Table 2.
Summary of findings on COVID-19 (n = 34 studies)
| Study ID | Country | Design | Population | N | Intervention | Outcome | Key findings | RoB |
|---|---|---|---|---|---|---|---|---|
|
Antibiotics
| ||||||||
| Furtado, 2020 [23] |
Brazil |
RCT |
≥18 y admitted with suspected or confirmed COVID-19 and at least one additional severity criteria |
397 |
PO 500mg azithromycin once daily for10 d in addition to standard of care vs standard of care (HCQ 400 mg twice daily for 10 d) |
Clinical status at 15-d using a six-level ordinal scale; mortality; hospital LOS |
No difference in clinical status between the azithromycin and control groups (OR = 1.36, 95% CI = 0.94 to 1.97, P = 0.11), death at 29 d (31% vs 30%, P = 0.63), or hospital LOS (26 vs 18 d, P = 0.064). |
Some Concerns |
| Sekhavati 2020 [24] |
Iran |
RCT |
≥18 y admitted with +COVID-19 PCR test and radiographic findings of COVID pulmonary involvement |
111 |
PO Azithromycin 500mg daily for 5 d in addition to standard of care vs standard of care (oral LPV/r 400/100 mg twice daily and oral HCQ 400 mg daily) |
Mortality; Hospital LOS; ICU admission; Vital Signs; QTc prolongation or cardiac arrhythmia |
No difference in mortality between groups (P = 0.495). Hospital LOS shorter (4.61 d vs 5.96 d; P = 0.02), RR lower (15.85 rpm vs .17.42 rpm; P = 0.010), and higher SpO2 (93.95%vs92.40%; P = 0.030) in treatment vs control group. No patients had cardiac arrhythmia or QTc prolongation. |
Some Concerns |
|
Antiparasitic
| ||||||||
| Abd-Elsalam, 2020 [25] |
Egypt |
RCT |
Patients with confirmed COVID-19 by RT-PCR with mild, moderate, severe disease |
194 |
Hydroxychloroquine 400mg BID day 1 then 200mg BID for 15 d vs standard of care (paracetamol, antibiotics, oseltamivir as needed) |
Recovery within 28 d; need for mechanical ventilation; death |
No difference in recovery at 28 d (53.6% vs 34%, P = 0.06), overall mortality (6.2% vs 5.2%, P = 0.77), or need for mechanical ventilation (4.1% vs 5.2%, P = 0.75) in HCQ vs control group. |
High |
| Borba, 2020 [26] |
Brazil |
RCT |
≥18 y with COVID-19 and RR>24rpm, SpO2 < 90%, or shock, admitted to hospital |
81 |
High-dose CQ (600mg BID for 10 d, total dose 12g) vs low-dose CQ (450mg BID tapering down Day 1-9, total dose 2.7g) |
28-d mortality; QTc prolongation |
Greater risk of death in (39% vs 15% (OR = 3.6, 95% CI = 1.2 to 10.6) in high vs low dose groups although no difference when age-adjusted. Greater QTc prolongation 18.9% vs 11.1% and VT 2.7% vs 0% in high vs low-dose group. |
Some Concerns |
| Cavalcanti, 2020 [27] |
Brazil |
RCT |
≥18 y admitted to hospital with suspected or confirmed mild to moderate COVID-19 |
665 |
Group 1: Standard care Group 2: Standard care + HCQ 400mg BID Group 3: Standard care + HCQ 400mg BID + Azithromycin 500mg once daily |
Clinical status at 15 d, using 6-level ordinal scale |
No difference in clinical status at 15 d for either HCQ alone (OR = 1.21; 95% CI = 0.69 to 2.11; P = 1.00) or HCQ plus azithromycin (OR = 0.99; 95% CI = 0.57 to 1.73; P = 1.00). No difference in hospital LOS, need for MV or in-hospital mortality. Prolongation of the QTc and elevation of liver-enzyme levels were more frequent in patients receiving hydroxychloroquine, alone or with azithromycin, than in those who were not receiving either agent. |
Some Concerns |
