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Integrated Biomarker And Imaging Study - 2

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT00268996
First received: December 21, 2005
Last updated: April 17, 2017
Last verified: April 2017
  Purpose
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.

Condition Intervention Phase
Atherosclerosis Drug: SB-480848 Drug: SB-480848 matching placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Mean circulating high sensitivity C- Reactive Protein (hs-CRP) levels at Week 52. [ Time Frame: 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.

  • 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. [ Time Frame: Baseline and 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.


Secondary Outcome Measures:
  • Circulating hs-CRP at the end of week 26. [ Time Frame: 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.

  • Mean Lipoprotein Phospholipase A2 (Lp-PLA2) activity at the end of week 26 and week 52 [ Time Frame: 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.

  • Change from Baseline in plaque volume as IVUS-Grey Scale Assessments at Week 52 [ Time Frame: Baseline and 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.

  • Change from Baseline in Percent obstruction volume as IVUS-Grey Scale Assessments at Week 52 [ Time Frame: Baseline and 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.

  • Change from Baseline in necrotic core volume as intravenous Ultrasound-Virtual Histology (IVUS-VH) assessments at Week 52 [ Time Frame: Baseline and 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.

  • Change from Baseline in necrotic core as a percent of IVUS-VH plaque at the end of week 52. [ Time Frame: Baseline and 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.

  • Mean Interlukin 6 (IL-6) levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 [ Time Frame: 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.

  • Mean Intercellular Adhesion Molecule-1 (ICAM-1) levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 [ Time Frame: 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.

  • Mean Myeloperoxidase (MPO) levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 [ Time Frame: 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.

  • Mean sCD40L levels as circulating biomarkers associated with inflammatory burden at Week 26 and Week 52 [ Time Frame: 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.

  • Mean matrix metaloproteinases-9 (MMP-9) levels as circulating biomarkers associated with plaque instability at Week 26 and Week 52. [ Time Frame: 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.

  • Mean levels of Oxidised Phospholipids/ Apolipoprotein B100 (oxPL/apoB) ratio as target circulating biomarkers at the end of week 26 and week 52. [ Time Frame: 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.

  • Mean levels of oxidized non-esterified fatty acids (ox-NEFA) as target circulating biomarkers at the end of week 26 and week 52 [ Time Frame: 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 was not evaluated.

  • Change from Baseline in vessel volume and lumen volume as IVUS-Grey Scale Assessments at Week 52. [ Time Frame: Baseline and 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.

  • Change from Baseline in mean plaque area, mean vessel area, and mean lumen area as IVUS-Grey Scale Assessments at Week 52. [ Time Frame: Baseline and 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.

  • Change from Baseline in fibrous tissue volume and fibro-fatty volume as IVUS-VH assessments at Week 52 [ Time Frame: Baseline and 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.


  • Change from Baseline in fibrous tissue and fibro-fatty as a percent of IVUS-VH plaque as IVUS-VH assessments at Week 52 [ Time Frame: Baseline and 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.


Enrollment: 336
Actual Study Start Date: November 10, 2005
Study Completion Date: August 28, 2007
Primary Completion Date: August 28, 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Subjects with ACS and evidence of MN:SB-480848
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
SB-480848 is available as enteric-coated, free-base micronized tablet
Placebo Comparator: Subjects with ACS and evidence of MN: placebo
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
Placebo is available as enteric-coated, free-base micronized tablet
Experimental: Non-ACS and ACS subjects without evidence of MN: SB-480848
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
SB-480848 is available as enteric-coated, free-base micronized tablet
Placebo Comparator: Non-ACS and those ACS subjects without evidence of MN: placebo
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
Placebo is available as enteric-coated, free-base micronized tablet

Detailed Description:
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.
  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00268996

Locations
Austria
GSK Investigational Site
Vienna, Austria, A-1140
Belgium
GSK Investigational Site
Aalst, Belgium, 9300
GSK Investigational Site
Antwerpen, Belgium, 2020
GSK Investigational Site
Liège, Belgium, 4000
Czech Republic
GSK Investigational Site
Praha 2, Czech Republic, 128 08
Denmark
GSK Investigational Site
Aarhus N, Denmark, DK-8200
France
GSK Investigational Site
Besancon, France, 25000
GSK Investigational Site
Brest Cedex, France, 29609
Germany
GSK Investigational Site
Heidelberg, Baden-Wuerttemberg, Germany, 69120
GSK Investigational Site
Ulm, Baden-Wuerttemberg, Germany, 89081
GSK Investigational Site
Muenchen, Bayern, Germany, 80336
GSK Investigational Site
Bad Nauheim, Hessen, Germany, 61231
GSK Investigational Site
Essen, Nordrhein-Westfalen, Germany, 45122
GSK Investigational Site
Bad Segeberg, Schleswig-Holstein, Germany, 23795
GSK Investigational Site
Hamburg, Germany, 22527
Netherlands
GSK Investigational Site
Eindhoven, Netherlands, 5623 EJ
GSK Investigational Site
Enschede, Netherlands, 7511JX
GSK Investigational Site
Leeuwarden, Netherlands, 8934 AD
GSK Investigational Site
Rotterdam, Netherlands, 3015 GD
GSK Investigational Site
Rotterdam, Netherlands, 3075 EA
Norway
GSK Investigational Site
Bergen, Norway, 5053
Poland
GSK Investigational Site
Katowice, Poland, 40-635
GSK Investigational Site
Krakow, Poland, 31-501
Spain
GSK Investigational Site
Marid, Spain, 28040
GSK Investigational Site
Santander, Spain, 38008
Switzerland
GSK Investigational Site
Luzern 16, Switzerland, 6000
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Publications:
Study Data/Documents: Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: SB-480848/026
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT00268996     History of Changes
Other Study ID Numbers: SB-480848/026
Study First Received: December 21, 2005
Last Updated: April 17, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Keywords provided by GlaxoSmithKline:
Coronary artery disease
Lipoprotein-associated Phospholipase A2
palpography
hs-CRP
endothelial function
intravascular ultrasound

Additional relevant MeSH terms:
Atherosclerosis
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Cardiovascular Diseases

ClinicalTrials.gov processed this record on August 18, 2017