Integrated Biomarker And Imaging Study - 2

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.

Time frame: 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.

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.

Time frame: 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.

Fibro-fatty as percentage of VH plaque and Fibrous tissue as percentage of VH plaque were derived from IVUS-VH system. 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 Fibro-fatty as percentage of VH plaque or Fibrous tissue as percentage of VH plaque at Week 52 minus baseline value. The data was reported based on observed cases. Data analyzed using ANCOVA, with ACS status, pooled country, baseline value , matched segment length and treatment included as covariates.

Time frame: Baseline and Week 52

Population: Imaging evaluable population

Change from baseline in fibrous tissue volume and fibro-fatty volume were derived from IVUS system at each IVUS grey scale assessment recorded. Fibrous tissue volume was calculated as mean fibro-fatty area multiplied by mean of Baseline and Follow-up length. Fibro-fatty volume was calculated as mean fibrous area multiplied by mean of Baseline and Follow-up length. 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 mean Fibrous tissue volume or Fibro-fatty volume at Week 52 minus baseline value. The data was reported based on observed cases. Data analyzed using ANCOVA, with ACS status, pooled country, baseline value , matched segment length and treatment included as covariates.

Time frame: Baseline and Week 52

Population: Imaging evaluable population

Change from baseline in was mean plaque area, mean vessel area, and mean lumen area were derived from IVUS system at each IVUS grey scale assessment recorded. 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 mean area of the parameter (plaque/vessel/lumen) at Week 52 minus baseline value. The data was reported based on observed cases. Data analyzed using ANCOVA, with ACS status, pooled country, baseline value, matched segment length and treatment included as covariates.

Time frame: 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.

Time frame: 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 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.

Time frame: Baseline and Week 52

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

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.

Time frame: 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.

Time frame: Baseline and Week 52

Population: Imaging evaluable population

Change from baseline in vessel volume and lumen volume calculated for each IVUS grey scale assessment recorded. Vessel volume (i.e., coronary remodelling) defined by the leading edge of echogenic adventitia/external elastic membrane (EEM) and calculated as, mean vessel area multiplied mean of vessel length at Baseline and Follow-up. Lumen volume was circumscribed by the leading edge of intima/plaque and calculated as mean lumen area multiplied by mean lumen length at Baseline and Follow-up. 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 vessel volume or lumen volume at Week 52 minus baseline value.

Time frame: Baseline and Week 52

Population: Imaging 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.

Time frame: Week 26

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.

Time frame: 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.

Time frame: 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.

Time frame: Week 26 and Week 52

Population: Biomarker evaluable population.

Mean ox-NEFA levels as circulating biomarkers associated with Lp-PLA2 target-related biomarkers at Week 26 and Week 52 was planned to be assessed. However, the parameter data were not collected for this endpoint.

Time frame: Week 26 and Week 52

Population: Biomarker evaluable population

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.

Time frame: Week 26 and 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.

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.

Time frame: 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.

Time frame: 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 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.

Time frame: 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.