Pharmacological treatment for patients with coronavirus disease 2019: systematic review of randomized controlled trials

doi:10.21203/rs.3.rs-90401/v1

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Systematic Review

Pharmacological treatment for patients with coronavirus disease 2019: systematic review of randomized controlled trials

https://doi.org/10.21203/rs.3.rs-90401/v1

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Background: The best treatment for COVID-19 is not known, with numerous agents under investigation. We determined the outcomes of patients with COVID-19 treated with different pharmacological agents.

Methods: In this systematic review, we searched Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Central Register of Controlled Trials for studies published between 1^stJanuary and 12^thAugust, 2020. We included randomized controlled trials (RCTs) of patients with COVID-19 treated with any pharmacological agent and compared with a different pharmacological agent, placebo or standard of care.

Results: From 6346 citations, 19 studies were included, with an overall low risk of bias. Two RCTs evaluated the use of remdesivir in laboratory-confirmed moderate-to-severe COVID-19. One study found that 10 days of remdesivir was associated with shortened recovery time. Neither found reduction in mortality. One RCT found no association of lopinavir/ritonavir with time to clinical improvement, or mortality benefit. Two RCTs of hydrochloroquine in patients with mild, early disease demonstrated no reduction in disease severity, hospitalization rate, death or viral load. Two RCTs observed no association of hydrochloroquine in hospitalized patients with mild-to-moderate disease with virological clearance, improvement in symptoms, need for respiratory support or death. One RCT showed that the use of steroids was associated with improved survival in patients with moderate-to-severe disease, especially those requiring respiratory support.

Conclusions: There is evidence for the benefit of steroids in patients with moderate-to-severe disease. Remdesivir might shorten recovery time in patients hospitalized with moderate-to-severe disease. There is currently no evidence to support the use of lopinavir/ritonavir or hydrochloroquine.

Study’s Registration: PROSPERO CRD42020184433.

Infectious Diseases

Coronavirus disease 2019

SARS-CoV-2

Steroids

Coronavirus disease 2019 (COVID-19) is a rapidly spreading and fatal pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Disease symptoms can range from mild-to-moderate influenza-like symptoms to severe acute respiratory disease syndrome (ARDS) necessitating admission to the intensive care unit (ICU) for ventilator and hemodynamic support, and leading to fatalities which are more prevalent in adults and older individuals with comorbidities (1-3). While mild-to-moderate COVID-19 is a self-resolving disease, pharmacological treatment might be indicated in more severe cases, and includes drugs that target either key steps of the virus life cycle or the host immune response to SARS-CoV-2. Given the current lack of evidence to support the use of most drugs, the use of COVID-19 pharmacological therapies is recommended mainly in the setting of clinical trials (4).

An observational study did not demonstrate benefit of lopinavir/ritonavir (1). Some other antiviral (remdesivir (5)) and immunomodulatory agents (e.g. hydrochloroquine [HCQ] and azithromycin(6)) have shown favorable results in non-randomized studies. However, these studies should be interpreted carefully due to limitations in study design. We aimed to review the outcomes of patients with COVID-19 treated with different pharmacological treatments in randomized controlled trials (RCTs).

Search strategy and selection criteria

In this systematic review, we used a methodologically rigorous approach (Cochrane Handbook of Systematic Reviews) including stringent formulation of the research question and development of the protocol; double-blind screening and selection of the literature; data extraction; and collation, and report of the results.We developed a search strategy and refined its parameters in consultation with a research librarian (member of our research team). We searched Ovid MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials databases for published studies in English exploring the benefit of different pharmacological agents on outcome in patients with COVID-19, published between 1^st January and 12^th August, 2020 following PRISMA guidelines (7) (Ovid MEDLINE search criteria in Supplementary method). We included randomized studies of patients with COVID-19 treated with a specific pharmacological agent and a control group treated with a different pharmacological agent, placebo or standard of care (SOC) only, in which outcomes (clinical, radiological, and/or virological) were reported. We excluded studies that did not contain a control group, non-human studies, non-randomized studies, cluster-randomized studies and studies in which no outcomes were reported. Letters, editorials and review articles containing no primary data were excluded. Inclusion and exclusion criteria were specified in advance and documented in the study protocol. References were screened by title and abstract by two authors, with disagreements resolved in a group discussion. Articles screened and found to be possibly eligible were fully assessed against inclusion and exclusion criteria by two authors, with controversies resolved by group discussion.

Data extraction

Data were extracted from articles that met the inclusion criteria independently by two authors and included the following: study settings, cohort characteristics, treatments investigated and main results. Disagreements between authors were resolved by discussion including a third author.

Risk of bias assessment

Risk of bias (ROB) of included RCTs was assessed against the Cochrane ROB tool for RCTs. The study was registered at PROSPERO International prospective register of systematic reviews (CRD42020184433).

Role of the funding source: There was no specific funding source for this study.

Overall, 6346 references were screened for eligibility. Of these, 39 full-text articles were assessed against inclusion and exclusion criteria. Nineteen articles met the inclusion criteria and were included in the systematic review and qualitative synthesis (Supplementary Figure 1). Thirteen out of 19 studies included patients with moderate-to-severe disease, and 16 studies enrolled hospitalized patients. Most of the studies were deemed to have low risk of bias (Supplementary Tables 1-3).

Two RCTs assessed the effect of remdesivir on hospitalized patients with laboratory-confirmed moderate-to-severe COVID-19. While a small study from China (n=237) did not find difference in time to clinical improvement between remdesivir and placebo during 28 days follow up, a larger multi-country study (n=1059) reported that 10 days of remdesivir was associated with shortened time to recovery (11 vs. 15 days) during 28 days follow up. Neither study found reduction in mortality at day 14 after enrollment (Table 1). ROB was low/unclear in some domains (Supplementary Table 1).