| Yu, 2020 [28] |
China |
Retrospective cohort |
≥18 y with COVID-19 admitted to hospital with critical illness |
550 |
PO HCQ 200mg BID for 7-10 d in addition to standard of care (including antivirals, antibiotics, IVIG comparable between groups) |
Hospital mortality; hospital LOS |
Decreased mortality 18.8% vs 47.4% (P < 0.001) in HCQ vs control group. No difference in mean hospital LOS 32 vs 30 d (P = 0.314) although longer hospital stay before death 15 vs 8 d (P = 0.027). |
Serious |
|
Antiviral
| ||||||||
| Abbaspour Kasgari, 2020 [29] |
Iran |
RCT |
18-80 y with moderate COVID-19 |
48 |
PO 400/60mg sofosbuvir/daclatasvir once daily and ribavirin 600mg twice daily vs hydroxychloroquine 400mg single dose with lopinavir/ritonavir 400/100mg BID with or without ribavirin 600mg BID (control) |
Hospital LOS; need for ICU admission, mechanical ventilation; mortality |
No difference in median length of hospital stay (6 d) in treatment vs control group (P = 0.398). No difference in need for ICU admission (P = 0.109), mechanical ventilation (P = 0.109) or death (P = 0.234). |
Some Concerns |
| Deng, 2020 [30] |
China |
Retrospective cohort |
≥18 y laboratory-confirmed COVID-19 admitted with pneumonia |
33 |
PO Arbidol 200mg q8H in addition to lopinavir/ritonavir 400mg/100mg q12h until negative RT-PCR |
Conversion to negative RT-PCR at day 7 and 14; pneumonia progression or improvement on chest CT at day 7 |
Negative RT-PCR combination vs monotherapy was 75% vs 35% (P < 0.05) at 7 d; 94% vs 52.9% (P < 0.05) at 14 d; improvement on chest CT at 7 d was 69% vs 29% (P < 0.05). |
Serious |
| Prasithsirikul, 2020 [31] |
Thailand |
Retrospective cohort |
All patients with COVID-19 confirmed on RT-PCR |
41 |
PO Favipiravir 200mg tablets BID. Day 1: 8 tablets, Day 2-10: 3 tablets |
Hospital LOS; time to viral clearance |
No significant difference in LOS between treatment vs control (8 vs 10 d; P = 0.86). Earlier median time to viral clearance in favipiravir vs control (6 vs 8 d; P = 0.11) |
Serious |
| Sadeghi, 2020 [32] |
Iran |
RCT |
≥18 y with moderate or severe COVID-19 admitted to hospital |
66 |
PO 400 mg sofosbuvir and 60 mg daclatasvir + standard care vs standard care alone (hydroxychloroquine 200mg BID with or without lopinavir/ritonavir 200 mg/50 mg BID). |
Clinical recovery at 14 d; Hospital LOS; Mortality; Mechanical Ventilation |
No difference in clinical recovery at 14 d between treatment vs control group (88% vs 67%, P = 0.076). Shorter LOS in treatment vs control (6 (IQR = 4-8) vs 8 (IQR = 5-13) days, P = 0.029). No difference in mortality (9% vs 15% P = 0.708) or mechanical ventilation (9% vs 21%, P = 0.303) between treatment and control. |
Low |
| Wang (Y), 2020 [33] |
China |
RCT |
≥18 y with severe COVID-19 admitted to hospital |
237 |
IV Remdesivir 200mg on Day 1 then 100mg Days 2-10 vs placebo. Concomitant use of lopinavir-ritonavir, interferons, and corticosteroids permitted (non-standardized, authors reported no differences between groups) |
Time to clinical improvement defined as decline of two levels on a 6-point ordinal scale of clinical status through Day 28; hospital LOS; mortality |
No difference in time to clinical improvement (HR = 1.23 d, 95% CI = 0.87 to 1.75), 28-d mortality (14% vs 13%, diff = 1.1%, 95% CI = -8.1 to 10.3) or hospital LOS (25 vs 24 d, diff 0 (95% CI = -4 to 4) in remdesivir vs control group. |
