Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial

Abstract

Individuals with kidney failure undergoing hemodialysis are at elevated risk for thromboembolic events. Factor (F) XI, which is in the intrinsic pathway of coagulation, is emerging as an attractive target for new anticoagulants that may be safer than existing agents. Osocimab-an inhibitory FXIa antibody-is a potential treatment option for such patients. We conducted a phase 2b, double-blind, placebo-controlled trial, in which 704 participants (448 male, 256 female) with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo. In total, 686 participants (436 male, 250 female) received treatment for ≤18 months (planned minimal treatment period of 6 months). The co-primary outcomes were clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) and a composite of the incidence of moderate, severe or serious adverse events. Clinically relevant bleeding occurred in 16/232 (6.9%) and 11/224 (4.9%) participants who received lower- and higher-dose osocimab, respectively, and in 18/230 participants (7.8%) who received a placebo. For the composite adverse event endpoint, incidences were 51%, 47% and 43% in the lower-dose osocimab, higher-dose osocimab and placebo groups, respectively. These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 .

Fig. 1. Study design.

Overview of the study design. Participants with kidney failure undergoing hemodialysis were randomized to receive lower- or higher-dose osocimab or placebo for ≤18 months. The follow-up period ended 5 months after the last study intervention and 4 months after the end of the main or extension treatment period.

Fig. 2. Patient disposition.

Summary of patient flow in the phase 2b CONVERT trial.

Fig. 3. Osocimab plasma concentrations and effects of osocimab treatment on the activated partial thromboplastin time and inhibition of factor XIa activity.

a, Box plots showing osocimab concentrations. b, Activated partial thromboplastin times relative to baseline values. c, Inhibition of factor XIa activity relative to baseline values. Medians are indicated by the horizontal lines in the boxes; boxes indicate 25th and 75th percentiles; the vertical lines extend to a maximum distance of 1.5 interquartile ranges; values outside of this range are plotted separately. Analyses are based on the pharmacodynamic analysis set, n = 686 (lower-dose osocimab, n = 232; higher-dose osocimab, n = 224; placebo, n = 230).

Extended Data Fig. 1. Cumulative incidence risk (Aalen–Johansen) of the time-to-first treatment-emergent composite of major and clinically relevant nonmajor bleeding (primary outcome; safety analysis set).

Cumulative incidence (%) = Aalen–Johansen estimates of the cumulative probability for an event, calculated as 100 x (1 minus the Aalen–Johansen estimate of the survival function). Overall study period: Only treatment-emergent events that occurred during the overall study period are considered. Treatment-emergent events are those that occurred after the start of the study treatment and until the last dose of the study treatment plus 30 days.

Extended Data Fig. 2. Cumulative incidence risk (Aalen–Johansen) of the time-to-first treatment-emergent moderate, severe, or serious adverse event (primary outcome; safety analysis set).

Cumulative incidence (%) = Aalen–Johansen estimates of the cumulative probability for an event, calculated as 100 x (1 minus the Aalen–Johansen estimate of the survival function). Overall study period: Only treatment-emergent events that occurred during the overall study period are considered. Treatment-emergent events are those that occurred after the start of the study treatment and until the last dose of the study treatment plus 30 days.

Extended Data Fig. 3. Cumulative incidence risk (Aalen–Johansen) of time-to-first arteriovenous fistula or graft thrombosis (exploratory outcome; safety analysis set).

Cumulative incidence (%) = Aalen–Johansen estimates of the cumulative probability for an event, calculated as 100 x (1 minus the Aalen–Johansen estimate of the survival function). Overall study period: Only treatment-emergent events that occurred during the overall study period are considered. Treatment-emergent events are those that occurred after the start of the study treatment and until the last dose of the study treatment plus 30 days.