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{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T3","span":{"begin":3329,"end":3341},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T4","span":{"begin":5706,"end":5718},"obj":"http://purl.obolibrary.org/obo/GO_0006954"},{"id":"T5","span":{"begin":8583,"end":8593},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T6","span":{"begin":11079,"end":11094},"obj":"http://purl.obolibrary.org/obo/GO_0061025"},{"id":"T7","span":{"begin":11756,"end":11767},"obj":"http://purl.obolibrary.org/obo/GO_0140253"},{"id":"T8","span":{"begin":11756,"end":11767},"obj":"http://purl.obolibrary.org/obo/GO_0045026"},{"id":"T9","span":{"begin":11756,"end":11767},"obj":"http://purl.obolibrary.org/obo/GO_0000768"},{"id":"T10","span":{"begin":11756,"end":11767},"obj":"http://purl.obolibrary.org/obo/GO_0000747"},{"id":"T11","span":{"begin":11791,"end":11804},"obj":"http://purl.obolibrary.org/obo/GO_0070085"},{"id":"T12","span":{"begin":19246,"end":19258},"obj":"http://purl.obolibrary.org/obo/GO_0006954"}],"text":"Table 2 Available and ongoing RCT on anti-infective and anti-inflammatory drugs most provided as off-label/compassionate treatments in the first phase of the COVID-19 pandemic\nDrug Class/mechanism Published RCT Ongoing RCT for treatment/prevention of COVID-19 (recruiting or not yet recruiting) registered at ClinicalTrials.gov\nLopinavir/ritonavir Lopinavir is an HIV type 1 protease inhibitor. Ritonavir is a CYP3A4 inhibitor that boosts lopinavir concentrations • Open-label RCT comparing lopinavir/ritonavir (99 patients) vs. standard of care (100) in patients with COVID-19 in China. Lopinavir/ritonavir was administered at the dosage of 400/100 mg for 14 days. The primary time-to-event endpoint was clinical improvement from randomization. In the primary study population (ITT), no statistically significant differences were observed with regard to the primary endpoint of clinical improvement (HR 1.24 with standard of care as reference, 95% CI 0.90 to 1.72) and the secondary endpoint of 28-day mortality (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7). In the mITT population, lopinavir/ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care. Median time between symptoms onset and randomization was 13 days (IQR 11–16) [22] • Comparison of lopinavir/ritonavir vs. hydroxychloroquine in patients with mild COVID-19. Open-label RCT (NCT04307693, recruiting). Primary endpoint: virus load at day 3, 5, 7, 10, 14 and 18.\n• Comparison of ASC09/ritonavir vs. lopinavir/ritonavir in patients with confirmed COVID-19 pneumoniae. Open-label RCT (NCT04261907, not yet recruiting). Primary endpoint: adverse outcome at day 14 (composite of Spo 2 ≤ 93% without oxygen supplementation, PaO2/FiO2 ≤ 300 mm Hg or respiratory rate ≥ 30 breaths per minute).\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus umifenovir in patients with COVID-19. Open-label RCT (NCT04252885, recruiting). Primary endpoint: rate of virus inhibition at day 0, 2, 4, 7, 10, 14 and 21.\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus ribavirin plus interferon beta 1b in patients with COVID-19. Open-label RCT (NCT04276688, recruiting). Primary endpoint: time to negative nasopharyngeal swab RT-PCR (follow-up 30 days).\n• Comparison of only supportive treatment vs. lopinavir/ritonavir vs. oseltamivir vs. umifenovir in patients with confirmed COVID-19 pneumonia. Open-label RCT (NCT04255017, recruiting). Primary endpoints: (a) rate of disease remission (mild disease: fever, cough and other symptoms relieved with improved lung CT; severe disease: fever, cough and other symptoms relieved with improved lung CT, Spo 2 \u003e 93% or Pao 2/Fio 2 \u003e 300 mm Hg); (b) time to lung recovery.\n• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19. Double-blind RCT (NCT04328285, not yet recruiting). Primary endpoint: occurrence of a symptomatic or asymptomatic COVID-19 (follow-up 2.5 months).\n• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia. Open-label RCT (NCT04286503, not yet recruiting). Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus xiyanping (injectable component derived from a plant used in traditional Chinese medicine) in patients with COVID-19. Open-label RCT (NCT04295551, not yet recruiting). Primary endpoint: clinical recovery time (follow-up 28 days).