Methylprednisolone Pulses Plus Tacrolimus in Addition to Standard of Care vs. Standard of Care Alone in Patients With Severe COVID-19. A Randomized Controlled Trial

Frontiers in Medicine

article

Xavier Solanich¹  Jordi Bas²  Vanesa Vicens-Zygmunt⁴  Jordi Niubó⁵  Nahum Calvo⁶  Santiago Bolivar⁶  Raúl Rigo-Bonnin⁷  Anna Mensa-Vilaró⁸  Laura Arregui⁹  Cristian Tebe²  Sebastià Videla²  Arnau Antolí¹  Pilar Hereu²  Xavier Corbella¹  Gemma Rocamora-Blanch¹  Núria Padullés^1,14  Marta Fanlo-Maresma¹  Adriana Iriarte¹  Francesca Mitjavila¹  Olga Capdevila¹  Antoni Riera-Mestre¹ 

[1] Department of Internal Medicine, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Faculty of Medicine and Health Sciences, Universitat de Barcelona;Department of Immunology, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Department of Pneumology, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Department of Microbiology, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Department of Diagnostic Imaging, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Department of Clinical Laboratory, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Department of Immunology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer;Spanish Clinical Research Network, Bellvitge Biomedical Research Institute (IDIBELL);Department of Biostatistics, Bellvitge Biomedical Research Institute (IDIBELL);Department of Clinical Pharmacology, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL);Clinical Research and Clinical Trial Unit (UICEC-IDIBELL), Spanish Clinical Research Network, Bellvitge Biomedical Research Institute (IDIBELL);School of Medicine, Universitat Internacional de Catalunya;Department of Pharmacy, Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL)

关键词: COVID-19;    SARS-CoV-2;    methylprednisolone;    tacrolimus;    inflammation;    lung injury;   

DOI  :  10.3389/fmed.2021.691712

学科分类：社会科学、人文和艺术（综合）

来源: Frontiers

【 摘 要 】

Introduction: Severe lung injury is triggered by both the SARS-CoV-2 infection and the subsequent host-immune response in some COVID-19 patients. Methods: We conducted a randomized, single-center, open-label, phase II trial with the aim to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus plus standard of care (SoC) vs. SoC alone, in hospitalized patients with severe COVID-19. The primary outcome was time to clinical stability within 56 days after randomization. Results: From April 1 to May 2, 2020, 55 patients were prospectively included for subsequent randomization; 27 were assigned to the experimental group and 28 to the control group. The experimental treatment was not associated with a difference in time to clinical stability (hazard ratio 0.73 [95% CI 0.39–1.37]) nor most secondary outcomes. Median methylprednisolone cumulative doses were significantly lower (360 mg [IQR 360–842] vs. 870 mg [IQR 364–1451]; p = 0.007), and administered for a shorter time (median of 4.00 days [3.00–17.5] vs. 18.5 days [3.00–53.2]; p = 0.011) in the experimental group than in the control group. Although not statistically significant, those receiving the experimental therapy showed a numerically lower all-cause mortality than those receiving SoC, especially at day 10 [2 (7.41%) vs. 5 (17.9%); OR 0.39 (95% CI 0.05–2.1); p = 0.282]. The total number of non-serious adverse events was 42 in each the two groups. Those receiving experimental treatment had a numerically higher rate of non-serious infectious adverse events [16 (38%) vs. 10 (24%)] and serious infectious adverse events [7 (35%) vs. 3 (23%)] than those receiving SoC. Conclusions: The combined use of methylprednisolone pulses plus tacrolimus, in addition to the SoC, did not significantly improve the time to clinical stability or other secondary outcomes compared with the SoC alone in severe COVID-19. Although not statistically significant, patients receiving the experimental therapy had numerically lower all-cause mortality than those receiving SoC, supporting recent non-randomized studies with calcineurin inhibitors. It is noteworthy that the present trial had a limited sample size and several other limitations. Therefore, further RCTs should be done to assess the efficacy and safety of tacrolimus to tackle the inflammatory stages of COVID-19. Clinical Trial Registration: Identifier [NCT04341038/EudraCT: 2020-001445-39].

【 授权许可】

CC BY