Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score <7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of <24 hours. While patients scheduled for surgery in <12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

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