\n• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus xiyanping injection in patients with COVID-19. Open-label RCT (NCT04275388, not yet recruiting). Primary endpoint: clinical recovery time (follow-up 14 days).\n• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus traditional Chinese medicines in patients with COVID-19. Open-label RCT (NCT04251871, recruiting). Primary endpoint: time to complete remission of symptoms (follow-up 28 days).\n• Comparison of lopinavir/ritonavir plus hydroxychloroquine vs. lopinavir/ritonavir plus hydroxychloroquine plus levamisole pill plus budesonide plus formoterol inhaler in patients with nonsevere COVID-19 pneumonia. Partly blinded RCT (NCT04331470, not yet recruiting). Primary endpoint: (a) clear CT scan at 3–7 days; (b) negative RT-PCR at 3–7 days.\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19. Double-blind, adaptive RCT (NCT04328012, not yet recruiting). Primary endpoint: NIAID COVID-19 ordinal severity scale (follow-up 60 days).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\n• Comparison of lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) vs. natural honey plus lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) in patients with COVID-19. Single-blind RCT (NCT04323345, not yet recruiting). Primary endpoints: (a) positive to negative swabs at day 14; (b) fever to normal temperature in days (follow-up 14 days); (c) resolution of lung inflammation in CT or X-ray (follow-up 30 days).\n• Comparison of colchicine (with or without lopinavir/ritonavir) vs. local standard of care in patients with moderate to severe COVID-19. Open-label RCT (NCT04328480, not yet recruiting). Primary endpoint: all-cause mortality (follow-up 30 days).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\nRemdesivir Adenosine analogue. It binds to RNA-dependent RNA polymerase and acts as an RNA-chain terminator • Not available • Comparison of remdesivir vs. placebo in patients with severe COVID-19. Double-blind RCT (NCT04257656, recruiting). Primary endpoint: clinical status, assessed by an ordinal scale at days 7, 14, 21 and 28.\n• Comparison of remdesivir vs. placebo in patients with mild to moderate COVID-19. Double-blind RCT (NCT04252664, recruiting). Primary endpoint: time to clinical recovery in hours (follow-up 28 days).\n• Comparison of remdesivir vs. local standard of care in patients with severe COVID-19. Open-label RCT (NCT04252664, recruiting). Primary endpoint: composite of fever normalization and oxygen saturation normalization (follow-up 14 days).\n• Comparison of remdesivir vs. local standard of care in patients with moderate COVID-19. Open-label RCT (NCT04292730, recruiting). Primary endpoint: discharged status at day 14.\n• Comparison of remdesivir vs. placebo in patients with COVID-19. Double-blind RCT (NCT04280705, recruiting). Primary endpoint: severity rating on a 8-point ordinal scale at day 15.\n• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19. Open-label adaptive RCT (NCT04321616, not yet recruiting). Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\nDarunavir/cobicistat Darunavir is an HIV type 1 protease inhibitor. Cobicistat is a CYP3A4 inhibitor that boosts darunavir concentrations • Not available • Comparison of darunavir/cobicistat vs. standard of care in patients with COVID-19 pneumonia. Open-label RCT (NCT04252274, recruiting). Primary endpoint: virologic clearance rate of throat swabs, sputum or lower respiratory tract secretions at day 7.\nFavipiravir Anti-influenza RNA-dependent RNA polymerase inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir. The manuscript is publicly available but still to be peer reviewed [30] • Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19. Open-label RCT (NCT04310228, recruiting). Primary endpoint: clinical cure (follow-up 3 months).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\n• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19. Open-label RCT (NCT04304053, recruiting). Primary endpoint: incidence of secondary cases among contacts of a case and contacts of contacts (follow-up 14 days).\n• Comparison of chloroquine plus favipiravir vs. favipiravir vs. placebo in patients with COVID-19. Double-blind RCT (NCT04319900, recruiting). Primary endpoints: (a) time to improvement/recovery and frequency of improvement/recovery (follow-up 10 days); (b) time to negative swab/sputum RT-PCR (follow-up 10 days).