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Thromb Haemost 2014; 112(01): 205-215
DOI: 10.1160/TH13-08-0681
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Antithrombotic properties of rafigrelide: a phase 1, open-label, non-randomised, single-sequence, crossover study

Karthik Balasubramaniam
1   Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
,
Girish Viswanathan
1   Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
,
Jeff Dragone
2   Shire Development LLC, Wayne, Pennsylvania, USA
,
Rachael Grose-Hodge
3   Shire Pharmaceuticals Development Ltd., Basingstoke, UK
,
Patrick Martin
2   Shire Development LLC, Wayne, Pennsylvania, USA
,
Steve Troy
2   Shire Development LLC, Wayne, Pennsylvania, USA
,
Peter Preston
2   Shire Development LLC, Wayne, Pennsylvania, USA
,
Azfar G. Zaman
1   Institute of Cellular Medicine, Newcastle University, Newcastle-upon-Tyne, UK
4   Cardiology Department, Freeman Hospital, Newcastle upon Tyne, UK
› Author Affiliations Financial support: This protocol was funded by Shire Pharmaceutical Development Ltd. KB was supported by a grant from the Biomedical Research Unit at Newcastle University. PP is a consultant at Shire Pharmaceuticals Inc. AZ was supported by a Clinical Research Leave Fellowship from the British Heart Foundation (FS/07/33). Editorial and medical writing assistance for this manuscript was funded by Shire Pharmaceuticals.
Further Information

Publication History

Received: 19 August 2013

Accepted after major revision: 19 January 2014

Publication Date:
01 December 2017 (online)

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Summary

Platelets play a central role in atherothrombotic events. We investigated the effect of a novel platelet-lowering agent, rafigrelide, on thrombus formation and characteristics. In this phase 1, open-label, non-randomised, single-sequence, crossover study, healthy male volunteers received rafigrelide for 14 days (Period 1). Following a ≥6-week washout period, they then received rafigrelide + acetylsalicylic acid (ASA) for 14 days (Period 2). Thrombus formation was assessed ex vivo using the Badimon perfusion chamber, and thrombus characteristics were assessed using thromboelastography. A total of 15 volunteers were enrolled in the study and were assigned to Panel A or Panel B, which had different schedules of assessments. In Panel A, after treatment with rafigrelide alone (Period 1), mean (± standard deviation) platelet count was reduced from 283 (± 17) × 109/l at Day 1, to 125 (± 47) × 109/l at Day 14 (n=6) and thrombus area reduced under high and low shear conditions. Reductions in thrombus area under high shear conditions correlated with reductions in platelet count (r2=0.11, p=0.022; n=12). Rafigrelide treatment prolonged clot formation time and reduced clot strength. The addition of ASA to rafigrelide (Period 2) had no additional effect on platelet count or thrombus area under high or low shear conditions. Similar results were seen in Panel B for all parameters. The most common adverse events (≥3 participants per period) were thrombocytopenia and headache. While confirming the platelet-lowering effects of rafigrelide, this early phase study also indicates that rafigrelide has antithrombotic properties under both high and low shear conditions.

Keywords

Rafigrelide - platelet-lowering - thrombus formation - Badimon perfu-sion chamber - thromboelastography
 

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