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      Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial

      , MD a , c , , , MD d , , , Prof, PhD e , , , Prof, MD f , , , Prof, MD g , , , Prof, MD h , , , Prof, MD i , , , Prof, MD j , , , Prof, MD k , , , Prof, MD l , , , Prof, MD m , , , Prof, MD n , , , Prof, PhD e , , Prof, PhD e , , MD d , , MS d , , MS d , , MD f , , MD f , , MD g , , MD g , , MD h , , MD h , , MD i , , MD j , , MD k , , MD l , , MD m , , MD n , , MS b , , MD a , , MD a , , PhD b , , MD o , , MD a , p , , MD a , , BD q , , BD q , , BD q , , PhD r , , PhD s , , Prof, PhD t , u , , Prof, MD v , , Prof, MD w , , Prof, MD a , c , x , y , * , , Prof, MD a , x , y , z , **

      Lancet (London, England)

      Elsevier Ltd.

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          No specific antiviral drug has been proven effective for treatment of patients with severe coronavirus disease 2019 (COVID-19). Remdesivir (GS-5734), a nucleoside analogue prodrug, has inhibitory effects on pathogenic animal and human coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro, and inhibits Middle East respiratory syndrome coronavirus, SARS-CoV-1, and SARS-CoV-2 replication in animal models.


          We did a randomised, double-blind, placebo-controlled, multicentre trial at ten hospitals in Hubei, China. Eligible patients were adults (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection, with an interval from symptom onset to enrolment of 12 days or less, oxygen saturation of 94% or less on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen of 300 mm Hg or less, and radiologically confirmed pneumonia. Patients were randomly assigned in a 2:1 ratio to intravenous remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) or the same volume of placebo infusions for 10 days. Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids. The primary endpoint was time to clinical improvement up to day 28, defined as the time (in days) from randomisation to the point of a decline of two levels on a six-point ordinal scale of clinical status (from 1=discharged to 6=death) or discharged alive from hospital, whichever came first. Primary analysis was done in the intention-to-treat (ITT) population and safety analysis was done in all patients who started their assigned treatment. This trial is registered with, NCT04257656.


          Between Feb 6, 2020, and March 12, 2020, 237 patients were enrolled and randomly assigned to a treatment group (158 to remdesivir and 79 to placebo); one patient in the placebo group who withdrew after randomisation was not included in the ITT population. Remdesivir use was not associated with a difference in time to clinical improvement (hazard ratio 1·23 [95% CI 0·87–1·75]). Although not statistically significant, patients receiving remdesivir had a numerically faster time to clinical improvement than those receiving placebo among patients with symptom duration of 10 days or less (hazard ratio 1·52 [0·95–2·43]). Adverse events were reported in 102 (66%) of 155 remdesivir recipients versus 50 (64%) of 78 placebo recipients. Remdesivir was stopped early because of adverse events in 18 (12%) patients versus four (5%) patients who stopped placebo early.


          In this study of adult patients admitted to hospital for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in those treated earlier requires confirmation in larger studies.


          Chinese Academy of Medical Sciences Emergency Project of COVID-19, National Key Research and Development Program of China, the Beijing Science and Technology Project.

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          Most cited references 3

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          Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial

          Abstract Objectives To assess the efficacy and safety of hydroxychloroquine (HCQ) plus standard-of-care (SOC) compared with SOC alone in adult patients with COVID-19. Design Multicenter, open-label, randomized controlled trial. Setting 16 government-designated COVID-19 treatment centers in China through 11 to 29 in February 2020. Participants 150 patients hospitalized with COVID-19. 75 patients were assigned to HCQ plus SOC and 75 were assigned to SOC alone (control group). Interventions HCQ was administrated with a loading dose of 1, 200 mg daily for three days followed by a maintained dose of 800 mg daily for the remaining days (total treatment duration: 2 or 3 weeks for mild/moderate or severe patients, respectively). Main outcome measures The primary endpoint was the 28-day negative conversion rate of SARS-CoV-2. The assessed secondary endpoints were negative conversion rate at day 4, 7, 10, 14 or 21, the improvement rate of clinical symptoms within 28-day, normalization of C-reactive protein and blood lymphocyte count within 28-day. Primary and secondary analysis was by intention to treat. Adverse events were assessed in the safety population. Results The overall 28-day negative conversion rate was not different between SOC plus HCQ and SOC group (Kaplan-Meier estimates 85.4% versus 81.3%, P=0.341). Negative conversion rate at day 4, 7, 10, 14 or 21 was also similar between the two groups. No different 28-day symptoms alleviation rate was observed between the two groups. A significant efficacy of HCQ on alleviating symptoms was observed when the confounding effects of anti-viral agents were removed in the post-hoc analysis (Hazard ratio, 8.83, 95%CI, 1.09 to 71.3). This was further supported by a significantly greater reduction of CRP (6.986 in SOC plus HCQ versus 2.723 in SOC, milligram/liter, P=0.045) conferred by the addition of HCQ, which also led to more rapid recovery of lymphopenia, albeit no statistical significance. Adverse events were found in 8.8% of SOC and 30% of HCQ recipients with two serious adverse events. The most common adverse event in the HCQ recipients was diarrhea (10%). Conclusions The administration of HCQ did not result in a higher negative conversion rate but more alleviation of clinical symptoms than SOC alone in patients hospitalized with COVID-19 without receiving antiviral treatment, possibly through anti-inflammatory effects. Adverse events were significantly increased in HCQ recipients but no apparently increase of serious adverse events. Trial registration ChiCTR2000029868.
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            Group sequential clinical trials with triangular continuation regions.

            In this paper a new class of group sequential procedures for clinical trials is introduced, and the use of these procedures is illustrated by reference to a recently completed comparative study. In a group sequential trial the decision to stop or to continue is made at regular intervals throughout the trial, but not as frequently as after every patient response. This more practical formulation retains most of the advantages of sequential analysis, particularly the economy in sample size. Comparisons are made with group sequential designs derived from the repeated significance test.
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              Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

              Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

                Author and article information

                Lancet (London, England)
                Elsevier Ltd.
                29 April 2020
                29 April 2020
                [a ]Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China
                [b ]Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China
                [c ]Department of Respiratory Medicine, Capital Medical University, Beijing, China
                [d ]Jin Yin-tan Hospital, Wuhan, Hubei, China
                [e ]Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
                [f ]Wuhan Lung Hospital, Wuhan, China
                [g ]Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
                [h ]Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China
                [i ]Wuhan Third Hospital, Wuhan, China
                [j ]Renmin Hospital of Wuhan University, Wuhan, China
                [k ]Zhongnan Hospital of Wuhan University, Wuhan, China
                [l ]Wuhan Fourth Hospital, Wuhan, China
                [m ]The Central Hospital of Wuhan, Wuhan, China
                [n ]Wuhan First Hospital, Wuhan, China
                [o ]Tsinghua University School of Medicine, Beijing, China
                [p ]Beijing University of Chinese Medicine, Beijing, China
                [q ]Tigermed Consulting, Hangzhou, China
                [r ]Teddy Clinical Research Laboratory, Shanghai, China
                [s ]Hangzhou DI'AN Medical Laboratory, Hangzhou, China
                [t ]Lancaster University, Lancaster, UK
                [u ]University of Cambridge, Cambridge, UK
                [v ]University of Virginia School of Medicine, Charlottesville, VA, USA
                [w ]International Severe Acute Respiratory and Emerging Infection Consortium, University of Oxford, Oxford, UK
                [x ]Institute of Respiratory Medicine, Chinese Academy of Medical Science, Beijing, China
                [y ]Tsinghua University–Peking University Joint Center for Life Sciences, Beijiing, China
                [z ]Peking Union Medical College, Beijing, China
                Author notes
                [* ]Correspondence to: Prof Bin Cao, Department of Pulmonary and Critical Care Medicine, China-Japan Friendship Hospital, Beijing 100029, China caobin_ben@
                [** ]Prof Chen Wang, Peking Union Medical College, Beijing 100730, China wangchen@

                Contributed equally

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