Randomized active-controlled trial of safety and pharmacodynamics of two blinded doses of RBD4059 (vortosiran) versus apixaban in non-valvular atrial fibrillation

The primary objective is to evaluate the effect of vortosiran on the percent change from baseline in factor XI (FXI) activity at Week 16, thereby assessing the potential of FXI modulation to reduce thromboembolic risk while maintaining hemostatic balance in patients with non-valvular atrial fibrillation. The secondary objectives include:

• Assessment of safety, specifically the frequency and severity of bleeding events, with subcutaneously administered vortosiran compared with apixaban.
• Evaluation of safety, including bleeding outcomes, when vortosiran is co‑administered with apixaban.
• Quantification of absolute and percentage changes from baseline in FXI activity and FXI antigen levels at each evaluable time point.
• Characterization of plasma exposure of vortosiran.
• Measurement of anti‑drug antibodies to determine immunogenicity, if indicated by emerging safety, pharmacokinetic, or pharmacodynamic data.
• Investigation of the impact of vortosiran on coagulation biomarkers, namely activated partial thromboplastin time (aPTT) and prothrombin time/international normalized ratio (PT/INR).
• Evaluation of the effect of vortosiran on additional exploratory parameters (designated xx).

The sponsor did not provide the total number of participants. Eligible individuals were adults aged ≥ 45 years of either sex, with a documented diagnosis of non-valvular atrial fibrillation made within the previous 12 months and confirmed by electrocardiographic evidence. All participants were required to have been receiving continuous treatment with a direct oral anticoagulant for stroke prevention for at least three months prior to enrollment and to be capable of providing signed informed consent. The trial population comprised patients meeting these clinical criteria; no additional information on lifestyle factors such as diet or physical activity was supplied.

The study is a randomized, double‑blind, active‑controlled Phase IIb trial evaluating two blinded dose levels of vortosiran administered subcutaneously against open‑label apixaban 10 mg daily in patients with non-valvular atrial fibrillation. After obtaining written informed consent, eligible participants undergo a screening visit to confirm eligibility criteria, followed by a baseline visit on which participants are randomized to receive either vortosiran or matching placebo in addition to apixaban. Treatment continues for 16 weeks, with scheduled follow‑up visits at weeks 4, 8, 12 and 16 to assess safety, pharmacodynamics, and plasma concentrations; the primary efficacy endpoint is the percent change from baseline in FXI activity at week 16. An end‑of‑study visit occurs after the final assessment to finalize data collection. Participant involvement therefore spans approximately 18 weeks, including screening. Early termination may occur if a participant experiences a serious adverse event related to the study drug, withdraws consent, fails to adhere to the protocol, or if the investigator determines that continuation is not in the participant’s best interest.

The investigational product, RBD4059, is supplied as a sterile injection for subcutaneous administration. Each dose contains 0 mg of the active substance in a single‑use vial. Dosing is performed according to the predefined study schedule, with each injection administered under direct observation to ensure proper technique and timing.

The active‑controlled comparator, apixaban, is provided in tablet form (pharmaceutical code PHF00099MIG). The tablet strength is 10 mg and is taken orally. Administration follows the trial‑specified regimen, with dosing recorded in the participant’s medication log and compliance verified by pill count at each visit.

The placebo consists of a 25 mm phosphate buffer solution containing 2 µg of vitamin B2 for colour identification only. It is presented in a matching injection device and administered subcutaneously on the same schedule as the investigational product. Placebo administration is blinded, and adherence is monitored in the same manner as active treatments.

Efficacy will be assessed primarily by the percentage change from baseline in FXI activity measured at Week 16. Blood samples for FXI activity will be collected at screening (baseline) and at the Week 16 visit, and the change will be calculated relative to the baseline value.

Secondary efficacy evaluations will include the absolute and percentage change from baseline in FXI activity at additional predefined time points throughout the trial, as well as changes in activated partial thromboplastin time (APTT) and prothrombin time/international normalized ratio (PT/INR) over the study period. All laboratory assessments will be performed using validated assays, and the resulting data will be summarized descriptively and analyzed according to the statistical analysis plan.