A study investigating lopinavir/ritonavir in patients with laboratory-confirmed COVID-19 did not meet the primary outcome of the study of time to clinical improvement, evaluated at day 28, and also did not show reduction in mortality (Table 1). ROB was low (Supplementary Table 1). Studies of combination regimens of lopinavir/ritonavir with other antivirals and other immunomodulators were also included. In patients receiving lopinavir/ritonavir combined with novaferon, compared with novaferon alone, the percentage of patients with negative SARS-CoV-2 PCR was higher at day 3 and 6 after randomization, and the median time until negative SARS-CoV-2 PCR was shorter (Table 1). In another study, the combination of lopinavir/ritonavir with IFN b-1b and ribavirin (RBV) was associated with shorter time until negative SARS-CoV-2 PCR, shorter time to resolution of symptoms and decreased hospital length of stay (LOS), compared with lopinavir/ritonavir alone. ROB was low in both studies (Supplementary Table 1).

Four RCTs investigated HCQ use in hospitalized and clinic patients. Two of these RCTs reported that early treatment of outpatients with mild disease (4-5 days after symptoms onset) did not reduce disease severity, hospitalization rate, death or SARS-CoV-2 viral load (Table 1). ROB was variable in these studies (Supplementary Table 1). Two other RCTs found no difference in virological clearance during 28 days follow up after HCQ administration in hospitalized patients with mild-to-moderate disease. HCQ administration was also not associated with difference in symptoms, need for respiratory support or death (Table 1). ROB was low for most domains in these two studies (Supplementary Table 1).

Two published RCTs that assessed the effect of administration of steroids on 28-day mortality were identified. The first was an interim analysis of the RECOVERY trial that found that administration of dexamethasone resulted in a lower case-fatality rate compared with standard of care. Subgroup analyses indicated that the finding was prominent among patients receiving invasive mechanical ventilation, but not observed in patients not receiving respiratory support at randomization. A study in Brazil with a lower number of patients randomized, reported that methylprednisolone did not result in a reduction in 7-day, 14-day or 28-day case-fatality rate compared with placebo (Table 2). The two studies had low ROB (Supplementary Table 2).

Four RCTs that evaluated immunomodulators (other than steroids) as single agents in treating COVID-19 patients were identified (Table 3). The rate of hospitalization was not different in outpatients treated with febuxostat compared with HCQ. Receipt of IFN b-1a did not result in improvement in time to clinical response, although mortality benefit was noted, especially if administered within 10 days of symptoms onset. In a small study, colchicine was associated with improved time to clinical deterioration. Ruxolitinib receipt did not result in reduction in time to clinical improvement or mortality benefit. Overall, the studies were found to have low ROB (Supplementary Table 3).

There is an urgent need to establish the optimal pharmacological treatment of patients with COVID-19. In this systematic review, we aimed to assess the effect of different pharmacological treatments on outcomes in patients with COVID-19. Remdesivir was found to be associated with shortened time to clinical improvement in patients hospitalized with moderate-severe disease. In addition, an improved survival rate was noted for steroids administered to patients, especially those who required mechanical ventilation and/or supplemental oxygen at diagnosis. Lopinavir/ritonavir was not associated with clinical improvement and did not demonstrate mortality benefit. HCQ administered to outpatients or inpatients did not reduce the severity of disease or hospitalization rates, enhance virological clearance, improve symptoms, reduce need for respiratory support or prevent death.

Remdesivir is an inhibitor of the viral RNA polymerase and has been shown to have inhibitory activity against SARS-CoV-2, SARS-CoV-1 and MERS-CoV in vitro (8-12). While a small study did not find that remdesivir administration was associated with shortening of time to clinical improvement (13), a multi-country study found that a 10 days course of Remdesivir was associated with shortening of time to recovery (14). However, current evidence from both studies did not support that there is reduction in mortality at day 14 after randomization. It should be noted that the former study did not complete full enrollment (due to the end of outbreak in China) of the target number of patients, and thus had a lower sample size that might have precluded any definite conclusion. In addition, the modest clinical benefit observed (14) with a highly expensive drug might challenge its use in some settings (e.g. low-middle income countries). Experience with other human coronaviruses is limited. In non-human primate studies, remdesivir reduced MERS-CoV lung virus levels and lung damage when initiated 12 hours after inoculation with the virus (15, 16).

Lopinavir is a protease inhibitor, and is combined with ritonavir to increase lopinavir’s plasma half-life through the inhibition of cytochrome P450. This combination is an established agent in the treatment of HIV. Lopinavir has in vitro inhibitory activity against SARS-CoV-1 (17, 18), the causative agent of SARS disease. Lopinavir also has activity against MERS-CoV observed in vitro (19) and in an animal model (20). The addition of RBV to lopinavir/ritonavir reduced the risk of ARDS or death, as well SARS-CoV-1 viral load among patients with SARS (21). The combination of lopinavir/ritonavir, RBV and IFN α has been associated with survival in case reports of patients with MERS (22-24). In this systematic review, one RCT did not find lopinavir/ritonavir to be associated with shorter time to clinical improvement, or have mortality benefit in patients with SARS-CoV-2 (25). One RCT found that the combination of IFN b-1b, lopinavir/ritonavir, and RBV was associated with shorter time to negative SARS-CoV-2 PCR, shorter time to resolution of symptoms and decreased hospital LOS, compared with lopinavir/ritonavir alone (26). This might have practical implications related to isolation precautions for patients. In addition, reduction of hospital LOS might enable health service to cope with higher load of patients, provide better care in severe disease, and might also reduce costs of hospitalization.

