Trial Outcomes & Findings for Integrated Biomarker And Imaging Study - 2 (NCT NCT00268996)

Last Updated: 2018-03-20

Results Overview

hs-CRP is a pentameric protein that is rapidly upregulated in response to inflammation and tissue damage and assessed as circulating biomarkers associated with atherosclerosis and cardiovascular risk. Last Observation Carried Forward (LOCF) data was reported. Only data from 3 months onwards was carried forward. hs-CRP has a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of hs-CRP levels at Week 52 were reported. The levels were analyzed using analysis of co-variance (ANCOVA), with Acute Coronary Syndrome (ACS) status, pooled country and treatment included as covariates.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

336 participants

Primary outcome timeframe

Week 52

Results posted on

2018-03-20

Participant Flow

The study was conducted in participants with angiographically documented coronary artery disease (CHD) at 23 sites in 10 countries. The study was initiated on 10 November 2005 and completed on 28 August 2007.

There were 451 participants screened for enrollment of whom 121 failed screening. A total of 330 participants were randomized to receive treatment. Among the randomized participants, 4 from placebo arm and 3 from darapladib arm did not receive study drug. The remaining 323 participants received at least one dose of study drug.

Participant milestones

Participant milestones
Measure	Placebo Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160mg EC Tablet Eligible participants received SB-480848 (darapladib) 160 milligram (mg) enteric coated (EC) tablets once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Overall Study STARTED	151	172
Overall Study COMPLETED	130	152
Overall Study NOT COMPLETED	21	20

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160mg EC Tablet Eligible participants received SB-480848 (darapladib) 160 milligram (mg) enteric coated (EC) tablets once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Overall Study Adverse Event	11	7
Overall Study Lost to Follow-up	3	1
Overall Study Withdrawal by Subject	5	11
Overall Study Non-compliance	1	0
Overall Study Other	1	1

Baseline Characteristics

Integrated Biomarker And Imaging Study - 2

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=151 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=172 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Total n=323 Participants Total of all reporting groups
Age, Continuous	57.3 Years STANDARD_DEVIATION 10.86 • n=5 Participants	59.4 Years STANDARD_DEVIATION 9.81 • n=7 Participants	58.4 Years STANDARD_DEVIATION 10.36 • n=5 Participants
Sex: Female, Male Female	25 Participants n=5 Participants	32 Participants n=7 Participants	57 Participants n=5 Participants
Sex: Female, Male Male	126 Participants n=5 Participants	140 Participants n=7 Participants	266 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	3 Participants n=5 Participants
Race (NIH/OMB) White	146 Participants n=5 Participants	171 Participants n=7 Participants	317 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 52

Population: The biomarker evaluable population was comprised of all randomized participants who received at least one dose of study drug, with an evaluable biomarker assessment at 3 months (Day 77) or later.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Circulating High Sensitivity C- Reactive Protein (Hs-CRP) Levels at Week 52.	1.034 mg per litre (mg/L) Interval 0.854 to 1.251	0.913 mg per litre (mg/L) Interval 0.765 to 1.09

PRIMARY outcome

Timeframe: Baseline and Week 52

Population: The imaging evaluable population was comprised of all randomized participants who received at least one dose of study drug, with an evaluable baseline and end of treatment imaging assessment at 6 months (Day 154) or later. The participants available at the time of assessment were included in the analysis.

The ROC grade III/IV strain spots per 10 millimetre (mm) within the ROI on intravascular ultrasound (IVUS) grey scale based palpography were assessed and change from Baseline at end of 52 was reported. Change from Baseline was calculated as the density of spots at the end of study minus the density of spots recorded at Baseline. If either value was considered missing then the change from Baseline value was missing for the participant. Between treatment group comparisons of change from Baseline were analyzed using ANCOVA adjusting for ACS status, pooled country, Baseline value, matched segment length and treatment. Adjusted means and associated standard errors for each treatment group were presented. The baseline value for each participant was defined as the last value prior to the first dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=115 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=131 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Change From Baseline in the Density of Rotterdam Classification (ROC) Grade III/IV Strain Spots/10 Millimeter (mm) Within the Region of Interest (ROI) on IVUS Grey Scale Based Palpography at the End of Week 52.	0.003 Spots/10 mm Standard Error 0.048	-0.079 Spots/10 mm Standard Error 0.045

