Integrated Biomarker And Imaging Study - 2

Study Overview
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Brief Summary
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IBIS-2 is a study using SB-480848 versus placebo in subjects with angiographically documented coronary heart disease. Endpoints include coronary imaging, endothelial function, biomarkers, safety and tolerability.

Detailed Description
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Integrated Biomarker and Imaging Study -2 (IBIS-2): An International, Multicenter, Randomized, Placebo-controlled, Parallel-group, 1 Year Treatment, Integrated Biomarkers and Imaging Study in Subjects with Angiographically Documented Coronary Heart Disease (CHD) to Examine the Effects of the Novel Lipoprotein-associated Phospholipase A2 (Lp-PLA2) inhibitor SB-480848 on Intermediate Cardiovascular Endpoints, Patient Safety and Tolerability.

Official Title
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An International, Multicenter, Randomized, Placebo-controlled, Parallel-group, 1 Year Treatment, Integrated Biomarkers and Imaging Study in Subjects With Angiographically Documented Coronary Heart Disease (CHD) to Examine the Effects of the Novel Lipoprotein-associated Phospholipase A2 (Lp-PLA2) Inhibitor SB-480848 on Intermediate Cardiovascular Endpoints, Patient Safety and Tolerability

Conditions
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Atherosclerosis

Intervention / Treatment
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* Drug: SB-480848
* Drug: SB-480848 matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Successful PCI (Percutaneous Coronary Intervention) or uncomplicated diagnostic catheterization Suitable non-intervened coronary artery with IVUS Antiplatelet therapy Exclusion criteria: Clinical instability Previous CABG (Coronary Artery By-pass Graft) surgery Planned major surgery Recent stroke Abnormal QTc Renal or hepatic impairment Uncontrolled hypertension Use of corticosteroids Class III or IV heart failure Asthma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects with ACS and evidence of MN:SB-480848<br>Enrolled subjects (subjects with ACS and evidence of myocardial necrosis) will receive 160mg of SB-480848 once daily with food for 52 weeks | Drug: SB-480848<br>* SB-480848 is available as enteric-coated, free-base micronized tablet<br>|
| Placebo Comparator: Subjects with ACS and evidence of MN: placebo<br>Enrolled subjects (subjects with ACS and evidence of myocardial necrosis) will receive SB-480848 matching placebo once daily with food for 52 weeks | Drug: SB-480848 matching placebo<br>* Placebo is available as enteric-coated, free-base micronized tablet<br>|
| Experimental: Non-ACS and ACS subjects without evidence of MN: SB-480848<br>Enrolled subjects (non-ACS subjects and those ACS subjects without evidence of myocardial necrosis) will receive 160mg of SB-480848 once daily with food for 52 weeks | Drug: SB-480848<br>* SB-480848 is available as enteric-coated, free-base micronized tablet<br>|
| Placebo Comparator: Non-ACS and those ACS subjects without evidence of MN: placebo<br>Enrolled subjects (non-ACS subjects and those ACS subjects without evidence of myocardial necrosis) will receive SB-480848 matching placebo once daily with food for 52 weeks | Drug: SB-480848 matching placebo<br>* Placebo is available as enteric-coated, free-base micronized tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Circulating High Sensitivity C- Reactive Protein (Hs-CRP) Levels at Week 52. | 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. | Week 52 | 
| 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. | 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. | Baseline and Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Circulating Hs-CRP at the End of Week 26. | 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. | Week 26 | 
| Mean Lipoprotein Phospholipase A2 (Lp-PLA2) Activity at the End of 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. | Week 26 and Week 52 | 
| Change From Baseline in Plaque Volume as IVUS-Grey Scale Assessments at Week 52 | 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. | Baseline and Week 52 | 
| Change From Baseline in Percent Obstruction Volume as IVUS-Grey Scale Assessments at Week 52 | 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. | Baseline and Week 52 | 
| Change From Baseline in Necrotic Core Volume as Intravenous Ultrasound-Virtual Histology (IVUS-VH) Assessments at Week 52 | 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. | Baseline and Week 52 | 
| Change From Baseline in Necrotic Core as a Percent of IVUS-VH Plaque at the End of Week 52. | 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. | Baseline and Week 52 | 
| Mean Interlukin 6 (IL-6) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 | 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. | Week 26 and Week 52 | 
| Mean Intercellular Adhesion Molecule-1 (ICAM-1) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 | 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. | Week 26 and Week 52 | 
| Mean Myeloperoxidase (MPO) Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 | 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. | Week 26 and Week 52 | 
| Mean sCD40L Levels as Circulating Biomarkers Associated With Inflammatory Burden at Week 26 and Week 52 | 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. | Week 26 and Week 52 | 
| Mean Matrix Metaloproteinases-9 (MMP-9) Levels as Circulating Biomarkers Associated With Plaque Instability at Week 26 and Week 52. | 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. | Week 26 and Week 52 | 
| Mean Levels of Oxidised Phospholipids/ Apolipoprotein B100 (oxPL/apoB) Ratio as Target Circulating Biomarkers at the End of Week 26 and Week 52. | 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. | Week 26 and Week 52 | 
| Mean Levels of Oxidized Non-esterified Fatty Acids (Ox-NEFA) as Target Circulating Biomarkers at the End of Week 26 and Week 52 | 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. | Week 26 and Week 52 | 
| Change From Baseline in Vessel Volume and Lumen Volume as IVUS-Grey Scale Assessments at Week 52. | 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. | Baseline and Week 52 | 
| Change From Baseline in Mean Plaque Area, Mean Vessel Area, and Mean Lumen Area as IVUS-Grey Scale Assessments at Week 52. | 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. | Baseline and Week 52 | 
| Change From Baseline in Fibrous Tissue Volume and Fibro-fatty Volume as IVUS-VH Assessments at Week 52 | 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. | Baseline and Week 52 | 
| Change From Baseline in Fibrous Tissue and Fibro-fatty as a Percent of IVUS-VH Plaque as IVUS-VH Assessments at Week 52 | 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. | Baseline and Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronary artery disease, Lipoprotein-associated Phospholipase A2, palpography, hs-CRP, endothelial function, intravascular ultrasound