Chloroquine and its hydroxyl analogue HCQ are well known as antimalarial drugs. Both drugs have been shown to block the viral replication of SARS-CoV-2 in cell cultures, suggesting that they might have potent antiviral activity against SARS-CoV-2 in vivo (12, 27). In our systematic review, two RCTs performed on outpatients found no reduced disease severity or hospitalization rates after treatment with HCQ early in the course of mild disease (28, 29). Two RCTS on the use of HCQ in hospitalized patients also failed to demonstrate that HCQ administration for patients with mild-moderate disease enhanced virological clearance, improved symptoms, reduced need for respiratory support or prevented death (30, 31).

One of two published studies showed that dexamethasone treatment was associated with reduction in 28-day mortality, especially among patients who required invasive mechanical ventilation or supplemental oxygen (32). While this finding was not supported by a recent study from Brazil, which also recruited patients with moderate to severe COVID-19, differences in the results might stem from the lower number of patients, the later presentation after symptoms onset and the higher baseline mortality rate without steroids in the latter compared with the former study (33). A recent prospective meta-analysis of RCTs that evaluated the efficacy of corticosteroids in critically ill patients found that corticosteroid administration was associated with a reduction in 28-day mortality when compared with SOC or placebo (odds ratio 0.66, 95% CI: 0.53-0.82) (34). Thus, The World Health Organization (WHO) is currently considering amending their COVID treatment guidelines to recommend the use of steroids in the treatment of critically ill patients. Limited data from earlier SARS outbreaks were not conclusive regarding the benefit of steroids (35). Systematic review of the use of corticosteroids in patients with MERS did not suggest a reduction in mortality, and was associated with delayed MERS-CoV RNA clearance (36).

Investigation of other immunomodulatory agents as a single agent has shown less promising results, and published articles were limited by small number of patients. Among the 4 articles identified, receipt of IFN -1a might have mortality benefit especially if administered early in the course of the disease (37). However, the high costs of these drugs might preclude their use, especially in low-middle income countries settings. IFN b was found to be the most potent inhibitor of SARS-CoV among other IFNs (38). However, a retrospective study showed that RBV plus recombinant IFN (rIFN-α2a, rIFN-α2b, or rIFN-β1a) did not result in a reduction in 90-day mortality amongst patients with severe MERS-CoV infection (38).

Remdesivir is associated with shortening time to clinical improvement in patients hospitalized with moderate-severe disease, and its use should be supported by future research. Currently, there is no evidence to support the use of HCQ in either outpatients with mild disease or inpatients with mild-moderate disease, nor the use of lopinavir/ritonavir in hospitalized patients. Our systematic review supports the use of steroids in critically ill patients.

There is a need to investigate the role of pharmacological treatment in adults with some underlying comorbidities (e.g. human immunodeficiency virus infection) or other specific populations (e.g. pediatric population, pregnant women) who have up to now largely been excluded from RCTs. In addition, there is a need to further explore the role of steroids in the treatment of moderate-severe COVID-19 as well as the optimal dose and duration of corticosteroid therapy in critically ill cases. Meta-analysis of effects of different pharmacological treatments may be possible as additional RCTs are published.

COVID-19: Coronavirus disease 2019

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

ARDS: acute respiratory disease syndrome

ICU: intensive care unit

HCQ: hydrochloroquine

RCTs: randomized controlled trials

SOC: standard of care

ROB: Risk of bias

RBV: ribavirin

LOS: length of stay

Ethics approval and consent to participate: Not applicable.

Consent for publication: Not applicable.

Availability of data and material: Not applicable.

Competing interests: BA, VK, HM, AC, RL, CP, RC declare no competing interests. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Pfizer, Sanofi-Pasteur, Seqirus, Symvivo and VBI Vaccines. All funds have been paid to his institute, and he has not received any personal payments.

Acknowledgement: BA is supported by the Canadian Health and Research Institute Vanier Canada Graduate scholarship. HM is supported through the University of British Columbia Clinician Investigator Program. RD is supported by the Canadian Immunization Research Network Trainee Scholarship and the Michael Smith Foundation for Health Research Trainee Award. MS is supported via salary awards from the BC Children’s Hospital Foundation, the Canadian Child Health Clinician Scientist Program and the Michael Smith Foundation for Health Research.

Funding: This study did not receive any specific funding.

Authors' contributions: All authors conceived and designed the systematic review. BA, VK, HM, AC, RL, CP, RC searched the scientific literature. BA, HM, AC, RL, CP, RC, RD drafted the tables. BA wrote the first draft of the manuscript. All authors critically reviewed and edited the manuscript. All authors reviewed and approved the final version of the manuscript.

Acknowledgements: Not applicable.

Table 1: Summary of findings table of randomized controlled trials of anti-infective agents for treatment of COVID-19

