Design of a Randomized, Controlled Study to Evaluate Reversal of Anticoagulation of Ciraparantag in Healthy Adults: Whole Blood Clotting Time Assessed By Automated and Manual Methods

There is a need for safe and effective reversal agents for patients on chronic anticoagulant therapy in cases such as serious or life-threatening bleeding, urgent or emergency surgery, after major trauma, or in cases of anticoagulant overdose. Ciraparantag, an anticoagulant reversal agent in clinical development, which is believed to bind directly to anticoagulant molecules through non-covalent bonds, with no binding to blood coagulation factors or proteins in the blood. Phase 2 clinical studies have shown that ciraparantag reverses anticoagulation in healthy volunteers treated with edoxaban, enoxaparin, apixaban, or rivaroxaban as assessed by manual whole blood clotting time (WBCT).

WBCT is the key pharmacodynamic marker because ciraparantag is cationic and binds to the anionic substances in standard blood collection tubes, and to anionic, colloidal activators used in the traditional coagulation assays such as PT or aPTT. Therefore, such assays are not appropriate markers for measuring ciraparantag's effect. WBCT is a direct measure of the time required for blood clot formation ex vivo and uses blood drawn into reagent-free collection equipment, using only glass as the activating agent.

A Phase 2b clinical study is planned to evaluate the efficacy and safety of ciraparantag for reversal of anticoagulation as measured by WBCT using an automated point-of-care (PoC) coagulometer (developed by Perosphere Technologies, Inc.) compared with a manual testing method. This is a randomized, double-blind, placebo-controlled study in healthy adults 18 to 75 years of age who are anticoagulated with apixaban (10 mg PO twice daily) or rivaroxaban (20 mg PO once daily). Subjects who reach steady-state anticoagulation will be stratified into 2 age groups and randomized 2:1 to receive a single IV dose of ciraparantag or placebo, followed by serial WBCT testing and standard safety assessments over 24 hours.

The primary efficacy endpoint is based on the extent and timing of reversal of anticoagulation following ciraparantag administration as compared with placebo, based on WBCT measured using the PoC coagulometer. Manual WBCT testing also will be performed at selected timepoints in order to describe the correlation between results obtained with the two methods. The coagulometer is expected to provide greater sensitivity and precision compared to the manual method.

Further details of the design of this study will be provided. The results of this study will inform dose selection for the future Phase 3 clinical trial and will provide data on the use of the PoC coagulometer for assessment of ciraparantag for reversal of anticoagulation.