Some Concerns |
|
Antiviral + antibiotic + steroid
| ||||||||
| Vahedi, 2020 [34] |
Iran |
Retrospective cohort |
≥18 y with laboratory confirmed moderate COVID-19 |
60 |
Group 1: Azithromycin 250mg daily, prednisolone 25mg daily, naproxen 250mg BID, and lopinavir/ritonavir 200/50 mg BID vs Group 2: meropenem 1g q8h, levofloxacin 500mg daily vancomycin 1g q12h, hydroxychloroquine 200mg q12h, oseltamivir 75mg BID |
Hospital LOS; vital signs; laboratory values at day 3 |
Decreased LOS in Group 1 with 6.97 d (SD = 3.08) vs 9.93 d (SD = 3.16) in Group 2 (P = 0.001). Compared to baseline at Day 3, decrease in CRP in Group 1 (79.5 to 24.0, P < 0.001), increase in SpO2 (86.7 to 89.8, P = 0.011), decrease in body temperature (37.7 to 37.0, P < 0.001), otherwise no differences in RR, heart rate, BP, or other laboratory markers. |
Serious |
|
Convalescent plasma
| ||||||||
| Agarwal, 2020 [35] |
India |
RCT |
≥18 y with moderate COVID-19 confirmed with RT-PCR admitted to hospital |
464 |
200mL convalescent plasma for 2 doses 24 h apart |
Composite of progression to severe disease (Pao2/FiO2 ratio <100 mm Hg) any time within 28 d of enrolment or all-cause mortality at 28 d |
No significant difference in composite outcome (19% vs 18%; RR = 1.04, 95% CI = 0.71 to 1.54). No difference in all-cause mortality (15% vs 14%; RR = 1.04, 95% CI = 0.66 to 1.63) or progression to severe disease (17% in both; RR = 1.04, 95% CI = 0.54 to 1.98) in plasma vs placebo at 28 d. |
Some Concerns |
| Li, 2020 [36] |
China |
RCT |
≥18 y with severe or critical COVID-19 confirmed with RT-PCR admitted to hospital |
103 |
Convalescent plasma 4-13 ml/kg of recipient body weight for single transfusion |
Time to clinical improvement within a 28-d period (reduction of 2 points on 6-point disease severity scale); 28-d mortality |
No significant difference in clinical improvement within 28 d (51.9% vs 43.1 plasma vs control; HR = 1.4, 95% CI = 0.79 to 2.49). No significant difference in 28-d mortality (15.7%vs 24.0% plasma vs control; OR = 0.59; 95% CI = 0.22 for 1.59. Possible benefit in those with severe (non-critical) disease with 91.3% vs 68.2% having clinical improvement at 28 d (HR = 2.15, 95% CI = 1.07 to 4.32; P = 0.03). |
Some Concerns |
|
Corticosteroids
| ||||||||
| Edalatifard, 2020 [37] |
Iran |
RCT |
≥18 y with COVID-19 admitted to hospital with hypoxia <90% and elevated CRP and IL-6 |
68 |
IV methylprednisolone 250mg daily for 3 d vs standard of care (hydroxychloroquine sulfate, lopinavir and naproxen) |
Time to clinical improvement or death; hospital LOS |
Reduced median days in hospital (11.62 vs 17.61, P = 0.006) and reduced median time to improvement (11.84 vs 16.44 d, P = 0.011) and reduced mortality (5.9% vs 42.9%, P < 0.001) in treatment vs control. |
Some Concerns |
| Jeronimo, 2020 [38] |
Brazil |
RCT |
≥18 y with COVID-19 admitted to hospital with Sp02 < 95% |
393 |
IV methylprednisolone 0.5mg/kg BID for 5 d |
28-d mortality; need for intubation |
No significant difference in mortality (37.1% vs 38.2%, P = 0.629) or need for intubation (19.4% vs 16.8%, P = 0.654) in methylprednisolone vs placebo. In subgroup analysis in patients over 60 y, lower mortality 46.6% vs 61.9%, P = 0.039). |
Low |
| Ma, 2020 [39] |
China |
Retrospective cohort |