	Study settings	Cohort characteristics					Treatment		Main results	Reference
	Study settings	Case definition	Severity	Age in years	Sex*	Main comorbidities*	Time between onset of symptoms and randomization, in days	Drugs: Agent, dosage, duration, number of patients	Main results	Reference
Lop-Rit
Lop-Rit vs. SOC	Jin Yin-Tan Hospital, Wuhan, China (18-Jan-2020 – 03 Feb 2020)	Laboratory- confirmed by SARS-CoV-2 RT-PCR of in respiratory tract samples, pneumonia confirmed by radiology	Moderate-severe	Median:58 (IQR: 49-68)	M: 120/199 (60.3%)	DM: 23/199 (11.6%), CVD: 13/199 (6.5%), Cancer: 6/199 (3%)	Median: 13, (IQR:11-16)	Group 1: Lop-Rit: 400mg and 100mg twice daily for 14 days, 99 patients Group 2: SOC, 100 patients	Per ITT: Primary outcome: - Time to clinical improvement on day 28 not different in Lop-Rit vs. SOC (median 16 v 16 days, HR= 1.31 (95% CI, 0.95-1.80) Other outcomes: - 28-day mortality not significantly different: Lop-Rit:19.2%; SOC:25.0% - ICU LOS was shorter for Lop-Rit vs. SOC (median 6 vs. 11 days) - Duration from randomization to hospital discharge was shorter in Lop-Rit vs. SOC (median: 12 vs 4 days) - Percentage of patients with clinical improvement at day 14 was significantly higher for Lop-Rit vs. SOC (45.5% vs. 30.0%) - No significant differences in duration of O2 therapy, hospital LOS, and time from randomization to death. - Percentage of patients with detectable viral RNA similar during 28-days follow up period.	(25)
Rem
Rem vs Pla	Ten hospitals in Hubei Province, China (06-Feb-2020-12-Mar 2020)	Laboratory-confirmed by SARS-CoV-2 RT-PCR and pneumonia confirmed by radiology	Moderate-severe	Median 65 years (IQR: 56–71)	M: 140/ 237 (59.0 %)	HTN: 167/237 (70.4%) DM: 56/237 (23.6%) CHD: 17/237 (7.1%)	Median 10-11 days	Group 1: Rem 200 mg on day 1, 100 mg on days 2–10 in single daily infusions, 158 patients Group 2: Pla, 79 patients (allowed steroids)	Per ITT: Primary outcome: - Time to clinical improvement up to day 28 not different in the Rem vs. Pla group (median 21 vs. 23 days, HR 1·23 (95% CI 0·87–1·75) (Per Protocol: not different in the Rem vs. Pla group (median 21days vs. 23 days, HR 1·27 (95% CI 0·89–1·80). Other outcomes: - All-cause mortality at day 28 similar in the Rem vs. Pla (14% vs. 13%) - Duration of IMV not significantly different in the Rem vs. Pla group (median 7·0 vs. 15·5 days) - No significant differences in the duration of oxygen therapy in Rem vs. Pla (Median 19 vs. 21 days), or the hospital LOS (median 25 vs. 24 days).	(13)
Rem vs. Pla	Multi-country****, (21-Feb-2020 to 19-April-2020)	Laboratory-confirmed COVID-19	Moderate – Severe	Mean 58.9 [SD:15]	M: 684/1063 (64.3%)	HTN: 460/928 (49.6%) Obesity: 342/925 (37%) DM: 275/927 (29.7%)	Median: 9 [IQR:6 -12].	Group 1: Rem: 200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days, 538 patients Group 2: Saline placebo, up to 10 days, 521 patients	Per ITT: Primary outcome: - Time to recovery (discharge from hospital or hospitalization for infection-control purposes only) significantly shorter in patients who received Rem compared with Pla (median time 11 vs. 15 days, respectively). Rate ratio: 1.32; 95% CI:1.12-1.55. Other outcomes: - No significant difference in mortality by day 14 in Rem vs. Pla (7.1% vs. 11.9%, respectively). Hazard ratio for death, 0.70; 95% CI:0.47-1.04.	(14)
HCQ
Hospitalized
HCQ plus SOC vs. SOC	Multi-center, 3 province in China (11 to 29 February 2020)	Laboratory confirmed COVID-19 by SARS-COV-2 RT-PCR	Mild-Moderate disease hospitalized (1% had severe disease)	Mean: 46 (SD:14.7)	M: 82/150 (55%)	DM: 21/150 (14%) HTN: 9/150 (6%)	Mean 16.6 (SD 10.5)	Group 1: HCQ 1200 mg daily for 3 days followed by 800 mg daily ( 2 weeks for mild-moderate disease and 3 weeks for severe disease), 75 patients. Group 2: SOC, 75 patients	Per ITT Primary outcome: -Probability of negative conversion of SARS-CoV-2 by 28 days similar between HCQ and SOC group; 85.4% (95% CI:73.8%-93.8%) vs. 81.3% (95% CI:71.2%-89.6%), respectively. - Median time to negative conversion similar in the HCQ vs. SOC (8 vs. 7 days) (HR: 0.85, 95% CI: 0.58 to 1.23). Other outcomes: - Probability of negative conversion by 4, 7, 10, 14, or 21 days similar in the 2 groups. - Probability of alleviation of symptoms by 28 days was similar in HCQ vs. SOC (59.9% vs. 66.6%)**	(30)
HCQ vs. HCQ and AZM vs. SOC	Multicenter, Brazil, (29 Mar 20 – 02 Jun 20)	Suspected or laboratory confirmed COVID-19 by SARS-CoV-2 RT-PCR .	Mild to moderate hospitalized	Mean: 50.3 (SD:14.6)	M: 388/665 (58.3%)	HTN: 258/665 (38.8%) DM: 127/665 (19.1%) OB: 37/665 (16.3%)	Median: 7 (IQR: 5-9)	Group 1: HCQ: 400mg dose 2x daily (7 days), 221 patients Group 2: HCQ: 400mg dose 2x daily (7 days) and AZM 500mg dose 1x daily (7 days), 217 patients Group 3: SOC, 227 patients	Modified ITT Primary Outcome: - No significant differences in clinical status at 15 days (median score of a 7-level ordinal scale is 1 in all groups. - No significant between-group differences in the proportional odds of having a higher (worse) score on the seven-point ordinal scale at 15 days (HCQ/AZM vs SOC: OR :0.99, 95% CI :0.57-1.73; HCQ vs SOC: OR:1.21, 95% CI:0.69 –2.11; HCQ/AZM vs HCQ: OR: 0.82, 95% CI:0.47-1.43). Other outcomes: -No statistically significant difference between groups in clinical status at 7 days, number of days free from respiratory support within 15 days, percentage of high-flow nasal cannula or noninvasive ventilation within 15 days, percentage of mechanical ventilation within 15 days, hospital LOS, number and percentage of inhospital deaths, number and percentage of thromboembolic complications within 15 days.	(31)
Outpatient
HCQ vs. Pla	Multi-site, United States and Canada (22-March-2020 to 20-May-2020)	Laboratory- confirmed by SARS-CoV-2 RT-PCR or COVID-19-compatible symptoms with epidemiologic link	Mild ,outpatients (4 or fewer days of symptoms)	Median 40 [IQR: 32-50]	M: 185/423 (44%)	Asthma: 48/423 (11%), HTN: 46/423, 11%), DM:15/423 (4%),	236/423 (56%) of participants enrolled within 1 day of symptom onset	Group 1: HCQ 800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 more days), 212 patients Group 2: Pla (folic acid 400 mcg, in Canada lactose), 211 patients	Per ITT Primary outcome: - No significant reduction in symptom severity scale over 14 days in patients treated with HCQ vs. Pla (mean reduction from baseline of 2.6 vs. 2.33). No significant differences in average improvement in symptom severity of 12% between the HCQ and Pla. Other outcomes: - The percentage of patients reporting symptoms was not statistically significantly different between patients who received HCQ vs. Pla, 54% vs. 56%, and 24% vs. 30%, at days 5 and 14, respectively. - Incidence of hospitalization or death did not significantly different between patients who received HCQ vs Pla.	(28)