SECONDARY outcome

Timeframe: Week 26

Population: Biomarker evaluable population

hs-CRP is a pentameric protein that is rapidly upregulated in response to inflammation and tissue damage and assessed as circulating biomarkers associated with atherosclerosis and cardiovascular risk. LOCF data was reported. Only data from 3 months onwards was carried forward. hs-CRP has a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of hs-CRP levels at Week 26 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Circulating Hs-CRP at the End of Week 26.	0.924 mg/L Interval 0.774 to 1.102	0.960 mg/L Interval 0.815 to 1.131

SECONDARY outcome

Timeframe: Week 26 and Week 52

Lp-PLA2 is a calcium-independent phospholipase A2 enzyme associated with low density lipoprotein (LDL) in plasma. Blood samples were collected at baseline and at Week 4, 13, 26, and 52 and Lp-PLA2 activity was determined. Percentage inhibition of Lp-PLA2 activity relative to baseline was calculated as, percent inhibition = (\[baseline value - post baseline value\] x 100) / baseline value. The baseline value for each participant was defined as the last value prior to the first dose of study drug.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Lipoprotein Phospholipase A2 (Lp-PLA2) Activity at the End of Week 26 and Week 52 Week 26 LOCF	151.412 micromole per minute per Litre Interval 143.592 to 159.657	59.449 micromole per minute per Litre Interval 56.591 to 62.452
Mean Lipoprotein Phospholipase A2 (Lp-PLA2) Activity at the End of Week 26 and Week 52 Week 52 LOCF	152.061 micromole per minute per Litre Interval 144.109 to 160.452	61.850 micromole per minute per Litre Interval 58.838 to 65.015

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Imaging evaluable population

Change from Baseline was calculated for each IVUS grey scale assessment recorded at the end of study. The Baseline value for each participant was defined as the last value prior to the first dose of study drug. Change from Baseline was calculated as plaque volume at Week 52 minus Baseline value. The data was analyzed using ANCOVA, with ACS status, pooled country, Baseline value, matched segment length and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=118 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=143 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Change From Baseline in Plaque Volume as IVUS-Grey Scale Assessments at Week 52	-5.126 Cubic millimetre (mm^3) Standard Error 2.715	-4.873 Cubic millimetre (mm^3) Standard Error 2.464

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Imaging evaluable population

Change from Baseline in percent obstruction volume was calculated for each IVUS grey scale assessment recorded. Percent obstruction volume was calculated as (Plaque volume/ Vessel volume \*100). The Baseline value for each participant was defined as the last value prior to the first dose of study drug. Change from Baseline was calculated as plaque volume at Week 52 minus Baseline value. The data was analyzed using ANCOVA, with ACS status, pooled country, baseline value, matched segment length and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=118 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=143 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Change From Baseline in Percent Obstruction Volume as IVUS-Grey Scale Assessments at Week 52	0.007 Percentage of mm^3 Standard Error 0.354	-0.054 Percentage of mm^3 Standard Error 0.321

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Imaging evaluable population. Only those participants with data available at the indicated time points were analyzed.

Change from Baseline was calculated for each IVUS-VH assessment recorded at the end of study. The necrotic core volume was calculated as mean necrotic area multiplied by mean of Baseline and follow-up length. Change from Baseline was calculated as plaque volume at Week 52 minus Baseline value. The data was analyzed using ANCOVA, with ACS status, pooled country, Baseline value, matched segment length and treatment included as covariates. The Baseline value for each participant was defined as the last value prior to the first dose of study drug. Change from Baseline in necrotic core volume as IVUS-VH assessments at Week 52 was reported.