Adult patients with COVID-19 admitted to hospital |
72 |
Corticosteroid use vs no corticosteroid use. Low-dose: 40mg/d Shock-dose: 80mg/d |
Hospital mortality; hospital LOS; time to viral clearance |
No significant difference in hospital mortality (4.3% vs 8.0%, P = 0.550), LOS (18.7 vs 21.0 d, P = 0.212), and time of viral clearance (16.1 vs 19.4 d, P = 0.184). |
Moderate |
| Rana, 2020 [40] |
Pakistan |
Retrospective quasi-experimental |
Adult patients admitted to high-dependency unit (HDU)/ICU on BiPAP |
60 |
Dexamethasone 8mg BID vs methylprednisolone 40mg BID |
P/F ratio |
Greater improvement in P:F in the dexamethasone vs methylprednisolone group (170 vs 118, P < 0.001). |
Moderate |
| Tomazini, 2020 [41] |
Brazil |
RCT |
≥18 y with confirmed or suspected COVID-19 infection receiving mechanical ventilation within 48 h of meeting criteria for moderate to severe ARDS |
299 |
IV Dexamethasone 20mg once daily for 5 d, then 10mg once daily for 5 d or until ICU discharge vs standard of care |
Ventilator-free days during first 28 d, defined as being alive and free from mechanical ventilation; 28-d mortality |
Higher mean number of ventilator-free days (6.6 vs 4.0 d, P = 0.04) in dexamethasone vs control group. No significant difference in all-cause mortality at 28-d (56.3% vs 61.5%, HR = 0.97, 95% CI = 0.72 to 1.31, P = 0.85). |
Low |
| Wu, 2020 [42] |
China |
Retrospective cohort |
Patients with laboratory-confirmed or clinically diagnosed severe or critical COVID-19 admitted to hospital |
1514 |
IV corticosteroid use |
Hospital mortality |
No benefit for corticosteroids on in-hospital mortality in either severe cases (HR = 1.77; 95% CI = 1.08 to 2.89; P = 0.023), or critical cases (HR = 2.07; 95% CI = 1.08 to 3.98; P = 0.028). |
Serious |
| Zha, 2020 [43] |
China |
Retrospective cohort |
Patients with COVID-19 confirmed by RT-PCR admitted to hospital |
31 |
Methylprednisolone 40mg once or twice daily |
Viral clearance time; hospital LOS; duration of symptoms |
No difference in virus clearance time (HR = 1.26; 95% CI, 0.58-2.74), hospital length of stay (HR = 0.77; 95% CI = 0.33 to 1.78), or duration of symptoms (HR = 0.86; 95% CI = 0.40 to 1.83) in corticosteroid vs non-corticosteroid groups. |
Low |
|
Immunomodulator
| ||||||||
| Cheng, 2020 [44] |
China |
RCT |
≥18 y with COVID-19 confirmed with RT-PCR, pneumonia on imaging, and lymphopenia (PBL cell count of 800 per uL) |
200 |
SQ rhG-CSF, 5 μg/kg, at days 0-2 |
Time to clinical improvement defined as decline of at least 1 point on a 7-point ordinal scale |
No difference in time to clinical improvement between the rhG-CSF group and the usual care groups (median (IQR) = 12 (10-16) vs 13 (11-17) days; HR = 1.28; 95% CI = 0.95 to 1.71). |
Some Concerns |
| Fu, 2020 [45] |
China |
Non-randomized clinical trial |
≥18 y with hospitalized with moderate COVID-19 disease |
33 |
Nasal inhalation TFF2 and IFN-k in water over 20-30 min by nasal mask 3 times every 48 h vs standard of care (included TCM and anti-pyretics) |
Safety of aerosol inhalation of IFN-k plus TFF2; Hospital LOS; cough resolution; improvement of CT imaging; rate of negative viral RNA at 10 d |
