An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19

被引:26
作者
Fu, Weihui [1 ,2 ]
Liu, Yan [1 ,2 ]
Liu, Li [1 ,2 ]
Hu, Huiliang [1 ,2 ]
Cheng, Xiaobo [1 ,2 ]
Liu, Ping [1 ,2 ]
Song, Zhigang [1 ,2 ]
Zha, Lijun [1 ,2 ]
Bai, Shimeng [1 ,2 ]
Xu, Tingting [1 ,2 ]
Yuan, Songhua [1 ,2 ]
Lu, Fengru [1 ,2 ]
Shang, Zhiying [1 ,2 ]
Zhao, Yihong [1 ,2 ]
Wang, Jing [1 ,2 ]
Zhao, Jun [1 ,2 ]
Ding, Longfei [1 ,2 ]
Chen, Jun [1 ,2 ]
Zhang, Lin [1 ,2 ]
Zhu, Tongyu [1 ,2 ]
Zhang, Xiaoyan [1 ,2 ]
Lu, Hongzhou [1 ,2 ]
Xu, Jianqing [1 ,2 ]
机构
[1] Fudan Univ, Shanghai Med Coll, Shanghai Publ Hlth Clin Ctr, 2901 Caolang Rd, Shanghai 201508, Peoples R China
[2] Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, 2901 Caolang Rd, Shanghai 201508, Peoples R China
基金
美国国家科学基金会;
关键词
COVID-19; SARS-CoV-2; TFF2; IFN-kappa; Clinical tiral; Aerosol inhalation; Treatment; INFLAMMATION; LOPINAVIR/RITONAVIR; CORONAVIRUS; INFECTION; MODEL; SARS;
D O I
10.1016/j.eclinm.2020.100547
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Epidemic outbreaks caused by SARS-CoV-2 are worsening around the world, and there are no target drugs to treat COVID-19. IFN-kappa inhibits the replication of SARS-CoV-2; and TFF2 is a small secreted polypeptide that promotes the repair of mucosal injury and reduces the inflammatory responses. We used the synergistic effect of both proteins to treat COVID-19. Methods: We conducted an open-label, randomized, clinical trial involving patients with moderate COVID-19. Patients were assigned in a 1:1 ratio to receive either aerosol inhalation treatment with IFN-kappa and TFF2 every 24 h for six consecutive dosages in addition to standard care (experimental group) or standard care alone (control group). The primary endpoint was the time until a viral RNA negative conversion for SARS-CoV-2 in all clinical samples. The secondary clinical endpoint was the time of CT imaging improvement. Data analysis was performed per protocol. This study was registered with chictr.org.cn, ChiCTR2000030262. Findings: Between March 23 and May 23 of 2020, 86 COVID-19 patients with symptoms of moderate illness were recruited, and 6 patients were excluded due to not matching the inclusion criteria (patients with pneumonia through chest radiography). Among the remaining 80 patients, 40 patients were assigned to experimental group, and the others were assigned to control group to only receive standard care. Efficacy and safety were evaluated for both groups. The time of viral RNA negative conversion in experimental group (Mean, 3.80 days, 95% CI 2.07-5.53), was significantly shorter than that in control group (7.40 days, 95% CI 4.57 to 10.23) (p = 0.031), and difference between means was 3.60 days. The percentage of patients in experimental group with reversion to negative viral RNA was significantly increased compared with control group on all sampling days (every day during the 12-day observation period) (p = 0.037). For the secondary endpoint, the experimental group had a significantly shorter time until improvement was seen by CT (Mean 6.21 days, N = 38/40, 95% CI 5.11-7.31) than that in control group (8.76 days, N = 34/40, 95% CI 7.57-9.96) (p = 0.002), and difference between means was 2.55 days. No discomfort or complications during aerosol inhalation were reported to the nurses by any experimental patients. Interpretation: In conclusion, we found that aerosol inhalation of IFN-kappa plus TFF2 in combination with standard care is safe and superior to standard care alone in shortening the time up to viral RNA negative conversion in all clinical samples. In addition, the patients in experimental group had a significantly shortened CT imaging improvement time than those in control group. This study suggested that this combination treatment is able to facilitate clinical improvement (negative for virus, improvement by CT, reduced hospitalization stay) and thereby result in an early release from the hospital. These data support the need for exploration with a large-scale trial of IFN-kappa plus TFF2 to treat COVID-19. (C) 2020 The Authors. Published by Elsevier Ltd.
