Background: Hyaluronan is an emerging target for COVID-19 and lung fibrosis. In an open-label study the hyaluronidase bovhyaluronidase azoximer (BA) was associated with improved pulmonary function and exercise tolerance in patients with pulmonary sequelae of COVID-19. In this randomized, double-blind, placebo-controlled trial we evaluated the effect of BA on patients up to 12 months after COVID-19, characterized by reduced pulmonary function, dyspnea, and decreased oxygen saturation. Methods: Patients (n=392) were randomized 1:1 to receive BA (3000U) or placebo every 5 days for 71 days. Percent of predicted forced vital capacity (ppFVC), respiratory symptoms, and exercise tolerance indicators were assessed at baseline and on days 71 and 180. The primary endpoint was a change from baseline in ppFVC by Day 71. Results: On Day 71, BA was associated with a significant reduction in the proportion of patients with exertional desaturation (OR=0.35, p=0.0051) and dyspnea (OR=0.62, p=0.043). There were no significant intergroup differences in the ppFVC growth rate. Analysis of sub-populations revealed that by Day 180, BA was associated with increased ppFVC in patients with cardiovascular comorbidities (diff=3.31%, p=0.042) and those with earlier SARS-CoV-2 infection (diff=4.17%, p=0.021). BA was generally safe and well-tolerated. Conclusion: In patients with long-term pulmonary sequelae of COVID-19, BA was associated with increased exercise tolerance. There was evidence of shorter pulmonary function recovery time following BA in patients with cardiovascular comorbidities and those with earlier COVID-19 disease.

Sergey N Avdeev reports personal fees (for speaking and consultancy). Galina L. Ignatova reports personal fees (for speaking). Veronica B. Popova has nothing to disclose. Ekaterina V. Melnikova has nothing to disclose. Tatiana I. Chudinovskikh has nothing to disclose. Olga V. Ryabova has nothing to disclose. Natalia V. Egorova has nothing to disclose. Tamara V. Rubanik reports personal fees (for speaking). Yury G. Shvarts has nothing to disclose. Svetlana A. Polyakova has nothing to disclose. Anna V. Antonova, Dmitry A. Zubkov, Mikhail S. Khmelevskii, Nadezhda F. Khomyakova, Mikhail A. Tsyferov, and Anton A. Tikhonov are employers of NPO Petrovax Pharm LLC. Tim C Hardman is the owner of Science & Technology Ltd. who assisted with study delivery and has nothing to disclose.

