Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial

• Published in: Lancet neurology 2021-09, Vol.20 (9), p.721-728
• Main Authors: Gusev, Eugene I, Martynov, Mikhail Yu, Nikonov, Alexey A, Shamalov, Nikolay A, Semenov, Michail P, Gerasimets, Eugene A, Yarovaya, Elena B, Semenov, Andrey M, Archakov, Alexander I, Markin, Sergey S, Aksentiev, Sergey B, Yunevich, Denis S., Alasheev, Andrey M, Androfagina, Olga V, Bobkov, Vladimir V, Choroshavina, Ksenia V, Chefranova, Janna Yu, Lykov, Yuriy A, Chuprina, Svetlana E, Vorobev, Andrey A, Dobrovolskiy, Alexey V, Elemanov, Ulukpan A, Fedaynin, Sergey A, Gorbachev, Vladimir I, Korobeinikov, Ivan V, Greshnova, Irina V, Korsunskaya, Larisa L, Nikonova, Anastasiya A, Kudinov, Vasily A, Artyushev, Rafael I, Kutsenko, Vladimir A, Nesterova, Valentina N, Nizov, Alexey A, Girivenko, Alexey I, Orlovsky, Alexey A, Ponomarev, Eduard A, Popov, Dmitriy V, Pribylov, Sergey A, Semikhin, Alexander S, Timchenko, Ludmila V, Jadan, Olga N, Zakharov, Sergey A, Chirkov, Alexander N, Zhukovskaya, Natalya V
• Format: Article
• Language: English
• Subjects: Adverse events; Angiography; Clinical trials; Drug dosages; Emergency medical care; Envelopes; Fibrin; Heart attacks; Hemorrhage; Immunogenicity; Intravenous administration; Ischemia; Medical research; Mortality; Patients; Reperfusion; Staphylokinase; Stroke; Thrombolysis
• ISSN: 1474-4422; 1474-4465
• DOI: 10.1016/S1474-4422(21)00210-6

Non-immunogenic staphylokinase is modified recombinant staphylokinase with low immunogenicity, high thrombolytic activity, and selectivity to fibrin. We aimed to assess the safety and efficacy of a single intravenous bolus of non-immunogenic staphylokinase compared with alteplase in patients with acute ischaemic stroke within 4·5 h after symptom onset. We did a randomised, open-label, multicentre, parallel-group, non-inferiority trial in 18 clinical sites in Russia. We included patients aged 18 years and older with a diagnosis of acute ischaemic stroke (up to 25 points on the National Institutes of Health Stroke Scale). The study drug had to be administered within 4·5 h after the onset of symptoms. Patients were randomly assigned to receive either non-immunogenic staphylokinase (10 mg) or alteplase (0·9 mg/kg, maximum 90 mg), both administered intravenously. The randomisation sequence was created by an independent biostatistician using computer-generated random numbers. 84 blocks (block size of four) of opaque sealed envelopes were numbered sequentially from 1 to 336 and were opened in numerical order. Patients were unaware of their assigned treatment and were assessed by the study investigators who were also unaware of the treatment assignment on all trial days. Emergency department staff, who administered the assigned drug and opened the envelopes, were not masked to treatment. The primary efficacy endpoint was a favourable outcome, defined as a modified Rankin scale (mRS) score of 0–1 on day 90. The margin of non-inferiority was established as 16% for the difference in mRS score of 0–1 on day 90. Non-inferiority was tested using Welch's t-test for the primary outcome only. Endpoints were analysed in the per-protocol population, which comprised all randomly assigned patients who completed treatment without any protocol violations; this population was identical to the intention-to-treat population. This trial is completed and registered at ClinicalTrials.gov, NCT03151993. Of 385 patients recruited from March 18, 2017, to March 23, 2019, 336 (87%) were included in the trial. 168 (50%) patients were randomly assigned to receive non-immunogenic staphylokinase and 168 (50%) to receive alteplase. The median duration of follow-up was 89 days (IQR 89–89). 84 (50%) of 168 patients in the non-immunogenic staphylokinase group had a favourable outcome at day 90 compared with 68 (40%) of 168 patients in the alteplase group (odds ratio [OR] 1·47, 95% CI 0·93 to 2·32;