HQC vs. SOC	Multisite, Spain (17-March-2020 to 26-May-2020).	Laboratory- confirmed by SARS-CoV-2 RT-PCR	Mild, outpatient(e.g. <5 days of symptoms)	Mean 41.6 (SD:12.6)	M: 31.4% 92/293	CVD: 35/293 (11.9%), RD: 17/293(5.8%), neurological disease: 40/293(13.7%)	Median 3 [IQR: 2-4]	Group 1: HCQ: 800 mg on day 1, followed by 400 mg once daily for 6 days, 136 patients Group 2: SOC, 157 patients	Per ITT Primary Outcome: - No significant differences in the mean reduction of viral load at day 3 or at day 7 (-1.41 vs. -1.41 and -3.37 vs. -3.44 Log₁₀ copies/mL in the SOC vs. Pla). Other outcomes: - Risk of hospitalization not significantly reduced in patients treated with SOC vs. HCQ (7.1% vs. 5.9%), respectively. - Time to complete resolution of symptoms not significantly different in Pla vs. HCQ groups (median 12 vs. 10 days).	(29)
Other treatments
RBV + IFNa vs. Lop.Rit + IFNa vs. RBV + LPV.Rit + IFNa	Chongqing Public Health Medical Center, China (20 Jan 2020 – 25 Feb 2020)	Laboratory confirmed by SARS-CoV-2 RT-PCR	Mild to moderate	Mean: 42.5 (SD:11.5)	M: 46/101(46%)	N/A	Median 4.0 (IQR:1.5-7.0)	Group 1: RBV: IV 2 g loading dose, oral doses 400-600mg/8 hour IFNa inhalation 5 million U or 50mg/dose 2 x daily (14 days), 33 patients Group 2: Lop.Rit: oral 400mg/100mg per dose 2x daily (14 days) IFNa: inhalation 5 million U or 50mg/dose 2 x daily (14 days), 36 patients Group 3: RBV: IV 2 g loading dose, oral doses 400-600mg/8 hours, Lop.Rit: oral dose 400mg/100mg per dose 2x daily (14 days), IFNa: inhalation 5 million U or 50mg/dose 2 x daily (14 days), 32 patients	Per ITT and PP: Primary outcome: - No significant difference in the time interval from treatment initiation to SARS-CoV-2 nucleic acid negativity among 3 regimens, median times in days (ITT: Group 1: 13, Group 2: 12, Group 3:15; PP: Group 1: 12, Group 2: 11, Group 3: 13). Other outcome: -No significant differences in proportion of patients with SARS-CoV-2 nucleic acid negativity at Day 14: (ITT: Group 1: 51.5%, Group 2: 61.1%, Group 3: 46.9%; PP: Group 1: 63%, Group 2: 67.9%, Group 3: 57.1%). -No significant differences in proportion of patients with disease progression	(39)
IFN beta-1b, Lop-Rit and RBV vs Lop-Rit	Six hospitals in Hong Kong, (10-Feb and 20-Mar 2020)	Laboratory confirmed COVID-19 t	Mild-moderate	Median: 52 (IQR: 32–62)	M: 68/127 (54%)	DM: 17/127 (13.4%), HTN: 36/127 (28.3%), CHD: 10/127 (7.9%)	Median 5 (IQR 4–7) in the combination group and 4 (IQR 3-8) in the control group	Group1: Lop 400 mg and Rit100 mg) every 12 h, RBV 400 mg every 12 h, and 1-3 doses of IFN beta-1b on alternate days , 86 patients. Group 2: Lop 400 mg and Rit 100 mg) every 12 h for 14 days, 41 patients	Per ITT Primary outcome: - Time until a negative SARS-CoV-2 RT-PCR significantly shorter in the combination vs. control group (median 7 vs. 12 days). HR:4·37 [95% CI:1·86–10·24]. Other outcomes: - Time to resolution of symptoms significantly shorter in the combination vs. control group ( Median 0 vs. 8 days), HR 3.92 [95% CI 1.66–9.23], - Time to reach SOFA score of 0 significantly shorter in the combination vs. control group (Median 3 vs. 8 days), HR 1.89 [1.03–3.49]. - Hospital LOS shorter in the combination vs. control group (Median 9 vs. 14·5 days), HR 2·72 [1·2–6·13].	(26)
Favipiravir vs. SOC	Six hospitals, Russia, Apr-May 2020	Laboratory confirmed COVID-19 pneumonia	Moderate	Favipiravir 1600/600 mg: mean 51.0 (15.6) Favipiravir 1800/800 mg: mean 52.6 (15) SOC: mean 48.6 (16.1)	M 30/60 (50%)	≥ 60 years and/or chronic diseases: 28/60 (46.7%)	N/A	Group 1: Favipiravir 1600 mg BID day 1, 600 mg BID days 2-14, 20 patients Group 2: Favipiravir 1800 mg BID day 1, 800 mg BID days 2-14, 20 patients (10% received steroids) Group 3: SOC, 20 patients (75% received HCQ or CQ, 5% Lop/Rit, 10% steroids	Per ITT: Primary outcome: - Viral clearance by day 10 not significantly different on Favipiravir vs. SOC (37/40 (92.5%) vs. 16/20 (80.0%) Other outcomes: - Viral clearance on day 5 significantly higher in Favipiravir vs. SOC (62.5% vs. 30.0%). - Median time to body temperature normalization (< 37oC) significantly lower in Favipiravir vs. SOC (2 vs 4 days). - No statistical difference between favipiravir and SOC in improvement of chest CT scans on day 15, Chest CT scans on Day 15 (36/40 (90%) vs 16/20 (80%)).	(40)
Nova vs. Nova plus Lop/Rit vs. Lop/Rit	Single Hospital, China 1-Feb-2020 to 20-Feb 2020	Laboratory confirmed COVID-19	Moderate-severe	Nova: Median 46.5 Days (IQR:40-63.8); Nova with Lop/Rit 50: (37.8-62.8); Lop/Rit :37 (26-54)	M: 42/89 (47.1%)	DM: 8/98 (9%) HTN: 6/89 (6.7%) CHD 3/89 (3.4%)	Nova: Median 4 (IQR:3-6.5); Nova with Lop/Rit 7.0 (3.3-11.3); Lop/Rit 4 days(3-6) in	Group 1: Inhaled Nova 20 μg BID alone, 30 patients Group 2: Inhaled Nova 20 μg BID with Lop/Rit, 2 tablets BID, 30 patients Group 3: Lop/Rit, 2 tablets BID, 29 patients	Per ITT: Primary outcome: - Day 3: SARS-CoV-2 clearance rate in Nova plus Lop/Rit significantly higher than in Lop/Rit group (36.7% vs. 10.3%), with no significant difference between Nova and Nova plus Lop/Rit. - Day 6: SARS-CoV-2 clearance rates significantly higher in Nova vs. Lop/Rit (50% vs. 24.1%) and significantly higher in Nova plus Lop/Rit vs. Lop/Rit (60% vs. 24.1%) - Day 9: clearance rates were not statistically significant differences between the groups. Other outcomes: - Median time to SARS-CoV-2 clearance were 6 vs. 6 vs. 9 days for Nova vs Nova plus Lop/Rit vs. Lop/Rit reaching significance in the latter two groups.	(41)
Leflunomide vs. SOC	Single Hospital, China 20-Feb-2020 to 28-Feb-2020	Laboratory confirmed using qRT-PCR for SARS-CoV-2	Moderate	Mean 54.9 [SD: 6.14]	M: 3/10 (30%)	HTN: 6/10 (60%), Hyperlipidemia: 1/10 (10%), atherosclerosis: 3/10 (30%), COPD: 1/10 (10%)	Mean 9.2 [SD:0.8]	Group 1: Oral Leflunomide (10 mg per tablet), 50 mg every 12 h, three consecutive times, after 20 mg every day – a total course of 10 days, 5 patients Group 2: Blank control without a placebo, but with SOC, 5 patients	Primary Outcome: - Data on the primary outcome (time from Leflunomide initiation to clinical improvement meeting the discharge criteria) not included in the article Other Outcomes: - Shorter viral shedding time in patients with Leflunomide vs. Pla (median vs. 11 days, respectively)	(42)
DRV/Cob vs. SOC	Shanghai Public Health Clinical Center, China, 30 Jan 2020 – 06 Feb 2020)	Laboratory confirmed using SARS-CoV-2 RT- PCT	Moderate to Severe.	Mean: 47.2 (SD: 2.8)	M: 18/30 (60%)	Cardio Vascular disease: 8/30 (26.7%) DM: 2/30 (6.7%)	Median: 4 (IQR: 2-5)	Group 1: DRV/Cob: 1 pill (800mg DRV, 150mg Cob) 1x daily (5 days), 15 Patients Group 2: SOC, no oral antiviral drugs, 15 Patients All received IFNa-2b + SOC per guidelines from China	Per ITT: Primary Outcome: - DRV/c receipt was not associated with faster SARS-CoV-2 clearance at day 7 post-randomization compared with SOC (HR: 0.82, 95% CI:0.36-1.88), or with higher percentage of viral clearance at day 7 (Group 1 – 46.7% (7/15), Group 2 –60% (9/15). Other outcome(s): - No statistically significant difference in viral clearance by day 3 and day 5, critical illness rate during the 14 days post-randomization, mortality rate at day 14 in the two groups.	(43)

