A novel approach to the evaluation of bleeding-related episodes in patients with chronic immune thrombocytopenia

Abstract

Objective:

In clinical studies of patients with severe thrombocytopenia, rescue treatments are used to prevent or stop bleeding. Estimating risk reductions of bleeding for clinical study medications can be challenging. This study evaluated a new and possibly more accurate way of assessing the effects of a treatment intervention on bleeding-related outcomes. We developed a composite endpoint, termed bleeding-related episodes (BRE).

Research design and methods:

BREs were assessed in a post-hoc analysis of patients with chronic immune thrombocytopenia (ITP) who participated in two romiplostim, phase 3, placebo-controlled studies. Patients received romiplostim or placebo once weekly for 24 weeks. A BRE was defined as an actual bleeding event and/or the use of rescue medication. In total, 125 patients (41 placebo, 84 romiplostim) with platelet counts <30 K were enrolled.

Clinical trial registration:

NCT00102323/NCT00102336.

Results:

The rate of all BREs across all studies was reduced by 56% in patients receiving romiplostim compared with placebo. The rate of BREs using immunoglobulin (IVIg or anti-D Ig) was reduced by 89% in patients receiving romiplostim compared with placebo. BREs were more frequent in both groups at platelet counts <50 × 10⁹/L. Results were similar between splenectomized and nonsplenectomized patients. We believe that prior to the development of this tool, bleeding events were underdiagnosed. The BRE tool allowed the identification of multiple interventions within bleeding episodes, which may have required separate interventions and were therefore considered to be additional BREs.

Conclusions:

In this study, the composite endpoint of a bleeding event and the use of rescue medication within close proximity of the bleeding event appears to be feasible and informative. The BRE tool allows for more precise understanding of the effect of rescue therapies in ITP and has broader applications to future clinical trials where assessment of bleeding risk can be complicated or masked by rescue interventions.

Limitations:

This was a post hoc analysis. The assignment of platelet counts to a BRE was based on the platelet count on the first day of a BRE, which may not reflect the platelet count during the entire episode, and the assignment of platelet counts was based on the estimation required for events that occurred between weekly measurements.

Keywords::

• Autoimmune
• Bleeding-related episodes
• BRE
• Hemorrhage
• Immunoglobulins
• ITP
• Platelet count
• Thrombocytopenia
• Thrombopoietin mimetic

Transparency

Declaration of funding

This research was funded by Amgen Inc., Thousand Oaks, CA, USA.

Declaration of financial/other relationships

I.W. has served on a speakers bureau for Amgen Inc. M.A.S. has served on a speakers bureau for Amgen Inc. D.H. has served on a speakers bureau and received research funding from Amgen Inc., Ortho Biotech, and Watson Pharma. M.S. has participated in an advisory committee for Amgen Inc. B.G. served on a speakers bureau for Amgen Inc., has acted as a consultant for Amgen Inc., Roche, and LFB, and has received research funding from Amgen Inc. and Roche. K.N., M.G., and M.D. have received research funding from Amgen Inc. and acted as consultants for Amgen Inc. R.D. is an employee of Amgen Inc. and holds stock options in the company.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

Writing assistance was provided by James O’Kelly, editorial and formatting assistance by Michelle Zakson, and quality control of the statistical analyses by Jason Legg, all employees of Amgen Inc.

Previous presentation at the 2009 ASH meeting: Evaluation of bleeding-related episodes in patients with chronic immune thrombocytopenia (ITP) treated with romiplostim in two phase 3 placebo-controlled clinical trials. Ilene Ceil Weitz, Miguel A Sanz, David H. Henry, Martin Schipperus, Bertrand Godeau, Michelle Gleeson, Mark Danese, and Robert Deuson. Blood (ASH Annual Meeting Abstracts) 2009;114:891.