NCT06383819

Study was funded by NPO Petrovax Pharm LLC. BA and matching placebo were produced and supplied by NPO Petrovax Pharm LLC.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study was independently approved by the following ethics committees: 1. Ethics Committee of the Russuan Ministry of Health, Moscow, Russia 2. Local Independent Ethics Committee of Regional Clinical Hospital No. 3, State Budgetary Healthcare Institution, Chelyabinsk, Russia 3. Independent Ethics Committee of Kuzbass Clinical Emergency Medical Hospital named after M.A. Podgorbunsky, State Autonomous Healthcare Institution, Kemerovo, Russia 4. Local Ethics Committee of the Medical Center "Reavita Med SPb," Therapy Department, LLC, St. Petersburg, Russia 5. Ethics Committee of the Medical Center for Diagnostics and Prevention Plus, LLC, Yaroslavl, Russia 6. Ethics Committee of the Consultative and Diagnostic Center No. 85, St. Petersburg State Budgetary Healthcare Institution, St. Petersburg, Russia 7. Independent Ethics Committee of the Siberian State Medical University, Federal State Budgetary Educational Institution of Higher Education, Ministry of Health of the Russian Federation, Tomsk, Russia 8. Ethics Committee of the Northern Medical Clinical Center named after N.A. Semashko, Federal State Budgetary Healthcare Institution, Federal Medical-Biological Agency, Arkhangelsk, Russia 9. Local Ethics Committee of Kirov State Medical University, Federal State Budgetary Educational Institution of Higher Education, Ministry of Health of the Russian Federation, Kirov, Russia 10. Local Ethics Committee of the First Moscow State Medical University named after I. M. Sechenov, Federal State Autonomous Educational Institution of Higher Education, Ministry of Health of the Russian Federation; University Clinical Hospital No. 4, Moscow, Russia 11. Local Ethics Committee of Alliance Biomedical-Ural Group, LLC, Izhevsk, Russia 12. Ethics Committee of the National Medical Research Center for Phthisiopulmonology and Infectious Diseases, Federal State Budgetary Healthcare Institution, Ministry of Health of the Russian Federation; Ural Research Institute of Phthisiopulmonology, Yekaterinburg, Russia 13. Local Ethics Committee of Kazan State Medical University, Federal State Budgetary Educational Institution of Higher Education, Ministry of Health of the Russian Federation, Kazan, Russia 14. Local Ethics Committee of UNIMED-S, CJSC, Moscow, Russia 15. Ethics Committee of Voronezh Regional Clinical Hospital No. 1, Budgetary Healthcare Institution of the Voronezh Region, Voronezh, Russia 16. Ethics Committee of Research Center Eco-Safety, LLC, St. Petersburg, Russia 17. Ethics Committee of the Clinical Hospital "RZD-Medicine" in Chelyabinsk, Private Healthcare Institution, Chelyabinsk, Russia 18. Local Ethics Committee of Medical Center "Reavita Med SPb," Rehabilitation Department, LLC, St. Petersburg, Russia 19. Local Ethics Committee of Ivanovo State Medical Academy, Federal State Budgetary Educational Institution of Higher Education, Ministry of Health of the Russian Federation, Kakhma, Russia 20. Ethics Committee of the National Medical Research Center for Therapy and Preventive Medicine, Federal State Budgetary Healthcare Institution, Ministry of Health of the Russian Federation, Moscow, Russia 21. Local Ethics Committee of Clinical Hospital No. 9, State Autonomous Healthcare Institution of the Yaroslavl Region, Yaroslavl, Russia 22. Local Ethics Committee of Energy of Health, LLC, St. Petersburg, Russia 23. Ethics Committee of Engels City Clinical Hospital No. 1, State Autonomous Healthcare Institution, Engels, Russia 24. Local Ethics Committee of Astarta, LLC, St. Petersburg, Russia 25. Ethics Committee of the City Consultative and Diagnostic Center No. 1, St. Petersburg State Budgetary Healthcare Institution, St. Petersburg, Russia 26. Independent Ethics Committee of Regional Clinical Hospital, State Healthcare Institution, Saratov, Russia 27. Ethics Committee of Professor's Clinic, LLC, Perm, Russia 28. Ethics Committee of RC Medical, LLC, Novosibirsk, Russia 29. Ethics Committee of the Consultative and Diagnostic Center with Polyclinic, Federal State Budgetary Institution, Presidential Administration of the Russian Federation, St. Petersburg, Russia 30. Ethics Committee of the Central Research Institute of Epidemiology, Federal Budgetary Institution of Science, Federal Service for Surveillance on Consumer Rights Protection and Human Wellbeing, Moscow, Russia 31. Ethics Committee of X7 Clinical Research, LLC, St. Petersburg, Russia 32. Ethics Committee of the Group of Companies Persona, LLC, Nizhny Novgorod, Russia 33. Ethics Committee of Aramil City Hospital, State Autonomous Healthcare Institution of the Sverdlovsk Region, Aramil, Russia 34. Ethics Committee of the Russian Scientific Center of Surgery named after Academician B.V. Petrovsky, Federal State Budgetary Scientific Institution, Moscow, Russia 35. Ethics Committee of Clinical Hospital No. 1, Regional State Budgetary Healthcare Institution, Smolensk, Russia 36. Local Ethics Committee of Saratov State Medical University named after V.I. Razumovsky, Federal State Budgetary Educational Institution of Higher Education, Ministry of Health of the Russian Federation; University Clinical Hospital No. 1 named after S.R. Mirotvortsev, Saratov, Russia 37. Ethics Committee of the Hospital for War Veterans of Kazan, State Autonomous Healthcare Institution, Kazan, Russia 38. Ethics Committee of Medical Center "Revma-Med," LLC, Kemerovo, Russia

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data forms a part of an ongoing research programme. Authors have the intention is to make the data publicly available once the programme is complete.