\n• Comparison of favipiravir vs. standard of care in patients with COVID-19. Open-label RCT (NCT04333589, not yet recruiting). Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs (follow-up 5 months).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\nUmifenovir Anti-influenza membrane fusion inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir. The manuscript is publicly available but still to be peer reviewed [30] • Comparison of umifenovir vs. standard of care in patients with COVID-19 pneumonia. Open-label RCT (NCT04260594, not yet recruiting). Primary endpoint: virus negative conversion rate (follow-up 7 days).\nChloroquine, hydroxychloroquine Some proposed mechanisms are the following: increase in the endosomal Ph necessary for the virus/host cell fusion; interference with the glycosylation of cell receptors; immunomodulatory activity • Not available • Comparison of different hydroxychloroquine dosages vs. placebo in three cohorts (outpatients, inpatients, healthcare workers a risk). Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting). Primary endpoints: (a) release from quarantine (outpatients, follow-up 14 days); (b) discharge (inpatients, follow-up 14 days); (c) development of COVID-19 (healthcare workers, follow-up 2 months).\n• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients. Double-blind RCT (NCT04328961, not yet recruiting). Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days).\n• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19. Open-label RCT (NCT04332094, not yet recruiting). Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).• Comparison of ciclesonide plus hydroxychloroquine vs. ciclesonide in patients with COVID-19. Open-label RCT (NCT04330586, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication (based on virus load) at day 14.\n• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and under biological treatment and/or JAK inhibitors. Double-blind RCT (NCT04330495, not yet recruiting). Primary endpoints: (a) incidence rate of COVID-19 (follow-up 27 weeks); (b) prevalence of COVID-19 (follow-up 27 weeks); (c) case fatality rate (follow-up 27 weeks); (d) ICU admission rate (follow-up 27 weeks).\n• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk. Double-blind RCT (NCT04328467, not yet recruiting). Primary endpoint: prevalence of COVID-19 (follow-up 12 weeks).\n• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19. Double-blind RCT (NCT04328285, not yet recruiting). Primary endpoint: Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection (follow-up 2.5 months).\n• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households. Double-blind RCT (NCT04308668, recruiting). Primary endpoints: (a) incidence of symptomatic COVID-19 among asymptomatic participants; (b) severity rating on a 3-point ordinal scale at day 14.\n• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19. Open-label adaptive RCT (NCT04321616, not yet recruiting). Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19. Double-blind, adaptive RCT (NCT04328012, not yet recruiting). Primary endpoint: NIAID COVID-19 Ordinal Severity Scale (follow-up 60 days).\n• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19. Open-label RCT (NCT04332835, not yet recruiting). Primary endpoints: (a) change in virus load at days 0, 4, 7, 14 and 28; (b) change in IgM COVID-19 titers at days 0, 4, 7, 14 and 28; (c) change in IgG at days 0, 4, 7, 14 and 28.\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta-1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\nMethylprednisolone A subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome which causes rapidly progressive pneumonia, ARDS and clinical deterioration and corticosteroids administration may halt the dysregulated cytokine release • Not available • Comparison of methylprednisolone vs. standard of care in patients with severe COVID-19. Open-label RCT (NCT04244591, recruiting). Primary endpoint: lower Murray lung injury score at days 7 and 14.\n• Comparison of methylprednisolone vs. standard of care in patients with COVID-19. Open-label RCT (NCT04273321, recruiting). Primary endpoint: treatment failure (follow-up 14 days).\n• Comparison of inhaled alpha interferon plus methylprednisolone plus umifenovir vs. thalidomide plus inhaled alpha interferon plus methylprednisolone plus umifenovir in patients with severe COVID-19. Double-blind RCT (NCT04273581, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 28 days).