Outcome measures

Outcome measures
Measure	Placebo n=110 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=129 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Change From Baseline in Necrotic Core Volume as Intravenous Ultrasound-Virtual Histology (IVUS-VH) Assessments at Week 52	4.633 mm^3 Standard Error 1.491	-0.531 mm^3 Standard Error 1.376

SECONDARY outcome

Timeframe: Baseline and Week 52

Population: Imaging evaluable population

Change from baseline was calculated for each IVUS-VH assessment recorded at the end of study. The baseline value for each participant was defined as the last value prior to the first dose of study drug. Change from baseline in percent necrotic core was calculated as percent necrotic core at Week 52 minus baseline value. The data was analyzed using ANCOVA, with ACS status, pooled country, baseline value, matched segment length and treatment included as covariates. Change from Baseline in necrotic core as a percent of IVUS-VH plaque at the end of week 52 was reported.

Outcome measures

Outcome measures
Measure	Placebo n=110 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=129 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Change From Baseline in Necrotic Core as a Percent of IVUS-VH Plaque at the End of Week 52.	2.502 Percent Necrotic core Standard Error 0.722	0.535 Percent Necrotic core Standard Error 0.666

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Biomarker evaluable population

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean IL-6 levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 were assessed and reported. LOCF data was reported. Only data from 3 months onwards was carried forward. IL-6 had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of IL-6 levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Interlukin 6 (IL-6) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 26 LOCF	1.851 Nanograms per litre (ng/L) Interval 1.609 to 2.128	1.979 Nanograms per litre (ng/L) Interval 1.741 to 2.25
Mean Interlukin 6 (IL-6) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 52 LOCF	2.019 Nanograms per litre (ng/L) Interval 1.749 to 2.331	2.267 Nanograms per litre (ng/L) Interval 1.985 to 2.588

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Biomarker evaluable population.

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean ICAM-1 levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 were assessed and reported. LOCF data was reported. Only data from 3 months onwards was carried forward. ICAM-1 had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of ICAM-1 levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=161 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Intercellular Adhesion Molecule-1 (ICAM-1) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 26 (LOCF)	269.444 nanogram per millilitre (ng/mL) Interval 258.932 to 280.383	266.447 nanogram per millilitre (ng/mL) Interval 256.744 to 276.516
Mean Intercellular Adhesion Molecule-1 (ICAM-1) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 52 (LOCF)	277.947 nanogram per millilitre (ng/mL) Interval 265.822 to 290.624	268.950 nanogram per millilitre (ng/mL) Interval 257.998 to 280.367

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Biomarker evaluable population

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean MPO levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 were assessed and reported. LOCF data was reported. Only data from 3 months onwards was carried forward. MPO had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of MPO levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=139 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Myeloperoxidase (MPO) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 52 (LOCF)	370.999 picomole per litre (pmol/L) Interval 331.989 to 414.592	405.339 picomole per litre (pmol/L) Interval 365.718 to 449.253
Mean Myeloperoxidase (MPO) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 26 (LOCF)	324.534 picomole per litre (pmol/L) Interval 294.535 to 357.589	378.811 picomole per litre (pmol/L) Interval 346.275 to 414.405

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Safety Population comprised of all randomized participants who received at least one dose of study drug. Only those participants with data available at the indicated time points were analyzed.

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean sCD40L levels as circulating biomarker associated with inflammatory burden at Week 26 and Week 52 were assessed and reported. sCD40L had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of sCD40L levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=151 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=172 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean sCD40L Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 26	178.738 pg/ml Interval 152.832 to 209.035	206.351 pg/ml Interval 177.412 to 240.012
Mean sCD40L Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 Week 52	183.449 pg/ml Interval 149.887 to 224.526	254.200 pg/ml Interval 208.84 to 309.412

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Biomarker evaluable population