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页数:11
相关论文
共 40 条
[1]   Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease [J].
Agostini, Maria L. ;
Andres, Erica L. ;
Sims, Amy C. ;
Graham, Rachel L. ;
Sheahan, Timothy P. ;
Lu, Xiaotao ;
Smith, Everett Clinton ;
Case, James Brett ;
Feng, Joy Y. ;
Jordan, Robert ;
Ray, Adrian S. ;
Cihlar, Tomas ;
Siegel, Dustin ;
Mackman, Richard L. ;
Clarke, Michael O. ;
Baric, Ralph S. ;
Denison, Mark R. .
MBIO, 2018, 9 (02)
[2]  
[Anonymous], 2017, common terminology criteria for adverse events (CTCAE) version 5.0
[3]  
Beigel JH, 2020, NEW ENGL J MED, V383, P1813, DOI [10.1056/NEJMc2022236, 10.1056/NEJMoa2007764]
[4]   Antiviral activity of transiently expressed IFN-κ is cell-associated [J].
Buontempo, PJ ;
Jubin, RG ;
Buontempo, CA ;
Wagner, NE ;
Reyes, GR ;
Baroudy, BM .
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH, 2006, 26 (01) :40-52
[5]  
Cao B, 2020, NEW ENGL J MED, V382, P1787, DOI [10.1056/NEJMc2008043, 10.1056/NEJMoa2001282]
[6]   Broad-spectrum antivirals for the emerging Middle East respiratory syndrome coronavirus [J].
Chan, Jasper F. W. ;
Chan, Kwok-Hung ;
Kao, Richard Y. T. ;
To, Kelvin K. W. ;
Zheng, Bo-Jian ;
Li, Clara P. Y. ;
Li, Patrick T. W. ;
Dai, Jun ;
Mok, Florence K. Y. ;
Chen, Honglin ;
Hayden, Frederick G. ;
Yuen, Kwok-Yung .
JOURNAL OF INFECTION, 2013, 67 (06) :606-616
[7]   Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset [J].
Chan, Jasper Fuk-Woo ;
Yao, Yanfeng ;
Yeung, Man-Lung ;
Deng, Wei ;
Bao, Linlin ;
Jia, Lilong ;
Li, Fengdi ;
Xiao, Chong ;
Gao, Hong ;
Yu, Pin ;
Cai, Jian-Piao ;
Chu, Hin ;
Zhou, Jie ;
Chen, Honglin ;
Qin, Chuan ;
Yuen, Kwok-Yung .
JOURNAL OF INFECTIOUS DISEASES, 2015, 212 (12) :1904-1913
[8]   In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds [J].
Chen, F ;
Chan, KH ;
Jiang, Y ;
Kao, RYT ;
Lu, HT ;
Fan, KW ;
Cheng, VCC ;
Tsui, WHW ;
Hung, IFN ;
Lee, TSW ;
Guan, Y ;
Peiris, JSM ;
Yuen, KY .
JOURNAL OF CLINICAL VIROLOGY, 2004, 31 (01) :69-75
[9]  
Chen Z, Multiscale Modeling Simulation
[10]   Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings [J].
Chu, CM ;
Cheng, VCC ;
Hung, IFN ;
Wong, MML ;
Chan, KH ;
Chan, KS ;
Kao, RYT ;
Poon, LLM ;
Wong, CLP ;
Guan, Y ;
Peiris, JSM ;
Yuen, KY .
THORAX, 2004, 59 (03) :252-256