No severe adverse effects in treatment group. Shorter hospital LOS – 12 d (IQR = 7-20) vs 15 d (IQR = 10-25), P < 0.001), median time to CT improvement = 5 (IQR = 3-9) vs 8.5 (IQR 3-17) days, P < 0.05), median time to viral clearance = 6 (IQR = 2-13) vs 9.5 (IQR = 3-23) days, P < 0.05), and median time to cough resolution = 4.5 d (IQR = 2.0-7.0) vs 10.0 d (IQR = 6.0-21.0), P < 0.005) in treatment vs control group. |
Serious |
| Gharebaghi, 2020 [46] |
Iran |
RCT |
≥18 y with severe COVID-19 admitted to hospital |
59 |
IV Immunoglobulin (IVIG) 5g daily for 3 d vs placebo |
In-hospital mortality |
Lower in-hospital mortality rate (20% vs 48.3%, P = 0.022) in IVIG vs control group. |
Some Concerns |
| Hao 2020 [47] |
China |
Case-control |
Confirmed SARS-CoV-2-positive hospitalized patients |
104 |
Recombinant human IFN-τ2b spray 100 000 U Q6H for 7 d |
Duration of SARS-CoV-2 viral shedding from the respiratory tract; Mechanical Ventilation; ICU admission |
No difference in viral shedding time (12 vs 15 d, P = 0.21) in IFN vs control group. No difference in hospital LOS (16 vs 21 d, P = 0.08) and or need for mechanical ventilation (25% vs 37%, P = 0.28) IFN vs control group |
Low |
| Rahmani, 2020 [48] |
Iran |
RCT |
≥18 y with severe COVID-19 pneumonia confirmed by PCR and radiographic imaging |
66 |
SQ IFN τ-1b 250mcg every other day for 2 weeks |
Time to clinical improvement defined as improvement of at least 2 points on 6-point ordinal scale; Hospital LOS; 28-d Mortality |
Shorter time to clinical improvement - 9 (IQR = 6-10) vs11 (IQR = 9-15) days, P = 0.002), shorter hospital LOS – 11 (IQR = 9-13) days in the IFN group vs 13 (IQR = 10-17) days, P = 0.05) in treatment vs control group. No difference in 28-d mortality (6.06% vs 18.18% IFN vs control, P = 0.12). |
Low |
| Zheng, 2020 [49] |
China |
Retrospective cohort |
18-85 y admitted with COVID-19 |
181 |
Tocilizumab 4-8mg/kg first dose. Second dose given if still febrile after 24 h vs conventional treatment (not specified) |
Hospital LOS; clinical symptoms and laboratory values |
Decreased WBC, CRP, Tmax, minimum SpO2, RR, heart rate post-treatment (P < 0.001). Shorter hospital LOS (mean = 16.4 vs 27.5 d, P < 0.001) and fewer deaths (1.1% vs 9.8%, P = 0.018) in conventional vs tocilizumab group although more patients with critical/severe illness (84.8% vs 46.1%, P < 0.001) in tocilizumab vs conventional |
Serious |
|
Nutrients and minerals
| ||||||||
| Abd-Elsalam, 2020 [50] |
Egypt |
RCT |
Patients with confirmed COVID-19 by RT-PCR with mild, moderate, severe, and critical disease |
191 |
Zinc sulfate 220mg BID + hydroxychloroquine 400mg BID on day 1 then 200mg BID for 5 d vs HCQ only |
Hospital LOS; clinical recovery at 28 d; mechanical ventilation; mortality |
No significant difference in hospital LOS LOS (13.5 vs 14 d, P = 0.553), clinical recovery at 28 d (79.2% vs 77.9%, P = 0.969), mechanical ventilation (P = 0.537) and mortality (94.8% vs 94.7%; P = 0.986) between Zinc vs control group |
Some Concerns |
|
Respiratory tract agent
| ||||||||
| Ansarin, 2020 [51] |
Iran |
RCT |
≥18 y with COVID-19 pneumonia admitted to hospital |
78 |
PO bromhexine hydrochloride 8mg Q8H + standard of care. Standard of care included HCQ 200 mg daily |
Rate of ICU admission, intubation/mechanical ventilation, and 28-d mortality |
Decreased ICU admissions (5.1% vs 28.2%, P = 0.006), need for mechanical ventilation (2.6% vs 23.1%, P = 0.007) and death (0% vs 12.8%, P = 0.027) in the bromhexine vs control group. |