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean MMP-9 levels as circulating biomarkers associated with plaque instability at Week 26 and Week 52 were assessed and reported. LOCF data was reported. Only data from 3 months onwards was carried forward MMP-9 had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of MMP-9 levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Matrix Metaloproteinases-9 (MMP-9) Levels as Circulating Biomarkers Associated With Plaque Instability at Week 26 and Week 52. Week 26 LOCF	481.581 microgram per litre (mcg/L) Interval 429.483 to 539.997	471.477 microgram per litre (mcg/L) Interval 423.894 to 524.401
Mean Matrix Metaloproteinases-9 (MMP-9) Levels as Circulating Biomarkers Associated With Plaque Instability at Week 26 and Week 52. Week 52 LOCF	488.998 microgram per litre (mcg/L) Interval 432.454 to 552.935	498.709 microgram per litre (mcg/L) Interval 444.895 to 559.032

SECONDARY outcome

Timeframe: Week 26 and Week 52

Population: Biomarker evaluable population.

Blood was collected at baseline, Week 4, 13, 26 and 52 for evaluation of biomarkers. Mean OXPL/LAPO B levels as circulating biomarkers associated with Lp-PLA2 target-related biomarkers at Week 26 and Week 52 were assessed and reported. LOCF data was reported. Only data from 3 months onwards was carried forward. OXPL/LAPO B had a skewed distribution and values were log transformed before analysis. The statistics was calculated on the log transformed data and back transformed. The adjusted geometric means of OXPL/LAPO B levels at Week 26 and 52 were reported. The levels were analyzed using ANCOVA, with ACS status, pooled country and treatment included as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=140 Participants Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=162 Participants Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Mean Levels of Oxidised Phospholipids/ Apolipoprotein B100 (oxPL/apoB) Ratio as Target Circulating Biomarkers at the End of Week 26 and Week 52. Week 26 LOCF	3114.718 Relative light units (RLU) Interval 2695.797 to 3598.739	3106.872 Relative light units (RLU) Interval 2716.642 to 3553.156
Mean Levels of Oxidised Phospholipids/ Apolipoprotein B100 (oxPL/apoB) Ratio as Target Circulating Biomarkers at the End of Week 26 and Week 52. Week 52 LOCF	2711.118 Relative light units (RLU) Interval 2017.411 to 3643.363	2478.376 Relative light units (RLU) Interval 1883.212 to 3261.634

Adverse Events

Placebo

Serious events: 45 serious events

Other events: 37 other events

Deaths: 0 deaths

Darapladib 160 mg EC Tablet

Serious events: 46 serious events

Other events: 59 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=151 participants at risk Eligible participants received the matching placebo for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.	Darapladib 160 mg EC Tablet n=172 participants at risk Eligible participants received darapladib 160 mg EC tablet once daily for 52 weeks. Participants were instructed to administer one tablet (swallowed intact and not chewed) in the morning each day with food.
Cardiac disorders Angina pectoris	7.9% 12/151 • Number of events 14 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	10.5% 18/172 • Number of events 23 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
Renal and urinary disorders Urine odour abnormal	2.6% 4/151 • Number of events 4 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	9.9% 17/172 • Number of events 17 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
Gastrointestinal disorders Abnormal faeces	1.3% 2/151 • Number of events 2 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	10.5% 18/172 • Number of events 18 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
General disorders Fatigue	6.6% 10/151 • Number of events 11 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	5.8% 10/172 • Number of events 10 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
Infections and infestations Nasopharyngitis	6.6% 10/151 • Number of events 12 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	4.1% 7/172 • Number of events 8 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
Gastrointestinal disorders Diarrhoea	2.0% 3/151 • Number of events 3 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	7.6% 13/172 • Number of events 15 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
General disorders Non-cardiac chest pain	4.6% 7/151 • Number of events 7 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	5.2% 9/172 • Number of events 11 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.
General disorders Oedema peripheral	1.3% 2/151 • Number of events 2 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.	5.2% 9/172 • Number of events 9 • Adverse events (AEs) were recorded from the time a participant consents to participate until completion of follow-up period (10 to 21 days after discontinuation of treatment). On-treatment (up to 52 weeks) serious-AE (SAE) and non-SAE are reported. Safety population was used for collection of AEs.

Additional Information

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GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
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