\n• Comparison of different dosages of methylprednisolone in patients with COVID-19. Open-label RCT (NCT04263402, recruiting). Primary endpoints: (a) disease readmission at day 7; (b) critical stage at day 7.\n• Comparison of siltuximab (anti–IL-6 monoclonal antibody) vs. methylprednisolone in patients with COVID-19. Open-label RCT (NCT04329650, not yet recruiting). Primary endpoint: ICU admission (follow-up 29 days)\nTocilizumab Humanized monoclonal IgG1 antibody, tocilizumab inhibits both membrane-bound and soluble IL-6 receptors. IL-6, is one of the main drivers of immunologic response and symptoms in patients with dysregulated cytokine release that has been observed in severe COVID-19 • Not available • Comparison of tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04331808, not yet recruiting). Primary endpoint: WHO progression scale at day 7 and 14 (severity rating on a 10-point ordinal scale).\n• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19. Open-label RCT (NCT04310228, recruiting). Primary endpoint: clinical cure (follow-up 3 months).\n• Comparison of tocilizumab vs. placebo in hospitalized patients with COVID-19. Double-blind RCT (NCT04320615, not yet recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 28.\n• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19. Open-label RCT (NCT04332094, not yet recruiting). Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).\n• Comparison of chloroquine analog (GNS651) vs. tocilizumab vs. nivolumab vs. standard of care in patients with advanced or metastatic cancer and COVID-19. Open-label RCT (NCT04333914, not yet recruiting). Primary endpoint: 28-day survival.\n• Comparison of tocilizumab intravenously vs. tocilizumab subcutaneously vs. sarilumab (anti-interleukin 6 receptor α monoclonal antibody) subcutaneously vs. standard of care in patients with COVID-19. Open-label RCT (NCT04322773, not yet recruiting). Primary endpoint: time to independence from supplementary oxygen therapy (follow-up 28 days).\n• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04330638, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 15 days).\n• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia. Open-label RCT (NCT04286503, not yet recruiting). Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.\nAnakinra Antagonist of IL-1 receptor. IL-1 is one of the main drivers of immunologic response and symptoms in patients with cytokine-release syndrome. • Not available • Comparison of anakinra vs. emapalumab (anti–interferon γ monoclonal antibody) vs. standard of care in patients with COVID-19. Open-label RCT (NCT04324021, not yet recruiting). Primary endpoint: treatment success at day 15.\n• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04330638, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 15 days).\nOff-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience. Of note, there are also registered RCT for other drugs to be investigated in patients with COVID-19 (e.g. the Janus kinase family inhibitors ruxolitinib, baricitinib and tofacitinib).\nARDS = acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease 2019; CT, computed tomography; EOT, end of treatment; HR, hazard ratio; Ig, immunoglobulin; IL-1, interleukin 1; IQR, interquartile range; ITT, intent to treat; mITT, modified intent to treat; Pao2/Fio2, of arterial oxygen partial pressure to fractional inspired oxygen; RCT, randomized controlled trial; RT-PCR, real-time PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization."}

LitCovid-sentences

2_test

{"project":"2_test","denotations":[{"id":"32360444-32187464-22369752","span":{"begin":1367,"end":1369},"obj":"32187464"}],"text":"Table 2 Available and ongoing RCT on anti-infective and anti-inflammatory drugs most provided as off-label/compassionate treatments in the first phase of the COVID-19 pandemic\nDrug Class/mechanism Published RCT Ongoing RCT for treatment/prevention of COVID-19 (recruiting or not yet recruiting) registered at ClinicalTrials.gov\nLopinavir/ritonavir Lopinavir is an HIV type 1 protease inhibitor. Ritonavir is a CYP3A4 inhibitor that boosts lopinavir concentrations • Open-label RCT comparing lopinavir/ritonavir (99 patients) vs. standard of care (100) in patients with COVID-19 in China. Lopinavir/ritonavir was administered at the dosage of 400/100 mg for 14 days. The primary time-to-event endpoint was clinical