Pan Hongchao, Peto Richard, Henao-Restrepo Ana-Maria, Preziosi Marie-Pierre, Sathiyamoorthy Vasee, Abdool Karim Quarraisha, Alejandria Marissa M, Hernández García César, Kieny Marie-Paule, Malekzadeh Reza, Murthy Srinivas, Reddy K Srinath, Roses Periago Mirta, Abi Hanna Pierre, Ader Florence, Al-Bader Abdullah M, Alhasawi Almonther, Allum Emma, Alotaibi Athari, Alvarez-Moreno Carlos A, Appadoo Sheila, Asiri Abdullah, Aukrust Pål, Barratt-Due Andreas, Bellani Samir, Branca Mattia, Cappel-Porter Heike B C, Cerrato Nery, Chow Ting S, Como Najada, Eustace Joe, García Patricia J, Godbole Sheela, Gotuzzo Eduardo, Griskevicius Laimonas, Hamra Rasha, Hassan Mariam, Hassany Mohamed, Hutton David, Irmansyah Irmansyah, Jancoriene Ligita, Kirwan Jana, Kumar Suresh, Lennon Peter, Lopardo Gustavo, Lydon Patrick, Magrini Nicola, Maguire Teresa, Manevska Suzana, Manuel Oriol, McGinty Sibylle, Medina Marco T, Mesa Rubio María L, Miranda-Montoya Maria C, Nel Jeremy, Nunes Estevao P, Perola Markus, Portolés Antonio, Rasmin Menaldi R, Raza Aun, Rees Helen, Reges Paula P S, Rogers Chris A, Salami Kolawole, Salvadori Marina I, Sinani Narvina, Sterne Jonathan A C, Stevanovikj Milena, Tacconelli Evelina, Tikkinen Kari A O, Trelle Sven, Zaid Hala, Røttingen John-Arne, Swaminathan Soumya
The affiliations of the members of the writing and steering committees are as follows: the Nuffield Department of Population Health and Medical Research Council Population Health Research Unit, University of Oxford, Oxford (H.P., R.P.), and the University of Bristol, Bristol (E.A., S.B., H.B.C.C.-P., D.H., J.K., C.A.R., J.A.C.S.) - both in the United Kingdom; the World Health Organization, Geneva (A.-M.H.-R., M.-P.P., V.S., P. Lydon, M.C.M.-M., K.S., S.S.), the University of Bern, Bern (S.A., M.B., S. McGinty, S.T.), and Lausanne University Hospital, Lausanne (O.M.) - all in Switzerland; the Centre for the AIDS Programme of Research in South Africa, Durban (Q.A.K.), and the University of the Witwatersrand (J.N.) and the Wits Reproductive Health and HIV Institute (H.R.), Johannesburg - all in South Africa; the Institute of National Epidemiology, National Institutes of Health, University of the Philippines, Manila (M.M.A.); the Agency of Medicine and Medical Devices (C.H.G.) and Hospital Clínico San Carlos, Universidad Complutense de Madrid, Spanish Clinical Research Network, Instituto de Investigación Sanitaria San Carlos (A.P.), Madrid; INSERM, Paris (M.-P.K.), and Hospices Civils de Lyon, Lyon (F.A.) - both in France; the Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran (R.M.); the University of British Columbia, Vancouver (S. Murthy), and the Public Health Agency of Canada, Ottawa (M.I.S.) - both in Canada; the Public Health Foundation of India, New Delhi (K.S.R.), and the Indian Council of Medical Research, National AIDS Research Institute, Pune (S.G.) - both in India; the National Academy of Sciences of Buenos Aires (M.R.P.) and Fundación del Centro de Estudios Infectológicos (G.L.), Buenos Aires; Rafic Hariri University Hospital (P.A.H.) and the Ministry of Public Health (R.H.), Beirut, Lebanon; the Ministry of Health (A.M.A.