Abbreviations: Ref: reference; Lop-Rit: Lopinavir-ritonavir; RT-PCR: reverse-transcriptase–polymerase- chain-reaction; NA: not available; SOC: standard of care; IQR: interquartile range; M: male; DM: Diabetes mellitus; ITT: intention to treat; LOS: length of stay; O2: oxygen; HTN: Hypertension; CHD: Coronary Heart Disease; Rem: Remdesivir; Pla: placebo; CQ: Chloroquine Diphosphate; CKD: Chronic kidney disease; OR: Odds ratio; IFN: interferon; SOFA: Sequential organ failure assessment; Nova: Novaferon; CVD: Cerebrovascular disease; IMV: invasive mechanical ventilation; N/A: not available; HR: Hazard ratio; HD: Heart Disease; CVD: cardio vascular disease; RD: respiratory disease; AZM: Azithromycin; OB: obesity; RBV: Ribavirin, LPV: Lopinavir, URT: Upper respiratory tract; COPD: Chronic obstructive pulmonary disease; DRV/c: Darunavir/cobiscistat, URT: upper respiratory tract; Cob: Cobicistat. * Number out of total and % ** Study terminated early and thus clinical outcomes not presented *** Use of glucocorticoids, immunomodulators, antivirals, antibiotics allowed for all groups; **** Countries included: US, Denmark, UK, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore.

