Integrated Biomarker And Imaging Study - 2

Atherosclerosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00268996
• Other study ID #: SB-480848/026
• Status: Completed
• Phase: Phase 2
• First received: December 21, 2005
• Last updated: February 20, 2018
• Start date: November 10, 2005
• Est. completion date: August 28, 2007

Study information

• Verified date: August 2017
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 336
• Est. completion date: August 28, 2007
• Est. primary completion date: August 28, 2007
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Atherosclerosis

Intervention

Drug:
• SB-480848
SB-480848 is available as enteric-coated, free-base micronized tablet
• SB-480848 matching placebo
Placebo is available as enteric-coated, free-base micronized tablet

Locations

Country	Name	City	State
Austria	GSK Investigational Site	Vienna
Belgium	GSK Investigational Site	Aalst
Belgium	GSK Investigational Site	Antwerpen
Belgium	GSK Investigational Site	Liège
Czechia	GSK Investigational Site	Praha 2
Denmark	GSK Investigational Site	Aarhus N
France	GSK Investigational Site	Besancon
France	GSK Investigational Site	Brest Cedex
Germany	GSK Investigational Site	Bad Nauheim	Hessen
Germany	GSK Investigational Site	Bad Segeberg	Schleswig-Holstein
Germany	GSK Investigational Site	Essen	Nordrhein-Westfalen
Germany	GSK Investigational Site	Hamburg
Germany	GSK Investigational Site	Heidelberg	Baden-Wuerttemberg
Germany	GSK Investigational Site	Muenchen	Bayern
Germany	GSK Investigational Site	Ulm	Baden-Wuerttemberg
Netherlands	GSK Investigational Site	Eindhoven
Netherlands	GSK Investigational Site	Enschede
Netherlands	GSK Investigational Site	Leeuwarden
Netherlands	GSK Investigational Site	Rotterdam
Netherlands	GSK Investigational Site	Rotterdam
Norway	GSK Investigational Site	Bergen
Poland	GSK Investigational Site	Katowice
Poland	GSK Investigational Site	Krakow
Spain	GSK Investigational Site	Marid
Spain	GSK Investigational Site	Santander
Switzerland	GSK Investigational Site	Luzern 16

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

Austria,  Belgium,  Czechia,  Denmark,  France,  Germany,  Netherlands,  Norway,  Poland,  Spain,  Switzerland, 

References & Publications (1)

Serruys PW, García-García HM, Buszman P, Erne P, Verheye S, Aschermann M, Duckers H, Bleie O, Dudek D, Bøtker HE, von Birgelen C, D'Amico D, Hutchinson T, Zambanini A, Mastik F, van Es GA, van der Steen AF, Vince DG, Ganz P, Hamm CW, Wijns W, Zalewski A; Integrated Biomarker and Imaging Study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008 Sep 9;118(11):1172-82. doi: 10.1161/CIRCULATIONAHA.108.771899. Epub 2008 Sep 1. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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