improvement from randomization. In the primary study population (ITT), no statistically significant differences were observed with regard to the primary endpoint of clinical improvement (HR 1.24 with standard of care as reference, 95% CI 0.90 to 1.72) and the secondary endpoint of 28-day mortality (19.2% vs. 25.0% in investigational and comparator arms, respectively; percentage difference −5.8%, 95% CI −17.3 to 5.7). In the mITT population, lopinavir/ritonavir led to a median time to clinical improvement that was shorter by 1 day than that observed with standard care. Median time between symptoms onset and randomization was 13 days (IQR 11–16) [22] • Comparison of lopinavir/ritonavir vs. hydroxychloroquine in patients with mild COVID-19. Open-label RCT (NCT04307693, recruiting). Primary endpoint: virus load at day 3, 5, 7, 10, 14 and 18.\n• Comparison of ASC09/ritonavir vs. lopinavir/ritonavir in patients with confirmed COVID-19 pneumoniae. Open-label RCT (NCT04261907, not yet recruiting). Primary endpoint: adverse outcome at day 14 (composite of Spo 2 ≤ 93% without oxygen supplementation, PaO2/FiO2 ≤ 300 mm Hg or respiratory rate ≥ 30 breaths per minute).\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus umifenovir in patients with COVID-19. Open-label RCT (NCT04252885, recruiting). Primary endpoint: rate of virus inhibition at day 0, 2, 4, 7, 10, 14 and 21.\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus ribavirin plus interferon beta 1b in patients with COVID-19. Open-label RCT (NCT04276688, recruiting). Primary endpoint: time to negative nasopharyngeal swab RT-PCR (follow-up 30 days).\n• Comparison of only supportive treatment vs. lopinavir/ritonavir vs. oseltamivir vs. umifenovir in patients with confirmed COVID-19 pneumonia. Open-label RCT (NCT04255017, recruiting). Primary endpoints: (a) rate of disease remission (mild disease: fever, cough and other symptoms relieved with improved lung CT; severe disease: fever, cough and other symptoms relieved with improved lung CT, Spo 2 \u003e 93% or Pao 2/Fio 2 \u003e 300 mm Hg); (b) time to lung recovery.\n• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19. Double-blind RCT (NCT04328285, not yet recruiting). Primary endpoint: occurrence of a symptomatic or asymptomatic COVID-19 (follow-up 2.5 months).\n• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia. Open-label RCT (NCT04286503, not yet recruiting). Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.\n• Comparison of lopinavir/ritonavir vs. lopinavir/ritonavir plus xiyanping (injectable component derived from a plant used in traditional Chinese medicine) in patients with COVID-19. Open-label RCT (NCT04295551, not yet recruiting). Primary endpoint: clinical recovery time (follow-up 28 days).\n• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus xiyanping injection in patients with COVID-19. Open-label RCT (NCT04275388, not yet recruiting). Primary endpoint: clinical recovery time (follow-up 14 days).\n• Comparison of lopinavir/ritonavir plus inhaled interferon alfa vs. lopinavir/ritonavir plus inhaled interferon alfa plus traditional Chinese medicines in patients with COVID-19. Open-label RCT (NCT04251871, recruiting). Primary endpoint: time to complete remission of symptoms (follow-up 28 days).\n• Comparison of lopinavir/ritonavir plus hydroxychloroquine vs. lopinavir/ritonavir plus hydroxychloroquine plus levamisole pill plus budesonide plus formoterol inhaler in patients with nonsevere COVID-19 pneumonia. Partly blinded RCT (NCT04331470, not yet recruiting). Primary endpoint: (a) clear CT scan at 3–7 days; (b) negative RT-PCR at 3–7 days.\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19. Double-blind, adaptive RCT (NCT04328012, not yet recruiting). Primary endpoint: NIAID COVID-19 ordinal severity scale (follow-up 60 days).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\n• Comparison of lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) vs. natural honey plus lopinavir/ritonavir or umifenovir or chloroquine or hydroxychloroquine or oseltamivir (with or without azithromycin) in patients with COVID-19. Single-blind RCT (NCT04323345, not yet recruiting). Primary endpoints: (a) positive to negative swabs at day 14; (b) fever to normal temperature in days (follow-up 14 days); (c) resolution of lung inflammation in CT or X-ray (follow-up 30 days).