Some Concerns |
| deAlencar 2020 [52] |
Brazil |
RCT |
≥18 y with severe COVID-19 (suspected or confirmed) admitted to hospital |
135 |
IV NAC 14g in first 4 h and 7g in next 16 h vs placebo |
Invasive mechanical ventilation; admission to ICU, time in ICU, and mortality |
No difference in need for mechanical ventilation between groups (20.6% vs 23.8%, P = 0.641). No difference in admission rate to ICU (43% vs 47%; P = 0.557) or mortality (14% both, P = 0.940) |
Low |
|
Traditional Chinese medicine
| ||||||||
| Liu, 2020 [53] |
China |
Retrospective cohort |
Patients with COVID-19 confirmed by RT-PCR without criteria for critical illness |
80 |
Jinhua Qinggan granules 6g BID for 7 d |
Time to viral clearance on RT-PCR from respiratory specimen; improvement on chest CT |
Time to viral clearance was 7 ± 4 vs 10 ± 4 d (P = 0.010) and pneumonia recovery time indicated by chest CT was 8 ± 4 vs 10 ± 5 d (P = 0.021) for treatment vs control group. |
Serious |
| Wang (J), 2020 [54] |
China |
RCT |
Patients with COVID-19 admitted to hospital without respiratory failure requiring mechanical ventilation |
47 |
Keguan-1 19.4g BID with standard of care vs standard of care (alpha interferon inhalation, 50 μg BID and lopinavir/ritonavir, 400mg/100 mg twice daily) |
Time to ARDS development; time to fever resolution and recovery of lung injury on CT or radiograph at day 7 and 14 |
Decreased development of ARDS 4.2% vs 26.1% (P = 0.048), shorter mean time to fever resolution 1.5 vs 3.0 d (P = 0.035), but no difference in proportion of recovery of lung injury 87.5% vs 69.6% (P = 0.168) in treatment vs control group. |
High |
| Xiao, 2020 [55] |
China |
RCT |
Adults aged 18-85 y old with suspected and diagnosed cases of COVID-19 meeting the diagnostic criteria |
283 |
Group 1: Huo Xiang Zhengqi dropping pills 2.6g BID and Lianhua Qingwen 6g q8h and standard of care Group 2: Lianhua Qingwen 6g q8h and standard of care Group 3: standard of care (PO oseltamivir 75mg daily, arbidol 200mg q8h, ribavirin 150mg q8h) |
Symptom improvement; progression to “severe status” at 14 d |
No significant difference in symptom resolution or progression to severe disease between the three groups (P = 0.089). |
Some Concerns |
| Xiong, 2020 [56] | China | RCT | Adults aged 18-75 y admitted with COVID-19 (mild to severe disease) | 42 | Xuanfei Baidu decoction 200ml BID in addition to standard of care vs standard of care (not specified) | Symptom resolution (cough, fever, fatigue) at 7 d | Higher rate of symptom resolution in fever 90% vs 72.3% (P = 0.043), cough 76.5% vs 38.9% (P = 0.028), and fatigue 78.9% vs 42.9% (P = 0.039) in treatment vs control group. | Some Concerns |
ARDS – acute respiratory distress syndrome, BID – twice daily, CI – confidence intervals, CRP – C reactive protein, CT – computed tomography, HCQ – hydroxychloroquine, HR – hazard ratio, ICU – intensive care unit, IFN – interferon, IQR – interquartile range, OR- odds ratio, IV – intravenous, LOS – length of stay, LPV/r – lopinavir/ritonavir, N – number of participants, NAC – N-acetylcysteine, P:F – Pao2:FiO2, PO – per oral; QTc – corrected QT interval; rhG-CSF – recombinant human granulocyte colony stimulating factor, RR – respiratory rate, RoB – risk of bias, SpO2 – oxygen saturation, WBC – white blood cells