Non-immunogenic staphylokinase — a thrombolytic agent in the treatment of massive pulmonary embolism: results of the FORPE clinical trial

Aim . To assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with massive pulmonary embolism and hemodynamic instability. Non-immunogenic staphylokinase is a modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity and fibrin selectivity. Material and methods . This multicenter, open-label, randomized, comparative clinical trial FORPE in two parallel groups was conducted in 23 clinical centers in Russia. A total of 310 patients aged 18 years and older with hemodynamic instability and computed tomography pulmonary angiography verified massive pulmonary embolism and right ventricular dysfunction were included. The patients were randomly assigned in either non-immunogenic staphylokinase (15 mg) or alteplase (100 mg) group. Both medicines were administered intravenously. An independent biostatistician created a randomization sequence using computer-generated random numbers. Randomization was performed using the envelopes. The study was open-label, and emergency unit staff, investigators, and patients were informed about the assigned drug. The primary efficacy endpoint was 7-day all-cause death after randomization. The non-inferiority margin was set at 10% for the difference in 7-day all-cause mortality after randomization between the compared groups. Non-inferiority was tested using the Welch t-test for the primary efficacy endpoint. Secondary efficacy endpoints were analyzed in both the intention-to-treat and per-protocol populations. Results . Of 348 patients screened between December 25, 2020, and July 31, 2023, 310 (89%) were included in the study. Of the total number, 155 (50%) patients were randomized to the non-immunogenic staphylokinase group and 155 (50%) to the alteplase group. In the non-immunogenic staphylokinase group, the primary efficacy endpoint, 7-day all-cause death, was 2% in the intent-to-treat population and 2% in the per-protocol population, whereas in the alteplase group it was 3% (odds ratio (OR) 0,75, 95% confidence interval (CI) 0,11-4,49; p=1,00) and 3% (OR 0,75, 95% CI 0,11-4,52; p=1,00), respectively. The difference in the primary efficacy endpoint was 0,6% (95% CI -2,8 to -4,0) in the intent-to-treat population and 0,6% (95% CI -2,9 to -4,2) in the per-protocol population. Thus, the lower limit of the 95% CI did not cross the non-inferiority margin (p