\n• Comparison of colchicine (with or without lopinavir/ritonavir) vs. local standard of care in patients with moderate to severe COVID-19. Open-label RCT (NCT04328480, not yet recruiting). Primary endpoint: all-cause mortality (follow-up 30 days).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\nRemdesivir Adenosine analogue. It binds to RNA-dependent RNA polymerase and acts as an RNA-chain terminator • Not available • Comparison of remdesivir vs. placebo in patients with severe COVID-19. Double-blind RCT (NCT04257656, recruiting). Primary endpoint: clinical status, assessed by an ordinal scale at days 7, 14, 21 and 28.\n• Comparison of remdesivir vs. placebo in patients with mild to moderate COVID-19. Double-blind RCT (NCT04252664, recruiting). Primary endpoint: time to clinical recovery in hours (follow-up 28 days).\n• Comparison of remdesivir vs. local standard of care in patients with severe COVID-19. Open-label RCT (NCT04252664, recruiting). Primary endpoint: composite of fever normalization and oxygen saturation normalization (follow-up 14 days).\n• Comparison of remdesivir vs. local standard of care in patients with moderate COVID-19. Open-label RCT (NCT04292730, recruiting). Primary endpoint: discharged status at day 14.\n• Comparison of remdesivir vs. placebo in patients with COVID-19. Double-blind RCT (NCT04280705, recruiting). Primary endpoint: severity rating on a 8-point ordinal scale at day 15.\n• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19. Open-label adaptive RCT (NCT04321616, not yet recruiting). Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta 1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\nDarunavir/cobicistat Darunavir is an HIV type 1 protease inhibitor. Cobicistat is a CYP3A4 inhibitor that boosts darunavir concentrations • Not available • Comparison of darunavir/cobicistat vs. standard of care in patients with COVID-19 pneumonia. Open-label RCT (NCT04252274, recruiting). Primary endpoint: virologic clearance rate of throat swabs, sputum or lower respiratory tract secretions at day 7.\nFavipiravir Anti-influenza RNA-dependent RNA polymerase inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir. The manuscript is publicly available but still to be peer reviewed [30] • Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19. Open-label RCT (NCT04310228, recruiting). Primary endpoint: clinical cure (follow-up 3 months).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\n• Comparison of hydroxychloroquine plus darunavir/cobicistat vs. standard of care in patients with COVID-19. Open-label RCT (NCT04304053, recruiting). Primary endpoint: incidence of secondary cases among contacts of a case and contacts of contacts (follow-up 14 days).\n• Comparison of chloroquine plus favipiravir vs. favipiravir vs. placebo in patients with COVID-19. Double-blind RCT (NCT04319900, recruiting). Primary endpoints: (a) time to improvement/recovery and frequency of improvement/recovery (follow-up 10 days); (b) time to negative swab/sputum RT-PCR (follow-up 10 days).\n• Comparison of favipiravir vs. standard of care in patients with COVID-19. Open-label RCT (NCT04333589, not yet recruiting). Primary endpoint: viral nucleic acid test negative conversion rate in nasopharyngeal swabs (follow-up 5 months).\n• Comparison of oseltamivir plus chloroquine vs. oseltamivir plus lopinavir/ritonavir in patients with mild COVID-19 and of lopinavir/ritonavir plus oseltamivir vs. darunavir/ritonavir plus oseltamivir vs. favipiravir plus lopinavir/ritonavir vs. darunavir/ritonavir plus oseltamivir plus chloroquine vs. darunavir/ritonavir plus favipiravir plus oseltamivir in patients with moderate to severe COVID-19. Open-label RCT (NCT04303299, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication time (follow-up 24 weeks).\nUmifenovir Anti-influenza membrane fusion inhibitor • In a recent RCT published on a preprint server and comparing 120 COVID-19 patients treated with favipiravir vs. 120 COVID-19 patients receiving umifenovir, higher rates of clinical recovery were observed in patients receiving favipiravir. The manuscript is publicly available but still to be peer reviewed [30] • Comparison of umifenovir vs. standard of care in patients with COVID-19 pneumonia. Open-label RCT (NCT04260594, not yet recruiting). Primary endpoint: virus negative conversion rate (follow-up 7 days).