Table 2: Summary of findings table of randomized controlled trials of steroid treatment for COVID-19

	Study settings	Cohort characteristics					Treatment		Main results	Ref
	Study settings	Case definition	Severity at admission	Age in years	Sex	Main comorbidities*	Time between onset of symptoms and randomization in days	Drugs: Agent, dosage, duration, number of patients	Main results	Ref
Dexamethasone vs. SOC	176 centers, UK (19-Mar to 8-June-2020)	Clinically suspected or laboratory-confirmed SARS-CoV-2 infection**	Moderate-critical	Mean (SD): 66.1 (15.7)	M: 4087/6425 (63.6%)	DM: 1546/6425 (24%), CHD: 1757/6425 (27.3)	Dexamethasone: median 8 (IQR: 5-13); SOC: median 9 (IQR: 5-13)	Group 1: IV/oral Dexamethasone (6 mg once daily) for up to 10 days plus SOC or until hospital discharge; 2104 patients Group 2: SOC (8% received dexamethasone as part of their care); 4321 patients	Per ITT: Primary outcome: - Mortality at 28 days significantly lower in the dexamethasone vs. SOC, 22.9% vs. 25.7%. - Mortality at 28 days significantly lower in the dexamethasone vs. SOC among patients receiving IMV, 29.3% vs. 41.4%. - Mortality at 28 days significantly lower in the dexamethasone vs. SOC among patients receiving oxygen without IMV, 23.3% vs. 26.2%. - Mortality at 28 days not significantly different in the dexamethasone vs. SOC among patients who were not receiving any respiratory support at randomization, 17.8% vs. 14.0%. Other outcomes: - Hospital LOS significantly shorter in dexamethasone vs. SOC (median 12 vs. 13 days) - Probability of discharge alive within 28 days higher in dexamethasone vs. SOC (rate ratio, 1.10; 95%CI-1.03-1.17), with greatest effect among patients receiving IMV at randomization. - Risk of progression to IMV lower in the dexamethasone vs. SOC (risk ratio, 0.77; 95% CI-0.62-0.95).	(32)
MP vs Pla	Hospital e Pronto-Socorro Delphina Rinaldi Abdel Aziz, Brazi (18-Apr-2020 –16-June-2020)	Hospitalized patients with clinical and/or radiological suspicion of COVID-19***	Moderate-severe	Mean (SD): 55 (15)	M: 254/ (64.6%)	DM: 106/364 (29.1%) HTN: 178/364: (48.9%%) Alcohol use disorder: 98/363 (27%)	Median: 13 days (IQR:9-16)	Group 1: IV sodium succinate MP 0.5 mg/kg, twice daily for 5 days; 194 patients Group 2: Placebo (saline); 199 patients	Per modified ITT: Primary outcome: - 28-day mortality not different in MP vs Pla, 37.1% vs. 38.1% (HR: 0.924, 95% CI-0.669 -1.275). Other outcomes: - 7-day and 14-day mortality not different in MP vs. Pla. - Presence of viral RNA in naso/oropharyngeal swab on day 5 and 7 not different in MP vs Pla - Need for IMV until day 7 or Hospital LOS not different in MP vs. Pla. - Reduced 28-day mortality in MP group in post-hoc analysis including patients >60 years.	(33)

Abbreviation: COVID-19: Coronavirus disease 19; Ref: reference; SD: Standard deviation; IQR: interquartile range; NA: not available; SOC: standard of care; M: male; DM: Diabetes mellitus; ITT: intention to treat; LOS: length of stay; O2: oxygen; HTN: Hypertension; CHD: Coronary Heart Disease; Pla: placebo; MP: Methylprednisolone; IV: Intravenous; IMV: invasive mechanical ventilation.