-B.) and Infectious Diseases Hospital (A. Alhasawi), Kuwait City, Kuwait; Universidad Nacional de Colombia and Clinica Colsanitas (C.A.A.-M.) and the Ministry of Health (M.L.M.R.), Bogota, Colombia; the Ministry for Preventive Health, Riyadh, Saudi Arabia (A. Asiri, A. Alotaibi); Oslo University Hospital (P.A., A.B.-D.) and Research Council of Norway (J.-A.R.), Oslo; Secretaria de Salud de Honduras (N. Cerrato) and the National Autonomous University of Honduras (M.T.M.), Tegucigalpa; Penang Hospital, Penang (T.S.C.), and Hospital Sungai Buloh and Jalan Hospital, Selangor (S.K.) - both in Malaysia; University Hospital Center Mother Theresa (N. Como) and the National Agency for Medicines and Medical Devices (N.S.), Tirana, Albania; the HRB Clinical Research Facility, University College Cork, Cork (J.E.), and the Department of Health and Children, Dublin (P. Lennon, T.M.) - both in Ireland; Universidad Peruana Cayetano Heredia, Lima, Peru (P.J.G., E.G.); Vilnius University Hospital Santaros Klinikos (L.G.) and Vilnius University, Institute of Clinical Medicine (L.J.), Vilnius, Lithuania; Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M. Hassan, A.R.); the National Hepatology and Tropical Medicine Research Institute (M. Hassany) and the Ministry of Health and Population (H.Z.), Cairo; the National Institute of Health Research and Development (I.I.) and Rumah Sakit Umum Pusat Persahabatan (M.R.R.), Jakarta, Indonesia; the Italian Medicines Agency, Rome (N.M.), and the University of Verona, Verona (E.T.) - both in Italy; the Ministry of Health (S. Manevska) and the University Clinic of Infectious Diseases and Febrile Conditions (M.S.), Skopje, North Macedonia; the Oswaldo Cruz Foundation, Rio de Janeiro (E.P.N., P.P.S.R.); and the Finnish Institute for Health and Welfare and the University of Finland (M.P.) and Helsinki University Hospital (K.A.O.T.), Helsinki, and South Karelian Central Hospital, Lappeenranta (K.A.O.T.) - all in Finland.
N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2.
World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).
We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.
At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).
世界卫生组织专家小组建议对四种重新利用的抗病毒药物——瑞德西韦、羟氯喹、洛匹那韦和干扰素β-1a——在因2019冠状病毒病（Covid-19）住院的患者中进行死亡率试验。
我们将Covid-19住院患者随机平均分配到当地可获得的一种试验药物方案和开放对照（最多五个选项，四个活性药物和当地标准治疗）中的一种。意向性治疗的主要分析在每种试验药物与其对照（药物可用但患者被分配到不使用该药物的相同治疗）的四次成对比较中检查住院死亡率。根据年龄和试验入组时的机械通气状态进行分层计算死亡的率比。
在30个国家的405家医院，11330名成年人进行了随机分组；2750人被分配接受瑞德西韦，954人接受羟氯喹，1411人接受洛匹那韦（不使用干扰素），2063人接受干扰素（包括651人接受干扰素加洛匹那韦），4088人不接受试验药物。治疗中期的依从率为94%至96%，交叉率为2%至6%。总共报告了1253例死亡（死亡中位数日为第8天；四分位间距为4至14天）。Kaplan-Meier 28天死亡率为11.8%（如果患者在随机分组时已经接受通气则为39.0%，否则为9.5%）。接受瑞德西韦的2743例患者中有301例死亡，接受其对照的270例8患者中有30例死亡（率比为0.95；95%置信区间[CI]为0.81至1.11；P = 0.50），接受羟氯喹的947例患者中有104例死亡，接受其对照的906例患者中有84例死亡（率比为1.19；95% CI为0.89至1.59；P = 0.23），接受洛匹那韦的1399例患者中有148例死亡，接受其对照的1372例患者中有146例死亡（率比为1.00；95% CI为0.79至1.25；P = 0.97），接受干扰素的2050例患者中有243例死亡，接受其对照的2050例患者中有216例死亡（率比为1.16；95% CI为0.96至1.39；P = 0.11）。没有药物能明确降低总体或任何亚组的死亡率，也没有降低通气启动率或住院时间。
这些瑞德西韦、羟氯喹、洛匹那韦和干扰素方案对Covid-19住院患者的总体死亡率、通气启动率和住院时间几乎没有或没有影响。（由世界卫生组织资助；国际标准随机对照试验编号，ISRCTN83971151；ClinicalTrials.gov编号，NCT04315948。）