\nChloroquine, hydroxychloroquine Some proposed mechanisms are the following: increase in the endosomal Ph necessary for the virus/host cell fusion; interference with the glycosylation of cell receptors; immunomodulatory activity • Not available • Comparison of different hydroxychloroquine dosages vs. placebo in three cohorts (outpatients, inpatients, healthcare workers a risk). Double-blind RCT for outpatients and healthcare workers and open-label RCT for inpatients (NCT04329923, not yet recruiting). Primary endpoints: (a) release from quarantine (outpatients, follow-up 14 days); (b) discharge (inpatients, follow-up 14 days); (c) development of COVID-19 (healthcare workers, follow-up 2 months).\n• Comparison of hydroxychloroquine vs. ascorbic acid in contacts of COVID-19 patients. Double-blind RCT (NCT04328961, not yet recruiting). Primary endpoint: laboratory-confirmed COVID-19 (follow-up 14 days).\n• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19. Open-label RCT (NCT04332094, not yet recruiting). Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).• Comparison of ciclesonide plus hydroxychloroquine vs. ciclesonide in patients with COVID-19. Open-label RCT (NCT04330586, not yet recruiting). Primary endpoint: SARS-CoV-2 eradication (based on virus load) at day 14.\n• Comparison of hydroxychloroquine vs. placebo in patients with COVID-19 and under biological treatment and/or JAK inhibitors. Double-blind RCT (NCT04330495, not yet recruiting). Primary endpoints: (a) incidence rate of COVID-19 (follow-up 27 weeks); (b) prevalence of COVID-19 (follow-up 27 weeks); (c) case fatality rate (follow-up 27 weeks); (d) ICU admission rate (follow-up 27 weeks).\n• Comparison of hydroxychloroquine vs. placebo for the prevention of COVID-19 in healthcare workers at risk. Double-blind RCT (NCT04328467, not yet recruiting). Primary endpoint: prevalence of COVID-19 (follow-up 12 weeks).\n• Comparison of chemoprophylaxis with lopinavir/ritonavir vs. placebo in healthcare workers exposed to COVID-19. Double-blind RCT (NCT04328285, not yet recruiting). Primary endpoint: Occurrence of a symptomatic or asymptomatic SARS-CoV-2 infection (follow-up 2.5 months).\n• Comparison of hydroxychloroquine vs. placebo in symptomatic COVID-19 patients or exposed healthcare workers/households. Double-blind RCT (NCT04308668, recruiting). Primary endpoints: (a) incidence of symptomatic COVID-19 among asymptomatic participants; (b) severity rating on a 3-point ordinal scale at day 14.\n• Comparison of remdesivir vs. hydroxychloroquine vs. remdesivir plus hydroxychloroquine in patients with COVID-19. Open-label adaptive RCT (NCT04321616, not yet recruiting). Primary endpoint: all-cause in-hospital mortality (follow-up 3 weeks).\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. losartan vs. placebos in patients with COVID-19. Double-blind, adaptive RCT (NCT04328012, not yet recruiting). Primary endpoint: NIAID COVID-19 Ordinal Severity Scale (follow-up 60 days).\n• Comparison of convalescent plasma plus hydroxychloroquine plus azithromycin vs. hydroxychloroquine plus azithromycin in hospitalized patients with COVID-19. Open-label RCT (NCT04332835, not yet recruiting). Primary endpoints: (a) change in virus load at days 0, 4, 7, 14 and 28; (b) change in IgM COVID-19 titers at days 0, 4, 7, 14 and 28; (c) change in IgG at days 0, 4, 7, 14 and 28.\n• Comparison of lopinavir/ritonavir vs. hydroxychloroquine vs. lopinavir/ritonavir plus interferon beta-1a vs. remdesivir vs. standard of care in patients with COVID-19. Double-blind, adaptive RCT (NCT04315948, recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 15.\nMethylprednisolone A subgroup of patients with severe COVID-19 might develop a cytokine storm syndrome which causes rapidly progressive pneumonia, ARDS and clinical deterioration and corticosteroids administration may halt the dysregulated cytokine release • Not available • Comparison of methylprednisolone vs. standard of care in patients with severe COVID-19. Open-label RCT (NCT04244591, recruiting). Primary endpoint: lower Murray lung injury score at days 7 and 14.\n• Comparison of methylprednisolone vs. standard of care in patients with COVID-19. Open-label RCT (NCT04273321, recruiting). Primary endpoint: treatment failure (follow-up 14 days).\n• Comparison of inhaled alpha interferon plus methylprednisolone plus umifenovir vs. thalidomide plus inhaled alpha interferon plus methylprednisolone plus umifenovir in patients with severe COVID-19. Double-blind RCT (NCT04273581, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 28 days).