* Number out of total and %; ** 88% confirmed in dexamethasone and 89% in SOC group; *** 83% of MP and 79% of Pla were laboratory confirmed by SARS-CoV-2 RT-PCR
Table 3: Summary of findings table of randomized controlled trials of immunomodulatory treatment for COVID-19

	Study settings	Cohort characteristics					Treatment		Main results	Ref
	Study settings	Case definition	Severity	Age in years	Sex	Main comorbidities*	Time between onset of symptoms and randomization in days	Drugs: Agent, dosage, duration, number of patients	Main results	Ref
FBX vs. HCQ	Mostafavian Fever Clinic in Sari, Iran (16-Mar-2020 to 10-Apr-2020)	Clinical and radiological suspicion of COVID-19, or clinical suspicion and epidemiological link to COVID-19 case	Moderate	Mean: 57.5 (SD: 1.26)	M: 32/54 (59.3%)	DM: 15/54 (27.8%) Lung Disease: 1/54 (1.9%)	N/A	Group 1: FBX – 80 mg PO per day x 5 days, 29 patients Group 2: HCQ – 200 mg PO twice daily X 5 days, 25 patients	Per protocol Primary outcome: - Rate of hospitalization not different (3 patients in each group) Other outcomes: -Symptom improvement at day 5 statistically significant from baseline in both groups but not difference between groups. - Mean percentages of lung involvement by chest CT significantly reduced from 16 to 7.3% in FBX and 19.2 to 8% in HCQ group at day 14	(44)
IFN b-1a vs. SOC	Imam Khomeini Hospital Comple, Iran) (29 Feb 2020 – 3 Apr 2020)	Laboratory confirmed by SARS-CoV-2 RT-PCR, or clinical and radiological suspicion of COVID-19	Severe	Mean: IFN 56.50 (SD: N/A) SOC– 61.00 (SD: N/A)	M: 44/81 (54.3%)	HTN: 31/81 (38.3%) DM: 22/81 (27.2%) CHD: 23/81 (28.4%)	IFN- Mean: 11.7 (SD:5.71) SOC: Mean: 9.31 (SD: 4.45)	Group 1: 44 μg /ml (12 million IU/ml) IFN b-1a SC 3x weekly for 2 consecutive weeks pus SOC (corticosteroids 61.9%), 42 patients Group 2: SOC – HCQ (400 mg BD 1^st day, then 200 mg with Lopinavir/Ritonavir (400/100 mg BD) or Atazanavir/Rit (300/100mg daily) for 7-10 days (corticosteroids: 43.6%), 39 patients	Per protocol Primary Outcome: - Time to the clinical response not significantly different between the IFN b-1a and the control groups (9.7 vs. 8.3 days). Other outcomes: - Administration of IFN b-1a before 10 days of symptom onset significantly reduced mortality (OR=13.5; 95% CI-1.5-118), while late administration did not show significant effects (OR=2.1; 95% CI-0.48-9.6). -Hospital LOS, ICU LOS and duration of mechanical ventilation not statistically different. - Receipt of IFN b-1a was independent factor for survival benefit at 28 days in multivariate analysis, and after adjustment for IVIG and corticosteroid receipt.	(37)
Colchicine vs. SOC	16 tertiary care hospitals, Greece (03-April- 2020 – 27 April 2020)	Laboratory- confirmed by SARS-CoV-2 RT-PCR	Moderate-severe	Median: 64 (IQR:54-76)	M: 61/105 (58.1%)	HTN: 47/105(44.7%) DM: 21/105 (20%) Dyslipidemia: 33/105 (31.4%), CAD (14/105,13.3%)	N/A	Group 1: Colchicine (1.5 mg loading dose followed by 0.5 mg and maintenance of 0.5 mg twice daily) for 3 weeks or until hospital discharge, 55 patients Group 2: SOC **, 50 patients.	Per ITT Primary outcome: - Deterioration by 2 points on a 7-grade scale, within 3 weeks or until discharge, was higher in the SOC vs. the Colchicine group (14% vs. 1.8%) (OR=0.11; 95% CI: 0.01-0.096). Other outcomes: - No significant differences in hospital LOS between Colchicine vs. SOC (median 12 vs. 13 days).	(45)
Ruxolitinib vs. Pla	Three hospitals, China (9-Feb-2020 – 28-Feb-2020)	Clinically suspected, epidemiologically linked or laboratory confirmed cases	Severe	Median: 63 (IQR:58-68)	M: 24 /41 (58.5%)	HTN: 16/41 (39.0%), DM: 8/41 (19.5), Coronary artery heart disease 3/41 (7.3%)	Median: 20 (IQR: 17-28)	Group 1: Ruxolitinib 5 mg twice a day with SOC, 20 patients) Group 2: Placebo (100 mg Vitamin C) twice a day with SOC, 21 patients SOC included: antiviral therapy, corticosteroid	Modified ITT: Primary outcome: - No significant differences in time to clinical improvement in Ruxolitinib vs. Pla groups (median 12 vs 15 days) (Hazard ratio: 1.669; 95% CI, 0.836 – 3.335) - Significantly higher percentage of patients showed significant improvement of follow up CT at day 14 in Ruxolitinib vs. Pla, (90% vs. 61.9%). Other outcomes: - 28-day mortality not statistically different in Ruxolitinib vs Pla (0% vs. 14.3%) - Time from randomization to discharge not statistically different (median 17 vs. 16 days). - Median time to virus clearance not statistically significant in Ruxolitinib vs. Pla (median 13 vs. 12 days) (Hazard ratio, 0.782; (95% CI:0.271-2.257).	(46)

Abbreviations: COVID19: Coronavirus disease 2019; Ref: reference; FBX: Febuxostat; HCQ: Hydrochloroquine; SOC: Standard of care; SC subcutaneous; SD: standard deviation; IQR: interquartile range; N/A: not available; ITT: Intention to treat; M: male: DM: Diabetes Mellitus; HTN: Hypertension; CHD: Coronary heart disease; OR: odds ratio; ICU: intensive car unit; CAD: Coronary artery disease. * Number out of total and % ** Chloroquine or hydroxychloroquine, azithromycin, lopinavir or ritonavir, tocilizumab.

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Pharmacological treatment for patients with coronavirus disease 2019: systematic review of randomized controlled trials

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