| Placebo | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 1 | -4.06 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 7.025 |
| Placebo | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 4 | -3.59 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 7.822 |
| SB-480848 40 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 1 | -48.25 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 15.929 |
| SB-480848 40 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 2 | -49.05 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 11.094 |
| SB-480848 40 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 4 | -49.05 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 13.472 |
| SB-480848 40 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 7 (Follow-up) | -7.65 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 11.408 |
| SB-480848 80 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 4 | -58.67 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 9.438 |
| SB-480848 80 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 7 (Follow-up) | -9.40 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 8.667 |
| SB-480848 80 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 2 | -58.95 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 8.258 |
| SB-480848 80 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 1 | -55.83 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 11.031 |
| SB-480848 160 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 2 | -67.52 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 9.402 |
| SB-480848 160 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 4 | -67.73 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 8.31 |
| SB-480848 160 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 1 | -66.03 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 7.656 |
| SB-480848 160 mg | Percent Inhibition of Lp-PLA2 Activity in Plasma Over Time | Week 7 (Follow-up) | -13.36 Percent inhibiton of Lp-PLA2 activity | Standard Deviation 10.244 |