\n• Comparison of different dosages of methylprednisolone in patients with COVID-19. Open-label RCT (NCT04263402, recruiting). Primary endpoints: (a) disease readmission at day 7; (b) critical stage at day 7.\n• Comparison of siltuximab (anti–IL-6 monoclonal antibody) vs. methylprednisolone in patients with COVID-19. Open-label RCT (NCT04329650, not yet recruiting). Primary endpoint: ICU admission (follow-up 29 days)\nTocilizumab Humanized monoclonal IgG1 antibody, tocilizumab inhibits both membrane-bound and soluble IL-6 receptors. IL-6, is one of the main drivers of immunologic response and symptoms in patients with dysregulated cytokine release that has been observed in severe COVID-19 • Not available • Comparison of tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04331808, not yet recruiting). Primary endpoint: WHO progression scale at day 7 and 14 (severity rating on a 10-point ordinal scale).\n• Comparison of favipiravir vs. tocilizumab vs. favipiravir plus tocilizumab in patients with COVID-19. Open-label RCT (NCT04310228, recruiting). Primary endpoint: clinical cure (follow-up 3 months).\n• Comparison of tocilizumab vs. placebo in hospitalized patients with COVID-19. Double-blind RCT (NCT04320615, not yet recruiting). Primary endpoint: severity rating on a 7-point ordinal scale at day 28.\n• Comparison of tocilizumab plus hydroxychloroquine plus azithromycin vs. tocilizumab plus hydroxychloroquine in patients with COVID-19. Open-label RCT (NCT04332094, not yet recruiting). Primary endpoints: (a) in-hospital mortality (follow-up 2 weeks); (b) need for mechanical ventilation in the ICU (follow-up 2 weeks).\n• Comparison of chloroquine analog (GNS651) vs. tocilizumab vs. nivolumab vs. standard of care in patients with advanced or metastatic cancer and COVID-19. Open-label RCT (NCT04333914, not yet recruiting). Primary endpoint: 28-day survival.\n• Comparison of tocilizumab intravenously vs. tocilizumab subcutaneously vs. sarilumab (anti-interleukin 6 receptor α monoclonal antibody) subcutaneously vs. standard of care in patients with COVID-19. Open-label RCT (NCT04322773, not yet recruiting). Primary endpoint: time to independence from supplementary oxygen therapy (follow-up 28 days).\n• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04330638, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 15 days).\n• Comparison of carrimycin vs. lopinavir/ritonavir or umifenovir or chloroquine in patients with COVID-19 pneumonia. Open-label RCT (NCT04286503, not yet recruiting). Primary endpoints: (a) fever to normal time (follow-up 30 days); (b) pulmonary inflammation resolution time (follow-up 30 days); (c) negative conversion of throat swab RT-PCR at EOT.\nAnakinra Antagonist of IL-1 receptor. IL-1 is one of the main drivers of immunologic response and symptoms in patients with cytokine-release syndrome. • Not available • Comparison of anakinra vs. emapalumab (anti–interferon γ monoclonal antibody) vs. standard of care in patients with COVID-19. Open-label RCT (NCT04324021, not yet recruiting). Primary endpoint: treatment success at day 15.\n• Comparison of tocilizumab vs. anakinra (recombinant IL-1 receptor antagonist) vs. siltuximab vs. anakinra plus siltuximab vs. anakinra plus tocilizumab vs. standard of care in patients with COVID-19. Open-label RCT (NCT04330638, not yet recruiting). Primary endpoint: time to clinical improvement (follow-up 15 days).\nOff-label drugs mostly provided in Italy during the first phase of the COVID-19 pandemic according to the authors' direct experience. Of note, there are also registered RCT for other drugs to be investigated in patients with COVID-19 (e.g. the Janus kinase family inhibitors ruxolitinib, baricitinib and tofacitinib).\nARDS = acute respiratory distress syndrome; CI, confidence interval; COVID-19, coronavirus disease 2019; CT, computed tomography; EOT, end of treatment; HR, hazard ratio; Ig, immunoglobulin; IL-1, interleukin 1; IQR, interquartile range; ITT, intent to treat; mITT, modified intent to treat; Pao2/Fio2, of arterial oxygen partial pressure to fractional inspired oxygen; RCT, randomized controlled trial; RT-PCR, real-time PCR; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health Organization."}

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