The University of Southampton
University of Southampton Institutional Repository

Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial

Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial
Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial
Background
The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.

Methods
Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n?=?34), 80 mg (n?=?34), or placebo (n?=?34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.

Results
Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P?=?0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.

Conclusions
Short-term treatment (14±4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.

Trial Registration Information

Name of Registry 1: ClinicalTrials.gov

Registry Number 1: NCT01916720

Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720

Name of Registry 2: GSK Clinical Study Register

Registry Number 2?480848/010

Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F
1932-6203
1-9
Johnson, Joel L.
d929df25-d9ba-4053-b453-141b29f63728
Shi, Yi
45de4c85-68fd-4e77-a449-d821d48910c8
Snipes, Rose
8d8f8397-11e4-41fa-99e5-4291b57e24b2
Janmohamed, Salim
2fda1a72-94cc-4a30-9df3-08bc24951653
Rolfe, Timothy E.
9229000a-830d-40b5-b343-cab2ab39fa01
Davis, Bill
b1fb2079-19dc-4d6a-b468-9804be999983
Postle, Anthony
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Macphee, Colin H.
838a5b97-c731-4707-96d1-5ed8e922be3c
Johnson, Joel L.
d929df25-d9ba-4053-b453-141b29f63728
Shi, Yi
45de4c85-68fd-4e77-a449-d821d48910c8
Snipes, Rose
8d8f8397-11e4-41fa-99e5-4291b57e24b2
Janmohamed, Salim
2fda1a72-94cc-4a30-9df3-08bc24951653
Rolfe, Timothy E.
9229000a-830d-40b5-b343-cab2ab39fa01
Davis, Bill
b1fb2079-19dc-4d6a-b468-9804be999983
Postle, Anthony
0fa17988-b4a0-4cdc-819a-9ae15c5dad66
Macphee, Colin H.
838a5b97-c731-4707-96d1-5ed8e922be3c

Johnson, Joel L., Shi, Yi, Snipes, Rose, Janmohamed, Salim, Rolfe, Timothy E., Davis, Bill, Postle, Anthony and Macphee, Colin H. (2014) Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial. PLoS ONE, 9 (2), 1-9. (doi:10.1371/journal.pone.0089034). (PMID:24586490)

Record type: Article

Abstract

Background
The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity.

Methods
Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n?=?34), 80 mg (n?=?34), or placebo (n?=?34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.

Results
Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P?=?0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.

Conclusions
Short-term treatment (14±4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.

Trial Registration Information

Name of Registry 1: ClinicalTrials.gov

Registry Number 1: NCT01916720

Trial URL in Registry Database 1: www.clinicaltrials.gov/ct2/show/NCT01916720

Name of Registry 2: GSK Clinical Study Register

Registry Number 2?480848/010

Trial URL in Registry Database 2: www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F

Other
asset_id=10.1371%2Fjournal.pone.0089034.PDF - Version of Record
Available under License Creative Commons Attribution.
Download (344kB)

More information

Accepted/In Press date: 10 January 2014
e-pub ahead of print date: 20 February 2014
Published date: 20 February 2014
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 396295
URI: https://eprints.soton.ac.uk/id/eprint/396295
ISSN: 1932-6203
PURE UUID: 61b64964-90f1-4f79-9e87-f8efba6606af
ORCID for Anthony Postle: ORCID iD orcid.org/0000-0001-7361-0756

Catalogue record

Date deposited: 03 Jun 2016 14:26
Last modified: 19 Nov 2019 02:04

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×